FR3090351A1 - Anti-aging agent and cosmetic composition comprising it - Google Patents

Abstract

The present invention thus relates to an anti-aging agent comprising the exo isomer of the monomethylisosorbide MMIb. The invention also relates to a process for preparing such a composition, as well as a cosmetic composition using such an anti-aging agent.

Description

Description

Title of the invention: Anti-aging agent and cosmetic composition comprising it

The invention relates to a new anti-aging agent, a cosmetic or dermatological composition containing it, as well as various cosmetic uses. Technical area

The skin is the first barrier protecting the body against external aggressions. The skin is mainly made up of three layers, namely, starting from the most superficial, the epidermis, the dermis and the hypodermis. The epidermis largely contributes to ensuring the protection of the skin and to maintaining its proper functioning.

Aging or photoaging of the skin, and the changes associated therewith, can manifest themselves in various ways, among which may be mentioned

- loss of firmness and elasticity due to tissue loss in the epidermis and / or dermis;

- loss of radiance due to the reduction of microcirculation and a slowing down of cell renewal in the epidermis;

- the appearance of pigment spots or wrinkles;

- roughness or thinning and / or

- skin dryness resulting from a decrease in the barrier function of the stratum corneum and a slowing down of epidermal renewal.

The treatment of these symptoms has become a major issue for the cosmetic industry.

However, if knowledge of the physiology of the skin has made it possible to propose cosmetic solutions to various dysfunctions induced by external aggressions, no satisfactory solution has been proposed at present by the prior art. prevent and repair the effects of aging skin.

Prior art

Among the main cosmetic active agents proposed by the prior art for improving the appearance of the skin, there may be mentioned, for example, compounds of plant origin such as polyphenols, whose antioxidant activity makes it possible to prevent oxidative stress. in the skin, by trapping free radicals resulting from external aggressions, for example exposure of the skin to ultra-violet (UV) rays. Caffeic acid and resveratrol are examples of polyphenols used in so-called anti-aging cosmetic compositions proposed by the prior art.

Another family of anti-aging compounds is that of retinoids, among which retinol is well known for stimulating the defenses of the skin and thus helping to fight against its aging, by activating cell renewal of the epidermis.

In another category of anti-aging active ingredients, rhamnose is a rare sugar, which activates a cascade of reactions from the dermis to the epidermis, passing through the dermo-epidermal junction, thus acting on the loss of firmness and wrinkles.

Vitamin C (or ascorbic acid) is also commonly used for a global anti-aging action. Incorporated into creams or serums, it prevents photoaging by neutralizing free radicals resulting from exposure to the sun, tobacco or pollution. Cosmetic products based on vitamin C are however not very suitable for sensitive skin or with rosacea. In addition, to observe the anti-aging effect of vitamin C, it is necessary to use it in high contents, in particular at least 10%, which makes the formulations more difficult to produce, and presents a cost.

[0008] Cosmetic compositions based on such anti-aging compounds make it possible, to a certain extent, to slow down the appearance of the symptoms of aging. Their effectiveness in terms of preventing the effects of aging is however limited, and they also do not make it possible to repair the effects of aging.

Technical problem

There is therefore a need to provide a multifunctional active agent capable of acting on a set of causes of skin damage due to aging and / or to a modification of the physiological mechanisms associated with aging.

The present invention thus aims to remedy the drawbacks of the antiaging compositions proposed by the prior art by proposing a new antiaging agent which makes it possible to effectively combat the effects of skin aging, by preventing it, and even repairing it. , symptoms.

It is to the credit of the applicant to have identified that the exo isomer of the monomethylisosorbide has a preventive and / or curative anti-aging cosmetic activity, in particular in regeneration of the dermis, with anti-wrinkle effect, in restructuring and firming. of the dermis, and in prevention of aging of the dermis.

Isosorbide is as such described as anti-wrinkle active as in patent application EP1891929. Many products derived from isosorbide by chemical substitution of the hydroxylated functions, in particular by alkylation, are also known, in particular for use in cosmetics. Among these, the methylation product of isosorbide, namely dimethylisosorbide, is commonly used in cosmetics as a solvent and as a penetration vector for certain active agents with which it has a particular chemical affinity. This is the case, for example, in patent application EP2836189.

In the field of cosmetics, the exo isomer of the monomethylisosorbide has never been envisaged, and a fortiori, its cosmetic effects have never been demonstrated.

Statement of the invention

The present invention thus relates, according to a first aspect, to an anti-aging agent comprising the exo isomer of the monomethylisosorbide MMIb.

The invention also relates to a process for the preparation of an anti-aging agent as described above, comprising:

- methylation of isosorbide, and

- separation by distillation to extract the exo isomer of the monomethylisosorbide MMIb.

According to a third aspect, the invention relates to a cosmetic or dermatological composition comprising, in a physiologically acceptable medium, at least one anti-aging agent as described above.

Finally, according to a fourth aspect, the invention relates to the use of such a cosmetic or dermatological composition to provide an anti-wrinkle effect, to promote regeneration of the dermis, adhesion and cohesion of the dermis-epidermis. , cell renewal, restructure or firm the skin, prevent the signs of aging, strengthen the barrier function of the skin and / or impart dullness.

