FR2815866A1 - METHOD AND DERMATOLOGICAL AND / OR COSMETIC COMPOSITION ANTAGONIZING THE ADHESION EFFECT OF CIRCULATING CELLS - Google Patents

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

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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.

les muqueuses ou les téguments. 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 posed: 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 effect of adhesion of circulating human cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes, During skin inflammation, many polynuclear cells migrate in the dermis and epidermis. 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.

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 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 repiderm: adhesion to endothelial cells, chemotaxis, adhesion to the 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.

Sa formule brute est CI, H2l N5 05. Son poids moléculaire est de 303, 3. Une revue sur ce produit a été publiée en particulier par Zanotti, Prodotto chimico, mars 1982 p. 25-28. The particular solution: arginine pyrrolidone carboxylate Arginine pyrrolidon carboxylate or arginine pidolate is a compound known for a long time and marketed under the name Argidone by the company UCB. It is a creamy white powder very soluble in water.

Its crude formula is CI, H2l N5 05. 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 pyrrolidon carboxylate is meant any salt formed by neutralization of pyrrolidone 2-carboxylic acid (or pyroglutamic acid) by arginine.

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L'arginine peut exister sous forme L (forme nature), sous forme D ou sous sonne DL (arginin synthétique).

Arginine can exist in L form (natural form), D form or DL ringing (synthetic arginin).

L'acide pyrrolidone carboxylique présente un carbone asymétrique et comme tel peut être dédoublé en sa forme lévogyre ou dextrogyre, ou exister sous forme de racémate. Arginine pytrolidone-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.

- émollient pour la peau et les cheveux (Ajinomoto KK-Shiseido KK), brevet japonais 56/071020 ; - applications cosmétiques (Shisheido KK), brevet japonais JP A-61/30509 ; - système antioxydant (L'Oréal), brevet français 2.675. 695 ; c'est-à-dire qu'il renforce reffet antioxydant de substances polyphénoliques comme le tocophérol, le BHT et ses dérivés, et les esters ou amides de l'acide caféique pour stabiliser les acides gras ou les matières grasses employées dans les compositions cosmétiques. 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 to say that it reinforces the antioxidant effect of polyphenolic substances such as tocopherol, BHT and its derivatives, and the esters or amides of caffeic acid to stabilize the fatty acids or the fats used in cosmetic compositions .

French patent 2,778 has been described. 562 the use of arginine salts, in combination or not, with sea water to inhibit mast cell reactivation induced by neuropeptides, in particular the degranulation of skin mast cells induced by substance P. Arginine salts are inhibitors of substance P-induced histamine release

However, according to the invention, we have just found that arginine pidolate also plays an important role in antagonizing the adhesion of cells.

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 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 for treating skin sensitive and / or reactive to smoke, in particular tobacco smoke, by means of antagonizing substances which have an adhesion effect on human circulating cells, in particular neutrophils, lymphocytes, monocytes, eosinophils, to other cells or molecules of the extracellular matrix, especially 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 pyrrolidon-2 arginine carboxylate, in particular pyrrolidon-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 principle composed of substances antagonizing the adhesion effect of human circulating cells, in particular neutrophils, lymphocytes, monocytes,

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 eosinophils, to other cells or molecules of the extracellular matrix, in particular with human keratinocytes.

dermatologique et/ou cosmétique pour la mise en oavre d'un procédé de traitement de peaux sensibles et/ou réactives aux fumées, notamment aux fumées de tabac. La composition contient un principe actif composé de substances antagonisant un effet d'adhésion, induit par lesdites fumées, des cellules circulantes humaines, notamment les neutrophiles, les lymphocytes, les monocytes, les éosinophiles, aux autres cellules ou molécules de la matrice extracellulaire, notamment avec des kératinocytes humains. The invention relates more particularly to a composition

dermatological and / or cosmetic for the implementation of a process for treating sensitive skin 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 pyrrolidon-2 arginine carboxylate, in particular pyrrolidon-2 carboxylate L-arginine.

