FR2913602A1 - Composition, useful e.g. for care of skin damaged by aesthetic treatment, cosmetic/therapeutic such as surgical interventions, laser treatment, dermabrasions and peelings, comprises peptide associated with oil having alpha-linolenic acid - Google Patents

Abstract

Cosmetic, dermatological or pharmaceutical composition for care of skin damaged by aesthetic treatment, cosmetic or therapeutic such as surgical interventions, laser treatment, dermabrasions and peelings, comprises at least peptide (I), associated with an oil having an alpha -linolenic acid content of greater than 15% and a ratio of omega-6 acid to omega-3 acid is = 5, in a medium. Cosmetic, dermatological or pharmaceutical composition for care of attacked skin by aesthetic treatment, cosmetic or therapeutic such as surgical interventions, laser treatment, dermabrasions and peelings, comprises at least peptide of formula (A-X-Gly-His-Lys-Y1) (I), associated with an oil having an alpha -linolenic acid content of greater than 15% and a ratio of omega-6 acid to omega-3 acid is = 5, in a medium. A : hydrogen (preferred) or radical corresponding to mono-carboxylic acid of formula (R-COOH); R : 1-11C aliphatic radical; X : a bond, lysine, arginine or ornithine; and Y1 : -OH (preferred) or NH 2group.

Description

The subject of the present invention is new cosmetic compositions,

  dermatological or pharmaceutical products having a soothing and restructuring effect of the dermis to fight against the associated aggressions, and more particularly against scars, to an intervention of cosmetic surgery or to a skin treatment by apparatus such as lasers.

  To effectively combat the consequences of these interventions, the associated assets exhibit a remarkable synergy combining an immediate soothing effect with an accelerated restructuring action.

  Women currently tend to want to look younger for as long as possible and seek to fade the marks of aging skin which results in a loosening of the skin tissue and the appearance of fine lines and wrinkles. The effects of aging are generally treated with cosmetic products containing active agents acting on the skin.

  In recent years, there has been a real enthusiasm for aesthetic interventionist actions performed by professionals, such as reconstructive surgery of the face, neck, body, scalp and the use of various devices such as as lasers, flash lamps that can treat many skin lesions (vascular spots, pigment spots) or fight against aging and wrinkles. The women who apply these techniques have experienced the first effects of aging such as fragility and decreased flexibility of the skin, appearance of fine lines and wrinkles.

  These phenomena are due essentially to profound modifications characterized by alterations of the Extracellular Matrix (ECM).

  The epidermis and the dermis separated by the basement membrane constitute the skin lining 35 which rests on the hypodermis. The epidermis is the most superficial layer of the skin and ensures its resistance and impermeability.

  The dermis, the inner layer of skin, connective tissue is composed of 40 cells (mainly fibroblasts) dispersed in a complex medium called Extracellular Matrix (ECM).

  This matrix consists of collagen and elastin fibers, glycoproteins (fibronectin and laminin) proteoglycans. The extracellular matrix is a framework for cells that allows the cohesion of tissues and organs in multicellular organisms.

  The dermis is the seat of profound changes during skin aging, the 50 most significant changes of the Extracellular Matrix (ECM) occur in the dermis. Fragmentation of the collagen fibers, alterations of the elastic material represent certain characteristics of the aging dermis.

  The main component of ECM is collagen, the major protein component of the dermis consisting of 2 subunits: collagen I (80% in adults) and collagen III. Together they constitute the fibrillar system which ensures the resistance of the skin.

  Fibronectin and laminin are structural glycoproteins located at the level of the epidermal junction; Fibronectin as an essential constituent of the temporary Matrix during skin repair is particularly important in the healing process.

  The alterations of the mechanical qualities of the aged skin are the consequence of the atrophy of the structural network of the ECM of the dermis and the prevention of skin aging goes through the maintenance of the integrity of this matrix.

  The consequences of these interventionist acts (reconstructive surgery, laser treatment, ...) are the appearance of inflammatory phenomena and the formation of scarring lesions.

  The Applicant has found that the deleterious effects of inflammation and scarring can be remedied on the one hand, and the repair and restructuring of the ECM on the other hand by combining:

  A family of biomimetic peptides of a growth factor of which one of the 25 compounds is marketed under the trademark Kollaren and is manufactured by the European Institute of Cell Biology

  • With oils having an alpha-linolenic acid content greater than 15% and an Omega-6 acid to Omega-3 ratio of less than or equal to 5. (I) The active peptides correspond to the general formula: AX-GIy- In which A may represent a hydrogen or a radical corresponding to a monocarboxylic acid of general formula R-COOH in which R represents a C 1 -C 11 aliphatic radical in which X may represent a bond; or lysine, arginine, ornithine, Y is -OH or NH 2. In the context of the present invention, the expression: Gly, glycine, Lys, lysine, His, histidine. Among the peptide compounds, mention may be made of the following peptides: • H-Gly-His-Lys-OH • H-Gly-His-Lys-NH2 50 • Ac-Lys-Gly-His-Lys-OH • Ac-Lys- Gly-His-Lys-NH2 These peptides have been described in patents FR 2 741 075 and FR 2 857 597 filed by the European Institute of Cell Biology.

