WO1998053795A1 - Cosmetic and dermopharmaceutical compositions containing threonine or serine derivatives - Google Patents

Abstract

The invention concerns the novel use of N-acyl-threonine and N-acyl serine derivatives which are β-hydroxylated acids in cosmetics or dermopharmaceutics to accelerate skin renewal, fight against wrinkles, improve general skin and scalp appearance by keratolytic effect, hydrating and/or stimulating the metabolism.

Description

TITLE Cosmetic and dermopharmaceutical compositions containing threonine or serine derivatives. The invention relates to cosmetic or dermopharmaceutical compositions. For several years, certain organic acids have been used, characterized in that they carry a hydroxyl group

OH in the α position relative to the carboxyl group (called alpha-hydroxy acids or AHA) in many formulas intended for topical use on the skin, hair and mucous membranes. Lactic acid, glycolic acid, malic acid are the best known and most used representatives.

Their claimed and / or demonstrated cosmetic or dermopharmaceutical activities mainly concern the keratolytic effect for the renewal of the stratum corneum. It has become apparent over time that the use of these acids on a large scale (in many products, and in high concentrations) leads to a significant number of cases of intolerance in users. High dose lactic or glycolic acid with low pH irritates, can cause erythema, feelings of discomfort, tingling. Some remedies (use of ceramides, calming plant extracts, etc.) have been proposed to resolve this problem.

Alternatively, salicylic acid, a ^β- hydroxy acid with an aromatic nucleus, has been proposed as a keratolytic agent. However, this acid cannot be used in all circumstances: because of its antimicrobial activity, salicylic acid and its salts are subject to European regulations on authorized antimicrobial preservatives in cosmetic products. Its use is limited to 0.5% (w / w) which is not enough for a notable keratolytic effect.

Its "chemical" nature (synthetic product, aromatic nucleus derived from phenol, similarity to Aspirin ^R ) does not favor either similar use to AHAs, although it is known to be less aggressive than these.

There were therefore the following technical problems to solve: find a keratolytic agent, moisturizing, stimulating in the same way as AHAs, but less aggressive, less irritating and ensuring that this agent is of natural origin, acceptable in cosmetic products or dermopharmaceuticals.

The invention described in this patent solves these problems. Amino acids, natural compounds of any protein in the biological domain (microbial, fungal, of plant or animal origin) do not have an acidic character in aqueous solution, despite their name. The amino function presents at the same time as the carboxylic function gives them a "Zwitterion" character, neither acidic nor basic. It has now been discovered that natural amino acids such as threonine or serine which contain a hydroxyl group in position β with respect to the carboxyl group - can be advantageously modified by a chemical reaction which consists in acylating the amino group (NH ₂ ) by a short chain fatty acid. This not only renders the acidity of the amino acid thus modified, but also transforms it into a β-hydroxylated (amino) acid, the cosmetic activity of which is equivalent to AHA and salicylic acid, without having the disadvantages mentioned above.

On the contrary, the amino acid modified according to the invention is not irritant, it is generally well soluble in the aqueous media usually used in cosmetics, and on the skin it changes slowly, under the effect of the protease enzymes. of the skin, in free amino acid and in acetate.

The use of threonine in the context of the invention - therefore in the form of N-acyl-threonine - is particularly advantageous since after the enzymatic digestion of the amide bond there remains the free threonine which is one of the essential amino acids, therefore beneficial and nutritious for the skin.

To carry out the invention, fatty acids containing between 2 and 10 carbons, preferably between 2 and 4 carbons, whose carbon chains are either linear or branched, saturated or unsaturated, hydroxylated or sulfur or phosphorylated or not, are used; particular preference is given to acetic acid. However, other modifications of the amino acid chosen which have the effect of blocking the amino group and canceling the "zwitterion" structure can be used: formation of Schiff bases with aldehydes, blockages by alkyloxycarbonyl groups (" boc "," fmoc "," Z ") and others usually used in peptide synthesis.

An interesting variant of the invention consists in also blocking the β-hydroxyl group of the amino acid chosen by a second acylation reaction.

The compound N-acyl, O-acyl-AA (AA = amino acid) can be advantageously combined with the compound N-acyl-AA. Its β-hydroxyl function (blocked in the form of an ester) will be released on the skin by esterases present within the epidermis, as the skin needs it. This gives a rapid effect (with the N-acyl compound) and a more persistent effect (with the N-acyl, O-acyl compound). The following examples illustrate the invention without limiting its scope. Example No. 1 Preparation of N-acetyl-L-threonine: 20 g of L-threonine are dissolved in 180 ml of IN ammonia and the mixture is cooled to T <5 ° C. 30 ml of acetic anhydride are added in portions and the basic medium is maintained by adding ammonia. The mixture is stirred at about 5 ° C for 3 hours. The disappearance of the initial threonine is verified by CCM, the medium is neutralized and eliminated water to obtain ammonium N-acetyl-L-threoninate. A passage of the compound thus obtained over an ion exchange resin (Amberlyste 15) leads to N-acety l-threonine. Yield = 80%; melting point 122 ° C. Example No. 2: Preparation of N-acetyl-serine

15 g of L-serine are reacted according to the same procedure to obtain N-acetyl-L-serine (yield 84%, melting point 132 ° C).