Description of the embodiments

USB) / Dimethylisosorbide fDMI) / Endo isomer of monomethylisosorbide fMMIa) / Exo isomer of monomethylisosorbide fMMIb)

The isosorbide (noted ISB in the present application) is 1,4 - 3, 6-dianhydrosorbitol. It is a heterocyclic compound of formula (I) obtained from the double dehydration reaction of sorbitol:

[Chem.l]

Isosorbide is usually used for the preparation of dimethylisosorbide (denoted DMI in the present application), compound of formula (II) by methylation according to the following reaction:

[0022]

[Chem. 2]

h <I> <)

H OMe

ISB DMI

MMIa MMIb

The alkylation reaction of the isosorbide causes, in addition to the desired formation of dimethylisosorbide formula (II), the joint appearance of monomethylisosorbide (denoted MMI in the present application) in the form of a mixture of two isomers:

- the endo isomer of monomethylisosorbide, also designated by “5-O-monomethylisosorbide” (noted MMIa in the present application) of formula (III) corresponding to the nomenclature IUP AC (3S, 3aS, 6R, 6aS) -6-methoxyhexahydrofuro [3,2-b] furan-3-ol), and

- the exo isomer of monomethylisosorbide, also designated by “2-O-monomethylisosorbide” (noted MMIb in the present application) of formula (IV) corresponding to the nomenclature IUP AC (3R, 3aS, 6S, 6aS) -6-methoxyhexahydrofuro [3,2-b] furan-3-ol).

Other derivatives of dianhydrohexitols have been synthesized by the Applicant: the methylated derivatives of isomannide or isoidide. These products are also useful for anti-aging effects, but since isomannide and isoidide are more difficult to synthesize, they are not preferred. The present application will focus on the methylated derivatives of isosorbide, which is more accessible industrially.

The processes for preparing dimethylisosorbide from isosorbide are well known to those skilled in the art and are for example described in application WO2007 / 096511 of the applicant. This method implements the etherification, of the methylation type, of an isosorbide composition with methyl chloride in the presence of at least one alkaline agent, and comprises at least one step of introducing a dimethylisosorbide composition in the reaction medium before and / or during the methylation reaction of the isosorbide.

It is to the credit of the applicant to have demonstrated that among the various products of the methylation reaction of isosorbide, the exo isomer of the monomethylisosorbide MMIb exhibited a particularly advantageous anti-aging activity, in order to provide a anti-wrinkle effect, promote regeneration of the dermis, adhesion and cohesion of the dermis-epidermis, cell renewal, restructure or firm the skin, prevent signs of aging, strengthen the barrier function of the skin and / or confer dullness.

The anti-aging agent according to the invention therefore comprises the exo isomer of the monomethyli5 sosorbide MMIb.

According to a preferred embodiment, the anti-aging agent according to the invention comprises from 75 to 100% by weight of the exo isomer of the monomethylisosorbide MMIb, preferably from 80 to 100% by weight, and more preferably from 90 to 100% by weight.

According to a preferred embodiment, the anti-aging agent according to the invention comprises from 75 to 100% by weight of the exo isomer of the monomethylisosorbide MMIb, preferably from 80 to 99% by weight, and more preferably from 90 to 95% by weight.

According to an even more preferred embodiment, the anti-aging agent according to the invention consists of the exo isomer of the monomethylisosorbide MMIb.

Preparation process

The anti-aging agent according to the invention can be obtained by a preparation process comprising the following steps:

- methylation of isosorbide, and

- separation by distillation of the compounds resulting from methylation, namely dimethylisosorbide, the endo and exo isomers of monomethylisosorbide and isosorbide, and the extraction of the exo isomer of monomethylisosorbide MMIb.

In the context of the present invention, the methylation of the isosorbide can be carried out with methyl chloride, as illustrated in application WO 2007/096511, or with dimethylsulfate (CAS No. 77-78-1) noted DMS, under basic catalysis, for example with sodium hydroxide. When methylation is carried out by the DMS, it is advantageous to carry out the reaction at two successive constant temperature stages: a first temperature stage of 50 to 70 ° C, preferably 60 ° C, and a second temperature stage from 80 to 100 ° C, preferably at 95 ° C.

The amount of dimethyl sulphate can be from 0.2 to 1.0 molar equivalent relative to the isosorbide, preferably from 0.4 to 0.8 molar equivalent, most preferably from 0.6 molar equivalent, and this quantity is added completely from the start of methylation, that is to say from the first temperature level between 50 and 70 ° C, preferably at 60 ° C. The total amount of sodium hydroxide is 1.9 to 2.3 mass equivalents relative to dimethyl sulphate, preferably 2.1 mass equivalents. This quantity is added to the reaction medium in two stages corresponding to the two temperature levels: 1.03 to 1.07, preferably 1.05 equivalents are added, co-poured with dimethylsulfate, at the start of the first temperature level between 50 and 70 ° C, preferably at 60 ° C; and 1.03 to 1.07, preferably 1.05 additional equivalents are added at the start of the second temperature level from 80 to 100 ° C, preferably at 95 ° C. In order to achieve full conversion of dimethyl sulfate, the duration of the second temperature plateau is at least 3 hours.

