WO2002036094A2

WO2002036094A2 - Method and dermatological and/or cosmetic composition for inhibiting the adhesion effect of circulating cells

Info

Publication number: WO2002036094A2
Application number: PCT/FR2001/003353
Authority: WO
Inventors: Francine Joly
Original assignee: Sephra
Priority date: 2000-10-31
Filing date: 2001-10-26
Publication date: 2002-05-10
Also published as: FR2815866A1; FR2815866B1; WO2002036094A3; AU2002215080A1; EP1330235A2

Abstract

The invention relates to the field of chemistry, and more particularly to the field of cosmetics and pharmaceutics, in particular dermatology. More particularly, it concerns a dermatological and/or cosmetic composition for implementing a method for treating sensitive skins and/or skins reactive to fumes, in particular tobacco smoke. The composition contains an active principle consisting of substances inhibiting adhesion effect, induced in particular by said fumes, of human circulating cells, in particular neutrocytes, lymphocytes, monocytes, acidophilic cells, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes. Among the substances antagonists of said adhesion effect, the invention more particularly concerns compositions having as active principle a pyrrolidone-2 arginine carboxylate, in particular pyrrolidone-2 L-arginine carboxylate. The composition has soothing, anti-irritant, anti-inflammatory and anti-ageing effects on the skin.

Description

Method and dermatological and / or cosmetic composition antagonizing the adhesion effect of circulating cells

The field concerned The present invention relates to the field of chemistry, and more particularly to the field of cosmetics or pharmaceuticals, in particular dermatology.

The product according to the invention (general concept) It relates to substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes. It more particularly relates to the use of substances antagonizing the adhesion effect of human circulating cells to other cells or molecules of the extracellular matrix, with a view to the production of new topical compositions intended to be applied to the skin, mucous membranes or integuments.

The problem: Skin inflammation

The explanation of physiological mechanisms

Indeed, we have just found - and this is what constitutes the basis of the present invention - that certain substances play an important role in antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, especially with human keratinocytes, During skin inflammation, many polynuclear cells migrate into the dermis and the epidemic. The infiltration of circulating cells in the skin plays an important role in the pathophysiology of various skin conditions: atopic dermatitis, psoriasis, eczema, etc. and in inflammatory skin reactions. The adhesion of human circulating cells is involved in all the stages which contribute to the influx of human circulating cells into the dermis and the epidemic: adhesion to endothelial cells, chemotaxis, adhesion to molecules of the extracellular matrix (fibrinogen, collagen, fibronectin, laminin, ...) and adhesion to keratinocytes. Thus during inflammatory dermatoses, the expression of adhesion molecules is increased - in particular by inflammatory cytokines - and thus promotes the recruitment of circulating cells. Cell adhesion plays an important role in the recruitment of these cells from the vessels.

The general solution: substances antagonizing the adhesion effect The production of new topical compositions intended to be applied to the skin, the mucous membranes or the integuments and comprising substances antagonizing the adhesion effect of human circulating cells to others cells or molecules of the extracellular matrix, therefore constitutes a remedy in the case of skin conditions. In addition, we have just found that among the substances antagonizing the adhesion effect of human circulating cells, arginine pidolate plays an important role. The special solution: arginine pyrrolidone carboxylate

Arginine pyrrolidone carboxylate or arginine pidolate is a compound known for a long time and marketed under the name Argidone by the firm UCB. It is a creamy white powder very soluble in water. Its raw formula is C _π H ₂₁ N ₅ 0 ₅ . Its molecular weight is 303.3. A review on this product has been published in particular by Zanotti,

Prodotto chimico, March 1982 p. 25-28.

By arginine pyrrolidone carboxylate is meant any salt formed by neutralization of pyrrolidone 2-carboxylic acid (or pyroglutamic acid) by arginine. Arginine can exist in L form (natural form), D form or DL form (synthetic arginine).

Arginine pyrrolidone-2 carboxylate corresponds to one of the following formulas:

Pyrrolidone carboxylic acid has an asymmetric carbon and as such can be split into its levorotatory or dextrorotatory form, or exist in the form of a racemate.