Example No. 3: Preparation of N-acetyl, O-acetyl-L-threonine: With 3 g of N-acetyl-threonine, which is dissolved in 10 ml of acetic acid

0.1 ml of concentrated sulfuric acid is added and heated to reflux.

The disappearance of N-acetyl-threonine is followed in TLC. After 12

hours, frozen at -20 ° C and lyophilized to remove acetic acid.

The residue is dissolved in water and purified on an exchange column

ions.

The fractions containing the diacety l-threonine are lyophilized m = 3.1g

(YId = 82%). Analysis: Solubility: water, methanol; melting point: 171-

172 ° C; TLC: solvent: (4/2/2: n-butanol / acetic acid / water); Infra¬

red: 3376/3286/2992/2940/1732/1668/1618/1562/1378/1248

/ 1164/1131 / 1072cm- ¹ .

où Rι= alkyloxy, aryloxy ou alkylaryloxy, alkyloxy car bonyl, aryloxycarbonyl ou alkylaryloxycarbonyl, avec "alkyloxy" représentant des chaînes carbonées de 2 à 10 carbones, préférentiellement de 2 à 4 carbones, linéaires ou ramifiées, saturées ou insaturées, hydroxylées, soufrées ou phosphorylées ou non, R₂ = H, CH₃ ou une chaîne alkyle de 2 à 4 atomes carbonés et R3 = H ou une chaîne alkyloxy de 2 à 10 atomes de carbone, préférentiellement de 2 à 4 carbones.The compounds produced according to the invention therefore correspond to the following general formula:

where Rι = alkyloxy, aryloxy or alkylaryloxy, alkyloxy car bonyl, aryloxycarbonyl or alkylaryloxycarbonyl, with "alkyloxy" representing carbon chains of 2 to 10 carbons, preferably from 2 to 4 carbons, linear or branched, saturated or unsaturated, hydroxylated, sulfurized or phosphorylated or not, R ₂ = H, CH ₃ or an alkyl chain of 2 to 4 carbon atoms and R3 = H or an alkyloxy chain of 2 to 10 carbon atoms, preferably of 2 to 4 carbons.

The carbon C ^x denotes an asymmetric carbon atom. It can be present either in L form (natural form of amino acids), in D form or in racemic DL form.

The particularly preferred compounds according to the invention are N-acetyl-

L-threonine, N-acetyl, O-acetyl-L-threonine, N-acetyl-L-serine and

N-acetyl, 0-acetyl-L-serine.

The compounds which are the subject of the patent can also be obtained by enzymatic synthesis in a preferably anhydrous medium.

Example No. 4: Fluid face care cream

(the proportions and percentages are given, unless otherwise indicated, by weight of the final formula):

Brij 72 ¹ 2.6 Brij 721 ¹ 2.4

Amerchol L101 ² 5.0

Silicone DC 344 ³ 3.0

Arlamol E ¹ 2.5

Abil 2434 ⁴ 1.0 Octyldodecanol 2.0 N-acety 1-L-threonine 3.0

Distilled water, preservatives, perfume qs 100, soda lye qs pH 4.

Example 5: Night cream

Eumulgine SMS ⁵ 3.0

Dehymuls SMS ⁵ 1.5

Cetyl alcohol 1.5

Silicone DC 200 2.0

Cerraphyl 375 ⁶ 3.0

Myritol 318 ⁵ 3.0

Propylene glycol 2.0

N-acetyl, O-acetyl-L-threonine 1.0

N-acetyl-L-serine 5.0

Distilled water, preservatives, perfume qs 100.

The use of the amino acids modified according to the invention is obvious to those skilled in the art. The derivatives which are the subject of the patent are generally soluble in water, but can also be dissolved in conventional cosmetic solvents of polyol type (propylene glycol, glycerin, b tylene glycols, ethoxydiglycol, polyethylene glycols). Those skilled in the art know the methods of prior solubilization of this kind of molecules. The derivatives which are the subject of this patent can also be previously incorporated into cosmetic vectors such as liposomes, chylomicrons, macro-, micro- and nanoparticles as well as macro-, micro- and nanocapsules, or be absorbed on powdery organic polymers, talcs, bentonites and other mineral supports.

These solutions or preparations can then be used in creams, lotions, ointments and any other cosmetic and dermopharmaceutical dosage form. The cosmetic or dermopharmaceutical effects of the derivatives which are the subject of this patent have been demonstrated in in vivo tests: Example No. 6:

20 volunteers were selected for this test. Cosmetic parameters are measured (hydration, wrinkles, skin profile, firmness, color and cell cohesion) at two opposite sites on the face of each volunteer. Then the panelists use two formulations, one placebo, the other containing 5% of N-acety 1-L-threonine (for example, a cream similar to that of example n ° 5, for a period of 4 weeks independently on both parts of the face. After this period, the same biometric parameters are studied and compared to the initial values. There is a significant increase in the state of hydration, firmness and radiance of the skin treated with the cream containing N-acetyl-threonine, compared to placebo. The skin profile becomes less rough, wrinkles decrease.