Dimethyl sulfate and sodium hydroxide are added by co-casting, that is to say simultaneously, to the reaction medium, and this at a moderate rate, for example over a period of approximately one hour when the mass of isosorbide engaged in methylation is 200 grams.

Following the implementation of the methylation conditions described above, the composition obtained is for example composed of:

5 to 95% by weight, in particular 10 to 50%, more preferably 15 to 30%, and even more preferably approximately 26% by weight of dimethylisosorbide, and

1 to 50% by weight, in particular 4 to 40%, more preferably 7 to 30%, and even more preferably approximately 26% by weight of the endo isomer of the monomethylisosorbide (MMIa), and

1 to 50% by weight, in particular 4 to 40%, more preferably 5 to 40%, and even more preferably approximately 21% by weight of exo isomer of the monomethylisosorbide (MMIb), and

0 to 50% by weight, in particular 5 to 40%, more preferably 10 to 30%, and even more preferably approximately 20% by weight of isosorbide, and

- 0 to 10% by weight, preferably from 1 to 6% by weight, more preferably about 4% by weight of sodium monomethyl sulfate.

The mass contents of these compounds are determined by a quantification method by nuclear magnetic resonance of the proton, called proton NMR. Preferably, the proton NMR analysis method is carried out at 25 ° C., in a deuterium oxide medium. Very preferably, 3-trimethyl-1-propane sulfonic acid (TSPSA) in the form of the sodium salt (CAS No. 2039-96-51), is used as an internal standard. For example, in the present application, the NMR analyzes were carried out on an AVANCE III 400 spectrometer, from Brucker Spectrospin, operating at 400 MHz, using 5 mm diameter NMR tubes, at 25 ° C. In particular, the quantification method provided in the examples could be used.

A separation of the constituents of this composition can be carried out by fractional vacuum distillation, for example under the conditions of Table 1, in order to isolate the compounds of interest and to completely eliminate the sodium monomethylsulfate. The latter is not volatile, it is indeed not distilled.

The exo isomer of monomethylisosorbide (MMIb) can be isolated from this composition by vacuum distillation at reflux, in particular by controlling the temperature of the vapors at the top of the column. For example, following the operating conditions of Table 1, under a vacuum ranging from 20 mbar to 10 mbar, the MMIb is distilled for vapor temperatures at the top of the column ranging from 143 ° C. to 136 ° C. It is thus possible to obtain the exo isomer of the monomethylisosorbide at a purity greater than or equal to 99%, for example greater than or equal to 99.6%.

[0040]

[Tables 1]

Boiler temperature (° C) Pressure in the column (mbar) Vapor temperature at the top of the column (° C) % mass gross MMIb % mass gross ISB Fraction 1 (not target) Start: 180 End: 195 Start: 20 End: 20 Start: 128 End: 142 38 0 Fraction 2 (target) Start: 202 End: 208 Start: 20 End: 10 Start: 143 End: 136 99.6- 99.9 0 Fraction 2 (not target) Start: 208 End: 220 Start: 10 End: 1.4 Start: 134 End: 129 10 90

Evaluation of the overall anti-aging effect

The overall anti-aging effect, that is to say grouping together the preventive anti-aging effects and the curative anti-aging effects, compositions, in particular anti-aging agents, according to the invention, has was evaluated by an in vitro measurement of activation of genes of cosmetic interest.

In vitro effects on the expression of genes of cosmetic interest

The measurement of the level of expression of the genes involved in the anti-cosmetic cosmetic benefits can be carried out by any quantitative PCR technique (in French "quantitative polymerase chain reaction"), also called real-time PCR, also designated by the acronym “RT-qPCR” (for Real-time quantitative polymerase chain reaction).

Anti-aging cosmetic activities were observed by the RT-qPCR method on normal human dermal fibroblasts, NHDE, and normal human epidermal keratinocytes, NHEK. This in-vitro method measures the activation or deactivation of the expression of the genes of these cells involved in cellular anti-aging functions. For a given cellular function, several genes are tested, and among these genes, those whose expression is modified compared to normal functioning, are identified, and the relative variations of the expressions of these genes are then calculated, by taking the functioning normal as base 0%.

The implementation of MMIb makes it possible to obtain the following effects:

- a significant increase in the level of expression of the genes coding for proteins of the extracellular matrix, and in particular DCN (Decorin) (NC_000012.12), EBN1 (Fibrillin 1) (NC_000015.10), COL1A1 (collagen type I alpha 1 chain) (NC_000017.11), COL5A1 (collagen type V alpha 1 chain) (NC_000009.12). At the dermis level, Decorin is a proteoglycan involved in the assembly of the extra cellular matrix. At the epidermis level, Decorin controls cell renewal in association with differentiation and limits inflammation. Fibrillin 1 is a structural protein involved in the maintenance of elastic fibers in the skin. C0L1A1 is the main collagen in the skin. Collagen V is localized in the connective tissues, it is also associated with type I. Such an increase promotes in particular the neosynthesis of proteins and the structure of the extracellular matrix.