Arginine pyrrolidone carboxylate has already been described in the literature for cosmetic applications: - emollient for the skin and hair (Ajinomoto KK - Shiseido KK), Japanese patent 56/071020;

- cosmetic applications (Shisheido KK), Japanese patent JP A-61/30509;

- antioxidant system (L'Oréal), French patent 2,675,695; that is, it enhances the antioxidant effect of polyphenolic substances such as tocopherol, BHT and its derivatives, and esters or amides of caffeic acid to stabilize the fatty acids or fats used in cosmetic compositions.

French patent 2,778,562 describes the use of arginine salts, in combination or not, with sea water to inhibit mast cell activation induced by neuropeptides, in particular degranulation of skin mast cells induced by substance P. Arginine salts are inhibitors of the histamine release induced by substance P. However, according to the invention, it has just been found that arginine pidolate also plays an important role in antagonizing cell adhesion circulating human, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

The claimed invention Method

The invention relates to a method for treating sensitive and / or reactive skin using substances which antagonize the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

The invention relates more particularly to a method of treating skin sensitive and / or reactive to smoke, in particular tobacco smoke, by means of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes. Tobacco smoke promotes the adhesion of human circulating cells to other cells or molecules of the extracellular matrix. The method according to the invention is therefore particularly suitable for the treatment of skin conditions originating from tobacco smoke.

Preferably, according to the invention the substances antagonizing the adhesion effect contain an active principle composed of pyrrolidone-2 arginine carboxylate, in particular pyrrolidone-2 carboxylate L-arginine.

Composition The invention also relates to a dermatological and / or cosmetic composition for implementing a method for treating sensitive and / or reactive skin. The composition contains an active ingredient composed of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes. The invention relates more particularly to a dermatological and / or cosmetic composition for the implementation of a process for the treatment of skin sensitive and / or reactive to smoke, in particular tobacco smoke. The composition contains an active principle composed of substances antagonizing an adhesion effect, induced by said fumes, of circulating human cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

Preferably, the composition according to the invention is such that the substances antagonizing said adhesion effect are compounds of pyrrolidone-2 arginine carboxylate, in particular pyrrolidone-2 carboxylate L-arginine. Preferably, the concentration of pyrrolidone-2 arginine carboxylate varies from 0.001 to 10%.

Preferably, the concentration of pyrrolidone-2 arginine carboxylate varies from 0.01 to 5%.

The cosmetic and / or dermatological composition is in solid, liquid or carbonated form. According to an alternative embodiment, the cosmetic and / or dermatological composition is in solid form and more particularly in the form of oily or non-oily ointments, creams, gels, powders or solid emulsions. According to an alternative embodiment, the cosmetic and / or dermatological composition is in liquid form and more particularly in the form of milks, solutions, suspensions, lotions, water in oil emulsions, oil emulsions in water or microemulsions. According to an alternative embodiment, the cosmetic and / or dermatological composition is in carbonated form and more particularly in the form of aerosols distributed using a propellant gas or using pressurized air. Among the propellants, mention may be made of chlorinated and / or fluorinated hydrocarbons, nitrous oxide, carbon dioxide or nitrogen. According to an alternative embodiment, the cosmetic and / or dermatological composition is in the form of tablets or capsules. It is thus possible to administer the composition orally and to use it in oral cosmetics or in nutraceuticals.

Preferably, the cosmetic and / or dermatological composition according to the invention is such that the substances antagonizing said adhesion effect, in particular composed of arginine 2-pyrrolidone-carboxylate, are associated with one or more additional active agents chosen from the agents antibacterials, antiparasitics, antifungals, antipruritics, anti-free radicals, local anesthetics, antivirals, anti-dandruff agents, anti-acne agents, antiseborrhoeic agents, healing agents and vitamin agents (vitamins A, E , B _l5 B ₂ , B ₆ , PP,

B ₁₂ ), anti-irritant, anti-redness, vasculoprotective, anti-metalloproteinase agents.

Preferably, the cosmetic and / or dermatological composition according to the invention comprises an agent regulating the PH. The pH of the composition according to the invention is adjusted in a zone extending from 5.5 to 9, and preferably in the pH zone compatible with the pH of the skin ranging from 6 to 8. The regulating agent is for example a buffering agent such as an alkali metal phosphate or a mixture of mono and dialkaline phosphate, or an alkali metal acetate-acetic acid mixture. The new topical compositions, based on arginine salt, are intended to be applied to the skin, the mucous membranes or the integuments, in particular the eyes and the nose in the event of inflammation.