The derivatives which are the subject of this patent can be used in any galenic form usually used in cosmetic or dermopharmaceutical formulation: O / W and W / O emulsions, milks, lotions, gels, ointments, balms, foams, body oils, hair lotions, shampoos, soaps, sticks and pencils, sprays, without this list being exhaustive.

The concentration of use of these derivatives which are the subject of this patent in the finished cosmetic product can vary between 0.001 and 30% (w / w), preferably between 0.1 and 10%, and particularly advantageously between 1 and 5% by weight of the composition. total.

The derivatives which are the subject of this patent can be combined in cosmetic compositions with any other ingredient usually used in cosmetics: extraction and / or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, hydro- active ingredients. or fat-soluble, extracts from other plants, tissue extracts, marine extracts.

The derivatives which are the subject of this patent in all their galenical forms (powder, solution, emulsion) can be used in the cosmetic and dermopharmaceutical fields for their hydrating, exfoliating, stimulating, keratolytic, rejuvenating activity.

Because of their very low irritant potential, they are advantageously used in products for sensitive skin, sun and after-sun creams, facial and hand care products, without this list being exhaustive. Their use is also recommended for all body or scalp care, particularly in combination with anti-cellulite slimming products, anti-dandruff products, hair growth stimulants and anti-aging prevention products.

Claims

CLAIMS 1. Characterized cosmetic or dermopharmaceutical compositions in that they contain one or more compounds which correspond to the general formula:

where Ri = alkyloxy, aryloxy or alkylaryloxy, alkyloxycarbonyl, aryloxycarbonyl or alkylaryloxycarbonyl, with "alkyloxy" representing carbon chains of 2 to 10 carbons, preferably 2 to 4 carbons, linear or branched, saturated or unsaturated, sulfur or phosphorylated or not, R ₂ = H, CH3 or an alkyl chain of 2 to 4 carbon atoms and R3 = H or an alkyloxy chain of 2 to 10 carbon atoms, preferably of 2 to 4 carbons, and the carbon C ^x denotes an asymmetric carbon atom which can be present in the L, D form or in racemic DL form. 2) Cosmetic or dermopharmaceutical compositions according to claim 1, characterized in that the compounds which are the subject of this patent are obtained either by organic synthesis in a homogeneous or heterogeneous medium according to conventional methods, or by enzymatic synthesis in a preferably anhydrous medium. 3) Cosmetic or dermopharmaceutical compositions according to claims 1 to 2, characterized in that the compounds are chosen from N-acyl-serine, N-acyl-threonine, N-Acyl, 0-acyl-serine and N-acyl, O- acy l-threonine. 4) Cosmetic or dermopharmaceutical compositions according to claims 1 to 3 characterized in that the amino acid derivative β- hydroxylated objects of the patent is N-acetyl-L-threonine or a mixture of N-acetyl-L-threonine and N, O-diacetyl-L-threonine. 5) Cosmetic or dermopharmaceutical compositions characterized in that the compounds according to any one of claims 1 to 4 are previously incorporated in cosmetic vectors such as liposomes, chylomicrons, macro-, micro- and nanoparticles as well as macro-, micro- and nanocapsules, or absorbed on powdery organic polymers, talcs, bentonites and other mineral supports. 6) Cosmetic or dermopharmaceutical compositions according to any one of Claims 1 to 5, characterized in that they contain the derivative (s) which are the subject of this patent at concentrations which can vary between 0.001 and 30% (w / w), preferably between 0.1 and 10% (w / w), particularly advantageously between 1 and 5% by weight of the total composition. 7) Cosmetic or dermopharmaceutical compositions according to any one of claims 1 to 6, characterized in that they represent any galenical form used in cosmetics or dermopharmacy, namely: O / W and W / O emulsions, milks, lotions, gels, ointments, balms, mousses, body oils, hair lotions, shampoos, soaps, sticks and pencils, sprays. 8) Cosmetic or dermopharmaceutical compositions according to any one of Claims 1 to 7, characterized in that the derivatives which are the subject of this patent are combined in the finished products with any other ingredient usually used in cosmetics or dermopharmacy: extraction lipids and / or synthetic, gelling and viscosifying polymers, surfactants and emulsifiers, water- or liposoluble active principles, plant extracts, tissue extracts, marine extracts. 9) Uses of the compounds which are the subject of this patent according to any one of claims 1 to 4 in the cosmetic or dermopharmaceutical compositions according to any one of claims 5 to 8 for skin or scalp care, particularly for renewal epidermal layers, to improve skin hydration, to reduce wrinkles and roughness of the skin.