- a significant increase in the level of expression of the genes coding for cohesion and the basal lamina, and in particular C0L17A1 (collagen type XVII alpha 1) (NC_000010.11), C0L7A1 (collagen type VII alpha 1) (NC_000003.12) , LAMC2 (laminin subunit gamma 2) (NC_000001.11) and ITGA2 (integrin subunit alpha 2) (NC_000005.10). Collagen XVII is a transmembrane protein that attaches to the basal lamina. Collagen VII is a constituent of the basal lamina. It forms fibrils allowing the anchoring of the basal lamina to the underlying connective tissue. LAMC2 is a component of Laminin 5, an adhesion molecule to the basal lamina. It promotes the anchoring of cells at the dermo-epidermal junction. ITGA2 is a subunit of integrins, receptors that interact with proteins in the basal lamina to promote cell adhesion.

- an increase in the level of expression of genes coding for longevity and cell renewal, and in particular SIRT4 (sirtuin 4) (NC_000012.12) and BSG (basigin) (NC_000019.10).

- a significant increase in the level of gene expression coding for antioxidant defense and barrier function, and in particular GLRX (glutaredoxin) (NC_000005.10), CAT (catalase) (NC_000011.10), HM0X1 (heme oxygenase 1) and IVL (involucrin) (NC_000001.11). Glutaredoxin participates in the elimination of oxygen radicals. Catalase is an antioxidant enzyme whose expression decreases with age. Heme Oxygenase is involved in resistance to environmental stress. It acts as a cytoprotective enzyme. Involucrine is an essential protein in the stratum corneum that activates the barrier function.

These results give MMIb an anti-wrinkle effect, promoting regeneration of the dermis, adhesion and cohesion of the dermis-epidermis, cell renewal, restructuring or firming the skin, preventing the signs of aging, strengthening the barrier function. of the skin and / or impart dullness.

Cosmetic or dermatological composition according to the invention:

The invention also relates to a cosmetic or dermatological composition comprising, in a physiologically acceptable medium, at least one anti-aging agent as described above.

In particular, the cosmetic or dermatological composition comprises from 0.01 to

15% by weight of said anti-aging agent, preferably from 0.1 to 10% by weight, relative to the total weight of the composition, more preferably from 0.1 to 5% by weight, and most preferably from 0.2 at 3% by weight.

According to a preferred embodiment, the cosmetic or dermatological composition comprises, as the sole anti-aging agent, the anti-aging agent as described above.

This anti-aging agent is introduced into a physiologically acceptable medium, and preferably in the aqueous phase, the anti-aging agent being soluble in water.

Physiologically acceptable medium:

By physiologically acceptable medium is meant, within the meaning of the present application, a medium which does not have deleterious side effects and in particular which does not produce redness, overheating, tightness or tingling unacceptable for l 'user.

The physiologically acceptable medium comprises for example a fatty phase and / or an aqueous phase.

Fat phase

The fatty phase can contain at least one oil.

For the purposes of the present invention, the term “oil” means a compound which is liquid at room temperature (25 ° C.) and which, when it is introduced in an amount of at least 1% by weight in water at 25 ° C, is not at all soluble in water, or soluble up to less than 10% by weight, relative to the weight of oil introduced into water.

The liquid fatty phase advantageously comprises one or more non-volatile oils which provide an emollient effect on the skin. Mention may be made of fatty esters such as cetearyl isononoate, isotridecyl isononoate, isostearyl isostearate, isopropyl isostearate, isopropyl myristate, isopropyl palmitate, butyl stearate , hexyl laurate, isononyl isononate, 2-ethyl-hexyl palmitate, 2-hexyldecyl laurate, 2-octyl decyl palmitate, myristate or 2-octyldodecyl lactate, succinate of 2-diethyl hexyl, diisostearyl malate, tracetin, tricprine, caprylic / capric acid triglycerides, mixture of caprate and coconut caprylate, benzoates of C12 to C15 alcohols, glycol esters such but butylene glycol cocoate, glycerin triisostearate, tocopherol acetate, higher fatty acids such as myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid or isostearic acid, higher fatty alcohols such as oleic alcohol, oils es such as avocado oil, camellia oil, hazelnut oil, tsubaki oil, cashew oil, argan oil, soybean oil, l grape seed oil, sesame oil, corn oil, wheat germ oil, rapeseed oil, sunflower oil, cottonseed oil, jojoba oil , peanut oil, olive oil and their mixtures, vegetable butters such as shea butter, camellia butter.

These oils can also be oils of hydrocarbon or silicone type such as paraffin oil, squalane oil, petrolatum, dimethyl siloxanes and their mixtures.

The liquid fatty phase can also include volatile oils. By volatile oil is meant an oil capable of evaporating from the skin, in less than an hour at room temperature and atmospheric pressure. The volatile oils can for example be chosen from silicone oils or triglycerides of short fatty acids to reduce the greasy feel.

The fatty phase of the composition according to the invention may also advantageously comprise at least one fatty phase structuring agent such as a lipophilic gelling agent, a wax and / or a pasty compound.

By “wax” is meant a fatty substance with a reversible liquid / solid state change, having a melting temperature above 30 ° C and generally below 90 ° C, which is liquid under the conditions of preparation of the composition and has an anisotropic crystalline organization in the solid state. The waxes used according to the invention may consist of polar or apolar waxes or of a mixture of the two. By “apolar” is meant a wax containing only carbon, hydrogen and / or phosphorus atoms and in particular a hydrocarbon.