Preferably, the concentration of pyrrolidone-2 arginine carboxylate varies from 0.001 to 10%.

Preferably, the concentration of pyrrolidon-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, suspension, 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

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 in the form of aerosols distributed with the aid of a propellant gas or with the aid of pressurized air Panni the propellant gases, mention may be made of chlorinated and / or fluorinated hydrocarbons, nitrous oxide, carbon dioxide or l 'nitrogen.

According to an alternative embodiment, the cosmetic and / or dermatological composition is in the form of tablets or capsules.

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;, B, B6, PP, B12), 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 pyrrolidon carboxylate, are used, in dennato-cosmetology, in an excipient, a diluent or a vehicle suitable for topical application.

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Les exemples suivants illustrent l'invention sans toutefois la limiter.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE I Pharmacological study of the compositions according to the invention The arginine pyrrolidon carboxylate is used in solution. The solution and the solvent are diluted in the culture medium; on D0, a 24-well plate containing a monolayer of human keratinocytes at confluence, 50 u, is added to each well. l of test substance (10 x concentrates) at different concentrations, in the presence of LPS at a rate of 3 Jlglml. 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, neutrophils are isolated from the blood of voluntary donors according to the usual techniques, then adjusted to the concentration of 20 × 10 6 cells per ml. The cells are then labeled with a fluorescent reagent (Calcein) for 30 minutes at 37 ° C. and then washed.

distillée sont ajoutés dans chacun des puits, puis chaque plaque est soumise à deux opérations de congélation/décongélation, afin de lyser les cellules. Five hundred thousand cells are harvested in each test. The non-adherent neutrophils are then removed by washing and suction. Two ml of water

distilled 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 demonstrated by the use in animal models of monoclonal antibodies directed against adhesion molecules vascular (ICAM-1, E-selectin ...) and

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intégrines leucocytaires (LFA-1, Mac-1-.). Des actifs, pour lesquels une action anti-adhesive sur les neutrophiles peut être démontrée, peuvent revendiquer des effets apaisants, anti-untants, anti-bflmnnmtoires et anti- vieillissement sur la peau.

leukocyte integrins (LFA-1, Mac-1-.). Active ingredients, for which an anti-adhesive action on neutrophils can be demonstrated, can claim soothing, anti-tint, anti-inflammatory and anti-aging effects on the skin.

collyre - Pymolidonecarboxylate d'arginine 2% - Sulfatede dextranne 1% - Agentconservateur 0, 01% - Eau distillée, qsp 100% EXEMPLE m Emulsion adoucissante pour peaux sensibles - Pyrrolidone carboxylate d'arginine 2% - Emulsion cosmétique pour peaux sensibles (alcools gras, alcools gras polyoxyéthylénés, huile minérale, palmitate d'isopropyle, glycérine, gélifiant, parfums, eau) qsp 100% - Agent conservateur (Germaben II) 0,07% EXEMPLE IV Crème protectrice de jour - Pyrrolidonecarboxylate d'arginine 4g - Stéarate de polyéthylèneglycol auto-émulsionnable 4g

- Alcool cétylique 1g - Alcool stéarylique 1g - Huile de vaseline 8g - Dimefhicone 0,5g - Acide stéarique 4g - Ascorbate de palmityle 0,2g - Parfum - Eau déminéralisée qsp 100ml EXAMPLE it

eye drops - Arginine Pymolidonecarboxylate 2% - Dextran sulphate 1% - Preservative agent 0.01% - Distilled water, qs 100% EXAMPLE m Softening emulsion for sensitive skin - Arginine pyrrolidone carboxylate 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 IV Day protective cream - Arginine pyrrolidonecarboxylate 4g - Stearate self-emulsifying polyethylene glycol 4g

- Cetyl alcohol 1g - Stearyl alcohol 1g - Vaseline oil 8g - Dimefhicone 0.5g - Stearic acid 4g - Palmityl ascorbate 0.2g - Perfume - Demineralized water qs 100ml