The new topical compositions, the active principle of which is an arginine pyrrolidone carboxylate, are used in dermato-cosmetology, in an excipient, diluent or vehicle suitable for topical application.

The following examples illustrate the invention without, however, limiting it. EXAMPLE I Pharmacological study of the compositions according to the invention

Arginine pyrrolidone carboxylate is used in solution. The solution and the solvent are diluted in the culture medium; at D ₀ is added to each of the wells of a 24-well plate containing a monolayer of human keratinocytes at confluence, 50 μl of test substance (10 × concentrated) at different concentrations, in the presence of LPS at a rate of 3 μg / ml. Dextran sulfate (1 μM) is used as a reference inhibitor. Each experimental point is performed in duplicate. The total volume of the test is 500 μl. The cells are then placed in an incubator at 37 ° C under 5% CO 2 for 24 hours. On day D _j, neutrophils are isolated from blood from volunteer donors according to the usual techniques, and then adjusted to the concentration of 20 x 10 ⁶ cell per ml. The cells are then labeled with a fluorescent reagent (Calcein) for 30 minutes at 37 ° C. and then washed. Five hundred thousand cells are harvested in each test. The non-adherent neutrophils are then removed by washing and suction. Two ml of distilled water are added to each of the wells, then each plate is subjected to two freezing / thawing operations, in order to lyse the cells. The contents of each well are centrifuged. The fluorescence of each supernatant liquid is measured (excitation at 494 nm, emission at 517 nm). The number of adhered neutrophils is calculated by relating the value of fluorescence to the overall fluorescence of 500,000 neutrophils labeled and lysed under the same conditions. The advantage of inhibiting adhesion molecules, with the aim of reducing tissue damage linked to inflammation, has been highlighted by the use in animal models of monoclonal antibodies directed against vascular adhesion molecules (ICAM-1, E-selectin ...) and leukocyte integrins (LFA-1, Mac-1 -.). Active ingredients, for which an anti-adhesive action on neutrophils can be demonstrated, can claim soothing, anti-irritant, anti-inflammatory and anti-aging effects on the skin. EXAMPLE II eye drops

- Arginine pyrrolidone carboxylate 2% - Dextran sulfate 1%

- Preservative 0.01%

- Distilled water, qs 100% EXAMPLE III

Softening emulsion for sensitive skin - Arginine pyrrolidone 2%

- Cosmetic emulsion for sensitive skin

(fatty alcohols, polyoxyethylenated fatty alcohols, mineral oil, isopropyl palmitate, glycerin, gelling agent, perfumes, water) qs 100%

- Preservative agent (Germaben II) 0.07% EXAMPLE Pv ⁷

Protective day cream

- Arginine pyrrolidone carboxylate 4g

- Self-emulsifying polyethylene glycol stearate 4g

- Cetyl alcohol lg - Stearyl alcohol lg

- Vaseline oil 8g

- Dimethicone 0.5g

- 4g stearic acid

- Paulity ascorbate 0.2g - Perfume

- Demineralized water qs 100ml EXAMPLE V

Arginine pyrrolidone carboxylate cream - Lanette 16 (cetyl alcohol) 2%

- Incroquat Behenyl TMC (mixture of behenyltrimonium chloride and cetearyl alcohol) 2%

- Lecinol S- 10 (hydrogenated lecithin) 0.30%

- Amphisol K (potassium cetyl phosphate) 1% - Transcutol (ethoxydiglycol) 0.15%

- Stearyl glycyrrhetinate

- Cetiol OE (dicaprylic ether)

- Cosmacol ELI (C ₁₂ -C ₁₃ alkyl lactate)

- DC - 1403 fluid (mixture of dimethiconol and dimethicone) 0.75% - Salcare SC96 (mixture of propylene glycol dicaprate, polyquaternium-37 and PPG-1 Trideceth-6) 2%

- Photoprotective complex 5%

- Propylene glycol 2%

- Arlatone 2121 (mixture of sorbitan stearate and Sucrose cocoate) 4%

- Germaben II 0.70%

- Perfume 0.05%

- Arginine pyrrolidone carboxylate 2.5%

- Water qs 100% EXAMPLE VI

It has been demonstrated that the tobacco rush (tar, nicotine) attacks the skin by promoting the adhesion of skin cells (keratinocytes) to circulating cells, either directly or indirectly by causing the release of neuromediators by the sensitive nerves skin. To this end, a co-culture of keratinocytes was carried out with mouse neurons. Tobacco fumes have been found to stimulate neurons and promote the adhesion of skin cells (keratinocytes) to circulating cells via the release of neuromediators. Consequently, the antagonizing effects of substances according to the invention have a beneficial action on the damage of the fumes. Description of the experimental protocols