The polar waxes can in particular be chosen from animal waxes, vegetable waxes and synthetic or silicone waxes containing polar groups such as esters. We can thus mention the waxes of Carnauba, Candelilla, bee (Cera alba), Chinese insect (Ericerus pela); from Japan, Sumac, Montan, triesters of C8-C20 acids and glycerin such as glycerin tribehenate, acetylated glycol stearate, and mixtures thereof. These waxes can in particular be used in a predispersed form in an oil, as is the case with mixtures of candelilla wax and jojoba seed oil.

The term “pasty compound” means lipophilic fatty substances which, like waxes, are capable of undergoing a reversible change of liquid / solid state and have an anisotropic crystalline organization in the solid state, but which differ from waxes by the fact that they contain, at a temperature of 23 ° C, a liquid fraction and a solid fraction.

Aqueous phase

The cosmetic composition according to the invention may, in addition, comprise an aqueous phase comprising water and optionally, one or more organic solvents miscible with water, and / or one or more humectants, and / or one or more rheology agents.

The humectant can be a polyol chosen from glycerol, sorbitol, xylitol;

or can be chosen from urea, amino acids, or weak acids and their salts. The rheology agent can in particular be a thickening agent for the aqueous phase, a gelling agent or a suspending agent, such as for example gums derived from plants such as gum arabic, konjac gum, guar gum or their derivatives; gums extracted from algae such as alginates or carrageenans; gums obtained from microbial fermentation such as xanthans, mannans, scleroglucans or their derivatives; cellulose and its derivatives such as carboxymethylcellulose or hydroxyethylcellulose; starch and its derivatives such as in particular modified starches, in particular acetylated, carboxymethylated, octenylsuccinates or hydroxypropylated; synthetic polymers such as polyacrylic acids or carbomers.

Surfactants

The cosmetic composition according to the invention may also comprise one or more surfactants, preferably chosen from water-in-oil (W / O) or oil-in-water (O / W) emulsifiers.

The oil-in-water (O / W) emulsifier can in particular be chosen from sorbitan esters which are optionally polyethoxylated, esters of fatty acids and glycerol, esters or polyesters of fatty acids and of sucrose, esters of fatty acids and of polyethylene glycol, modified polyether polysiloxanes, ethers of fatty alcohols and of polyethylene glycol, alkylpolyglycosides and hydrogenated lecithin, without this list being exhaustive.

The water-in-oil emulsifier (W / O) can be chosen from non-ethoxylated fatty esters of polyols, and in particular from non-ethoxylated fatty esters of glycerol, polyglycerols, sorbitol, sorbitan, anydrodrohexitols such as isosorbide, mannitol, xylitol, erythritol, maltitol, sucrose, glucose, polydextrose, hydrogenated glucose syrups, dextrins and hydrolyzed starches.

The W / O emulsifier can be chosen from non-ethoxylated fatty esters of polyols obtained from fatty acid or by trans-esterification from oil or mixtures of oils. The fatty acids used comprise from 8 to 22 carbon atoms, preferably from 10 to 18 carbon atoms, and in particular from 12 to 18 carbon atoms. These acids can be linear or branched, saturated or unsaturated, have one or more lateral hydroxyl functions. The oils can be saturated or unsaturated, from liquid to solid at room temperature, and optionally have hydroxyl functions, preferably with an iodine index of between 1 and 145, and in particular from 5 to 105.

Coloring matter

The cosmetic composition according to the invention may also comprise at least one coloring material chosen from water-soluble or liposoluble dyes, the fillers having the effect of coloring and / or opacifying the composition and / or coloring the lips, such as pigments, nacres, lacquers (water-soluble dyes adsorbed on an inert mineral support) and their mixtures. These coloring matters can optionally be treated on the surface with a hydrophobic agent such as silanes, silicones, fatty acid soaps, C9-15 fluoroalcohol phosphates, acrylate / dimethicone copolymers, mixed copolymers C9-15 fluoroalcohol phosphates / silicones, lecithins, wax camauba, polyethylene, chitosan and optionally acylated amino acids such as lauroyl lysine, disodium stearoyl glutamate and aluminum acyl glutamate. The pigments can be mineral or organic, natural or synthetic. Examples of pigments are in particular iron, titanium or zinc oxides, as well as composite pigments and goniochromatic, pearlescent, interference, photochromic or thermochromic pigments, without this list being exhaustive.

Expenses

The cosmetic composition according to the invention may also contain at least one filler. By this term is meant any particle of any shape (in particular spherical or lamellar), mineral or organic, insoluble in the composition. Examples of fillers are talc, mica, silica, kaolin, boron nitride, starch, starch modified with octenylsuccinic anhydride, polyamides, silicone resins, elastomer powders. silicone and acrylic polymer powders, in particular poly (methyl methacrylate) or styrene acrylate copolymer powders, cyclodextrins.

Assets

In addition to the anti-aging agent previously described, the cosmetic composition according to the invention can, moreover, comprise one or more hydrophilic or lipophilic active agents. In particular, the additional active agents can be chosen from the group consisting of vitamins, antioxidants, hydrating agents, anti-pollution agents, keratolytic agents, astringents, anti-inflammatories, whitening agents and agents promoting microcirculation. Preferably, in addition to the anti-aging agent previously described, the cosmetic composition according to the invention may comprise at least one active agent chosen from hydrating agents, antioxidants, agents promoting microcirculation and their mixtures.