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- Lecinol S- 10 (lecithine hydrogénée) 0, 30% - Amphisol K (Cetyl phosphate de potassium) 1% - Transcutol (ethoxydiglycol) 0,15% - Glycyrrhétinate de stéaryle - Cedol OE (éther dicaprylique) - Cosmacol ELI (lactate d'aile en Cj2-C ; 3) - DC - 1403 fluide (mélange de diméthiconol et de diméthicone) 0,75% - Salcare SC96 (mélange de dicaprate de propylène glycol, de polyquatemium-37 et de PPG-1 Trideceth-6) 2% - Complexe photoprotecteur 5% - Propylène glycol 2% - Arlatone 2121 (mélange de stéarate de sorbitane et de Cocoate de sucrose) 4% - Germabenn 0, 70% - Parfum 0, 05% - Pyrrolidone carboxylate d'arginine 2,5% - Eau qs 100% EXEMPLE VI Il a été mis en évidence que la fumée de tabac (goudron, nicotine) agresse la peau en favorisant l'adhésion des cellules de la peau (kératinocytes) aux cellules circulantes, soit directement soit indirectement en provoquant la

libération des neuromédiateurs par les nerfs sensitifs de la peau. A cet effet, on a procédé à une co-culture de kératinocytes avec des neurones de souris. Il a été constaté que les fumées de tabac provoquent la stimulation des EXAMPLE V Arginine carboxylate pyrrolidon base cream - Lanette 16 (cetyl alcohol) 2% - Incroquat Behenyl TMC (mixture of behenyl ammonium chloride and cetearyl alcohol) 2%

- Lecinol S- 10 (hydrogenated lecithin) 0.30% - Amphisol K (potassium cetyl phosphate) 1% - Transcutol (ethoxydiglycol) 0.15% - Stearyl glycyrrhetinate - Cedol OE (dicaprylic ether) - Cosmacol ELI (lactate d '' Cj2-C wing; 3) - DC - 1403 fluid (mixture of dimethiconol and dimethicone) 0.75% - Salcare SC96 (mixture of propylene glycol dicaprate, polyquatemium-37 and PPG-1 Trideceth-6) 2% - Photoprotective complex 5% - Propylene glycol 2% - Arlatone 2121 (mixture of sorbitan stearate and Sucrose cocoate) 4% - Germabenn 0, 70% - Fragrance 0, 05% - Arginine pyrrolidone 2,5 % - Water qs 100% EXAMPLE VI It has been demonstrated that tobacco smoke (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 of the skin. To this end, a co-culture of keratinocytes was carried out with mouse neurons. Tobacco fumes have been found to cause stimulation of

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 neurons and promotes, through the release of neuromediators, the adhesion of skin cells (keratinocytes) to circulating cells. 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. and then the neutrophils isolated from human blood labeled 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 to cigarette smoke which stimulates the release of neuropeptides (substance P ...) in the culture supernatants. The coculture previously exposed to tobacco smoke 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 (14)

Claims Process 1. Process for the cosmetic treatment of 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 molecules. the extracellular matrix, in particular with human keratinocytes. 2. Method of cosmetic treatment of 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, (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.  Composition 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 treating sensitive skin and / or reactive to smoke, <Desc / Clms Page number 12>  in particular tobacco smoke; said composition containing 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. 6. Composition according to any one of claims 4 or 5; said composition being such that said substances antagonizing said effect

 adhesion compounds are pyrrolidon-2 arginine carboxylate, in particular pynolidone-2 carboxylate L-arginine. 7. Composition according to claim 6 in which the concentration of pyrrolidon-2 arginine carboxylate varies from 0.001 to 10%. 8. Composition according to claim 7 in which the concentration of pyrrolidon-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 <Desc / Clms Page number 13>  of a propellant.

13. Cosmetic and / or dermatological composition, according to one of claims 4 to 12, in which is combined with the antagonizing substances said adhesion effect, in particular composed of pyrrolidon-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. 14. Cosmetic and / or dermatological composition, according to one of claims 4 to 13, comprising an agent regulating the PH.