A. Adhesion of human keratinocytes to human neutrophils induced by tobacco smoke Human keratinocytes are cultured to confluence. This culture is exposed to cigarette smoke for 15 min, at 37 ° C. then the neutrophils isolated from human blood marked with calcein are added to the keratinocytes. Non-adherent neutrophils are removed by washing and vacuuming. Two ml of distilled water are added to each of the wells then the cells are lysed; the number of adhered neutrophils is calculated by relating the value of fluorescence to the overall fluorescence of 500,000 neutrophils labeled and lysed under the same conditions.

B. Adhesion of a neuron-keratinocyte coculture to human neutrophils induced by tobacco smoke Sensitive neurons are isolated from spinal ganglia taken from rat embryos and then cultured in the presence of human keratinocytes, this coculture is exposed cigarette smoke which stimulates the release of neuropeptides (substance P ...) in culture supernatants. The coculture previously exposed to the tobacco branches is put in the presence of human neutrophils labeled with calcein. The calculation of the number of adherent neutrophils is carried out as above.

Claims

claims

1. Method for treating sensitive and / or reactive skin by means of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix , especially with human keratinocytes.

2. Process for the treatment of skins sensitive and / or reactive to smoke, in particular tobacco smoke, by means of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes, (so that the action of said tobacco smoke, promoting the adhesion effect, is inhibited by said substances).

3. Method according to any one of claims 1 or 2; said method being such that said substances antagonizing said adhesion effect contain an active principle composed of pyrrolidone-2 arginine carboxylate, in particular pyrrolidone-2 carboxylate L-arginine.

4. Dermatological and / or cosmetic composition for implementing a process for treating sensitive and / or reactive skin; said composition containing an active principle composed of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

5. Dermatological and / or cosmetic composition for the implementation of a process for the treatment of sensitive and / or reactive skins with ramines, in particular tobacco smoke; said composition containing a principle active compound of substances antagonizing an adhesion effect, induced by said fumes, of circulating human cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

6. Composition according to any one of claims 4 or 5; said composition being such that said substances antagonizing said adhesion effect are compounds of pyrrolidone-2 arginine carboxylate, in particular pyrrolidone-2 carboxylate L-arginine.

7. Composition according to Claim 6, in which the concentration of pyrrolidone-2 arginine carboxylate varies from 0.001 to 10%.

8. Composition according to claim 7 in which the concentration of pyrrolidone-2 arginine carboxylate varies from 0.01 to 5%.

9. Cosmetic and / or dermatological composition according to any one of claims 4 to 8 in solid, liquid or carbonated form.

10. Cosmetic and / or dermatological composition according to any one of claims 4 to 9; said composition being in solid form and more particularly in the form of oily or non-oily ointments, creams, gels, powders or solid emulsions.

11. Cosmetic and / or dermatological composition according to any one of claims 4 to 9; said composition being in liquid form and more particularly in the form of milks, solutions, suspensions, lotions, water in oil emulsions, oil in water emulsions or microemulsions.

12. Cosmetic and / or dermatological composition according to any one of claims 4 to 9; said composition being in carbonated form and more particularly in the form of aerosols distributed using a propellant gas.

13. Cosmetic and / or dermatological composition according to any one of claims 4 to 9; said composition being in the form of capsules or tablets.

14. Cosmetic and / or dermatological composition, according to one of claims 4 to 13, in which is combined with the substances antagonizing said adhesion effect, in particular composed of pyrrolidone-2 arginine carboxylate, one or more additional active agents chosen. among antibacterial agents, antiparasitics, antifungals, antipruritics, anti-free radicals, local anesthetics, antivirals, anti-dandruff agents, anti-acne agents, antiseborrhoeic agents, healing agents and vitamin agents, anti-irritant, anti-redness, vasculoprotective, anti-metalloproteinase agents.

15. Cosmetic and / or dermatological composition, according to one of claims 4 to 14, comprising an agent regulating the PH.