Additional usual cosmetic ingredients

The composition according to the invention can also comprise any usual cosmetic ingredient which can be chosen in particular from antioxidants, perfumes, preservatives, neutralizers, surfactants, sun filters, vitamins, moisturizers, self-contained compounds. bronzers, anti-wrinkle active agents, emollients, hydrophilic or lipophilic active agents, anti-free radical agents, deodorant agents, sequestering agents, film-forming agents, and mixtures thereof.

The invention is illustrated in more detail in the nonlimiting exemplary embodiments below.

Examples

Example 1: synthesis of the exo isomer of the monomethylisosorbide MMIb

Dimethylisosorbide DMI was synthesized by direct methylation of the isosorbide with dimethylsulfate in the presence of sodium hydroxide in water. The raw materials used are as follows:

- isosorbide is the product Polysorb® P, which is a solid, marketed by Roquette Frères,

- Dimethyl sulfate, denoted DMS, is a liquid with a minimum content equal to 99% of dimethyl sulfate. Dimethyl sulfate is the methylating agent which will react on the isosorbide in the presence of a base, sodium hydroxide.

The methylation process consists of two stages:

a first step of bringing into contact an aqueous solution at 80% by mass of isosorbide, with 0.6 molar equivalent of dimethylsulfate relative to the isosorbide, and 1.05 equivalent of sodium hydroxide at 50% m in water compared to DMS. The addition of the methylant and the base is carried out by co-casting in the reactor at 60 ° C. over a period of 1 hour.

- a second step during which the reaction medium is heated to 95 ° C. 1.05 equivalent of sodium hydroxide 50% by mass relative to the DMS is again added over a period of 50 minutes. The medium is then left at 95 ° C for 3 hours.

Then the reaction medium is cooled to room temperature. The reaction medium is filtered to remove the salts formed, mainly sodium sulfate, and the salts are filtered with ethanol to recover the entire product. The filtered medium is neutralized with 96% m sulfuric acid to obtain a pH between 5.5 and 6.

The product obtained has an MMIa content of 20% by mass, in MMIb of 26% by mass, in DMI of 26% by mass, ISB of 20% by mass, in sodium monomethyl sulfate of 6% by mass.

We then proceeded to the separation of the constituent compounds the composition obtained to isolate the MMIb, and also eliminate the sodium monomethylsulfate. This separation was carried out by rectification on a vacuum distillation column. The distillation assembly consists of a double-jacket boiler with a capacity of 2L heated using an oil circulation, a rectification column provided with a Sulzer Mellapak © packing (section: 29 mm , filling height 55 cm), a cooler and an automatic reflux head.

1.7 kg of the composition obtained at the end of the methylation is used in a vacuum distillation carried out in batch. The column is equipped with a Sulzer Mellapak © packing, and an automatic reflux head controlled by the temperature of the vapors at the head of the column, manually incremented from 128 ° C to 150 ° C.

The composition is therefore placed in the boiler of a distillation column. We then proceed simultaneously to the heating, and this gradually from 180 ° C to 220 ° C, and to the vacuum, and this also gradually from 20 mbar to 1.4 mbar, following the start and end parameters of fraction provided in the table below. These parameters of vacuum and boiler temperature allow to obtain from 128 ° C to 150 ° C. The separated products are recovered at the head of the column according to the temperature of the vapors at the head of the column, as presented in Table 2:

[Tables2]

Boiler temperature (° C) Pressure in the column (mbar) Vapor temperature at the top of the column (° C) % mass gross MMIb % mass gross ISB Fraction 1 (not target) Start: 180 End: 195 Start: 20 End: 20 Start: 128 End: 142 38 0 Fraction 2 (target) Start: 202 End: 208 Start: 20 End: 10 Start: 143 End: 136 99.6-99.9 0 Fraction 2 (not target) Start: 208 End: 220 Start: 10 End: 1.4 Start: 134 End: 129 10 90

The fraction of interest is the second fraction. The other fractions are discarded. The mass contents of MMIb and ISB thus obtained were verified by a quantification method by NMR of the proton.

Method for quantifying the compositions by proton NMR:

The analysis is carried out by nuclear magnetic resonance, NMR, of the proton at 25 ° C in deuterium oxide solvent with a purity of at least 99.8%, on an AVANCE III spectrometer, by Brucker Spectrospin, operating at 400 MHz, using 5 mm NMR tubes. The quantification is carried out using an internal standard, 3-trimethyl-l-propane sulfonic acid (denoted TSPSA) in the form of the sodium salt (CAS N ° 2039-96-51).

The MMIa is designated by its name "5-O-monomethylisosorbide". MMIb is designated by its name "2-O-monomethylisosorbide".

An internal standard solution is prepared by dissolving 50 mg of TSPSA weighed to the nearest 0.1 mg, in 5 g of deuterium oxide, weighed to the nearest 0.1 mg.

A solution for quantitative analysis is prepared by weighing, in an NMR tube, 15 mg of sample, to the nearest 0.1 mg, then 50 μL of internal standard solution are added, and a vial of 0.75 mL of deuterium oxide with a purity of at least 99.96%. Stir to homogenize and / or dissolve completely.

Then the recording of the proton spectrum of the solution for quantitative analysis prepared above is carried out on the NMR spectrometer, without removal of solvent, without rotation, with a relaxation time of at least 10 seconds, after the adjustments instruments. The spectral window must be between -0.5 and 9 ppm by calibrating the spectrum on the TSPSA peak at 0 ppm. The spectrum is used after Eourier transformation, phase correction and subtraction of the baseline in manual mode (without exponential multiplication, LB = GB = 0).

We then obtain the full spectrum of Figure 1 in the appendix ([fig.l] full spectrum of proton NMR analysis), which we treat over the range 3.0 and 5.4 ppm, as indicated in FIG. 2 in the appendix ([Big 2] processing of the proton NMR signal between 3.0 and 5.4 ppm).

We assign the value 100 to the surface SE of the internal standard signal (counting for 9 TSPSA protons). The Si surfaces of the various compounds to be analyzed are integrated: Si to S ₄ for the CH signals in the range between 4.3 and 5 ppm; or If _M , S ₂ m, S _4m and S ₅ for the CH3 signals in the range 3.1 to 3.8 ppm The different signals are allocated as follows:

- at 4.82 or 4.54 ppm: If counting for 1 CH proton per mole of 5-O-methylisosorbide

- at 4.61 ppm: S ₂ counting for 2 CH protons per mole of 2-O-monomethylisosorbide

- at 4.54 ppm: S ₃ counting for 1 CH proton per mole of isosorbide

- at 4.65 ppm: S ₄ counting for 1 CH proton per mole of isosorbide + 1 CH proton per mole of dimethylisosorbide

- at 3.34 ppm: S ₅ counting for 3 protons per mole of methanol

- at 3,443 ppm: S _[M counting for 3 protons per mole of 5-O-monomethylisosorbide - at 3,437 ppm: S _4M counting for 3 protons per mole of dimethylisosorbide - at 3.40 ppm: S _2M counting for 3 protons per mole of dimethylisosorbide + counting for 3 protons per mole of 2-O-monomethylisosorbide

In the CH proton region, the surface of dimethylisosorbide is equal to S4 - S3. In the CH3 proton region, the surface of 2-O-monomethylisosorbide is equal to S 2M ^- S ₄ M ·

The mass content of compound i is expressed in% (gross m / m) using the following formula:

S. · X .¾ x 1¾ x Q xx 100% m compound i ~ ----——----- 'S _E XP _M XM _F X Pfe

Or :

P _E : number of protons from the internal standard = 9

P _M : number of protons from compound i according to the integrated Si surfaces (Pm ⁼ 1 for Si, S3 and S4-S3, Pyj - 2 for S2, Pm ⁼ 3 for S5, Sim, S4m and S ₂ m ^- S ₄ m) W _E : mass, in grams, of internal standard solution weighed

C _E : concentration, in dry milligrams / gram of the TSPSA solution M _e : molar mass, in grams per mole, of the TSPSA (M _E = 218 g / mole) M; : molar mass, in grams per mole, of compound i (MeOH: 32 g / mole; isosorbide: 146 g / mole; 2-O-monomethylisosorbide and 5-O-monomethylisosorbide: 160 g / mole; dimethylisosorbide: 174 g / mole ) PE: mass, in milligrams, of the sample to be analyzed.

S _E : surface of the TSPSA

If: surface of the compound to be analyzed

The exo isomer of the monomethylisosorbide MMIa was obtained with a purity greater than or equal to 99% by mass. The main impurity being the other isomer of MMI, MMIa.

Examples 2 and 3: Effect of the compositions according to the invention on the expression of skin cell genes

The RT-qPCR measurement technique on genes coding for the expression of proteins involved in the prevention and / or treatment of the effects of aging of skin cells, in particular keratonicytes and fibroblasts, was used to demonstrate in -vitro the preventive and / or curative anti-aging effect of the new anti-aging agent according to the invention.

In these examples, the expression of messenger RNAs was measured by the quantitative RT-qPCR technique (reverse transcription followed by polymerization chain reaction), after in vitro incubation of the different cell types in the absence or in the presence of compounds tested.

This study was carried out on normal human dermal fibroblasts (NHDF) or on normal human epidermal keratinocytes (NHEK), depending on the genes tested.

The cells were cultured at a concentration of 10,000 cells per well of 96-well plates, in the presence of standard culture medium depending on the cell type.

The compounds were then added at the concentration of 0.5% by mass in water, for 24 h.

The supernatant was removed and the cells were taken up in a specific buffer for the extraction of messenger RNA (mRNA). The mRNAs were purified and reverse transcribed in the presence of a commercial reverse transcriptase.

The complementary DNAs (cDNAs) obtained were used in a quantitative real-time PCR experiment, using suitable primers. The expression level of the mRNAs was normalized with 5 reference genes.

Example 2: curative anti-aging effect of MMIb

Examples 2.A and 2.B illustrate the genes beneficial for a curative anti-aging effect activated by the new anti-aging agent according to the invention.

Example 2.A: Genes encoding proteins of the extracellular matrix

The cells used for this example are normal human fibroblasts (NHDF) or normal human keratinocytes (NHEK). The contact with the MMIb was carried out for 24 hours. The results obtained, in terms of expression of different genes relative to the basal level (absence of compound, 0%), are shown in Table 3 below.

[0117] [Tables3]

Gene tested Cell type MMIb DCN (Decorin) (NC_000012.12) NHEK + 90% FBN1 (Fibrillin 1) (NC_000015.10) NHEK + 60% FBN1 (Fibrillin 1) (NC_000015.10) NHDF + 80% COL1A1 (collagen type I alpha 1 chain) (NC_000017.11) NHDF + 60% COL5A1 (collagen type V alpha 1 chain) (NC_000009.12) NHDF + 60%

We observe an increase in the level of expression of the genes tested. Such an increase promotes in particular the neosynthesis of proteins and the structure of the extracellular matrix.

Example 2.B: genes coding for cohesion and the basal lamina

The cells used for this example are normal human fibroblasts (NHDF) or normal human keratinocytes (NHEK). The contact with the MMIb was carried out for 24 hours. The results obtained, in terms of expression of different genes relative to the basal level (absence of compound, 0%), are shown in Table 4 below. [0121] [Tables4]

Gene tested Cell type MMIb COL 17Al (collagen type XVII alpha 1) (NC_000010.11) NHDE + 80% COL7A1 (collagen type VII alpha 1) (NC_000003.12) NHDE + 60% LAMC2 (laminin subunit gamma 2) (NC_000001.11) NHDE + 60% ITGA2 (integrin subunit alpha 2) (NC_000005.10) NHEK + 60%

We observe an increase in the level of expression of the genes tested. Such an increase promotes in particular the cohesion of the extracellular matrix and strengthens the basal lamina.

Examples 3: Preventive Anti-Aging Effect of MMIb

Examples 3.A and 3.B illustrate the genes beneficial for a preventive anti-aging effect by the new anti-aging agent according to the invention.

Example 3.A: Genes Coding for Longevity and Cell Renewal

The cells used for this example are normal human fibroblasts (NHDE) or normal human keratinocytes (NHEK). The contact with the MMIb was carried out for 24 hours. The results obtained, in terms of expression of the gene relative to the basal level (absence of compound, 0%), are shown in Table 5 below.

[0127] [Tables5]

Gene tested Cell type MMIb SIRT4 (sirtuin 4) (NC_000012.12) NHEK + 160% BSG (basigin) (NC_000019.10) NHDE + 60%

There is an increase in the level of expression of the gene tested. Such an increase notably promotes longevity and cell renewal.

Example 3 .B: Genes encoding the antioxidant defense and the barrier function

The cells used for this example are normal human fibroblasts (NHDE) or normal human keratinocytes (NHEK). The contact with the MMIb was carried out for 24 hours. The results obtained, in terms of expression of the gene relative to the basal level (absence of compound, 0%), are shown in Table 6 below.

[0131] [Tables6]

Gene tested Cell type MMIb GLRX (glutaredoxin) (NC_000005.10) NHEK + 130% CAT (catalase) (NC_000011.10) NHEK + 60% HM0X1 (heme oxygenase 1) (NC_000022.11) NHDF + 80% HM0X1 (heme oxygenase 1) (NC_000022.11) NHEK + 90% IVL (involucrin) (NC_000001.11) NHEK + 60%

It will be noted that the IVL gene also provides a curative anti-aging effect.

We observe an increase in the level of expression of the genes tested. Such an increase in particular promotes antioxidant defense and barrier function.

The exo isomer of the monomethylisosorbide MMIb therefore gives an anti-wrinkle effect, promotes regeneration of the dermis, adhesion and cohesion of the dermis-epidermis, cell renewal, restructures or firms the skin, prevents signs of aging, strengthens the barrier function of the skin and / or gives it mattness.

Claims (1)

Claims [Claim 1] Anti-aging agent comprising the exo isomer of the monomethylisosorbide MMIb. [Claim 2] Anti-aging agent according to claim 1, characterized in that it comprises from 75 to 100% by weight of the exo isomer of the monomethylisosorbide MMIb, preferably from 80 to 100% by weight, and more preferably from 90 to 100% in weight. [Claim 3] Anti-aging agent according to claim 1, characterized in that it consists of the exo isomer of the monomethylisosorbide MMIb. [Claim 4] Process for the preparation of an anti-aging agent according to claim 1, comprising: - methylation of isosorbide, and - separation by distillation to extract the exo isomer of the monomethylisosorbide MMIb. [Claim 5] Cosmetic or dermatological composition comprising, in a physiologically acceptable medium, at least one anti-aging agent according to any one of claims 1 to 3. [Claim 6] Composition according to Claim 3, characterized in that it comprises from 0.01 to 15% by weight of the exo isomer of the monomethylisosorbide, relative to the total weight of the composition. [Claim 7] Composition according to any one of Claims 5 or 6, characterized in that it comprises, as sole anti-aging agent, at least one anti-aging agent according to any one of Claims 1 to 2 [Claim 8] J. Use of a cosmetic or dermatological composition according to any one of claims 5 to 7, to provide an anti-wrinkle effect, promote regeneration of the dermis, adhesion and cohesion of the dermis-epidermis, cell renewal, restructure or firm the skin. , prevent the signs of aging, to prevent skin dryness resulting from a decrease in the barrier function of the skin and / or impart dullness. 1/1