  This family of peptides has the power to mimic the natural signal of skin renewal and the ability to reactivate the synthesis of extracellular matrix proteins, such as collagens, fibronectin, laminins, elastin.

  Among the oils corresponding to the preceding definition (I), mention may be made of linseed oil, hemp oil, camelina oil, walnut oil and normal rapeseed oil. It is known that lipids are essential components of our body.

  They play an important role at the cutaneous level, from a structural point of view cutaneous barrier function, from a mechanical point of view membrane flexibility and from a biological point of view involvement in inflammatory phenomena.

  Some of these lipids are not synthesized by our body, although essential, such as essential fatty acids. Their absorption triggers, with the aid of several enzymes, a cascade of chemical reactions.

  In the omega-3 PUFA family, only alpha-linolenic acid (ALA) is essential because the body can not make it.

  It is the precursor of: Eicosapentaenoic Acid (EPA) which itself can be converted into eicosanoids of series-3 which have anti-inflammatory effects. This EPA acid plays a regulatory role in inflammatory processes.

  Docosahexaenoic Acid (DHA) which is capable of stimulating the expression of glutathione peroxidase, hence an antioxidant protection.

  Many studies have shown that supplementation with omega-3 DHA and EPA acids has an effect on the skin. These very promising effects on the skin, obtained after food supplementation, led the cosmetics to look at the topical use of EPA and DHA acids.

  Their uses have been limited by their organoleptic characteristics related to their origin. The main source of these PUFAs is fish oils rich in EPAJDHA.

  However, these oils have many reasons for contestation that do not allow their use topically:

  Quality of the Raw Material, Reproducibility of this Raw Material, Stability of the technical characteristics, particularly the smell, 50 Extraction methods (deodorization). The Applicant has just discovered that alpha-linolenic acid can be biotransformed by skin cells such as keratinocytes to produce the two omega-3 PUFAs that are EPAIDHA.

  This phenomenon of metabolism of alpha-linolenic acid in EPA and DHA generally known had never been demonstrated topically.

  This biotransformation to generate EPAIDHA by skin cells plays an important role in inflammatory processes. It solves the problems related to the direct use of EPAIDHA acids constituting fish oils.

  For this effect to be effective, it is necessary to use oils such as those defined above and containing large amounts of alpha-linolenic acid.

  However, the Applicant has found that it achieves the most effective efficiency by combining the tripeptide-1, (INCI name), marketed under the trademark Kollaren manufactured by the European Institute of Cell Biology and Oil 20 Cameline marketed by the company PHYTOCOS.

  The combination of these 2 active agents makes it possible to effectively treat all types of skin attacked mechanically, especially the most affected area such as scars.

  Camelina oil, the richest oil in alpha-linolenic acid (40%) is very quickly absorbed by the skin and acts in the very short term. It ensures rapidly are action on the inflammatory process, following the bioconversion of alpha-linolenic acid into EPA / DHA.

  In addition, it has an action on the cutaneous barrier which it promotes the reconstitution.

  The tripeptide-1 (INCI), which mimics the natural signal of skin renewal, is an asset of choice for the repair and reconstruction of the ECM, by acting on different components of its structure.

  Its promoting action on the synthesis of collagen I and II, fibronectin, laminin and elastin has been demonstrated in vitro.

  Its action contributes to the restoration of the biomechanical properties of the skin, such as firmness, elasticity and promotes healing. The combination of these two assets makes it possible to obtain a real prolonged action of appeasement and repair.

  It is also possible to obtain a complementary regenerative action by combining 45 with the Kollaren-camelina oil combination, another peptide called Thymulen manufactured by the European Institute of Cell Biology able to fight the deficiencies of the skin defense mechanisms .

  Acetyl tetrapeptide-2 has an important cellular regeneration power accompanied by an ability to stimulate the skin's natural immune defenses. The present invention also relates to a cosmetic, dermatological or pharmaceutical composition comprising the combination of peptide-tripeptide -1- (Kollaren) and camelina oil.

  In the topical cosmetic composition, the tripeptide-1 may be present at a concentration of between 10-8M and 10-2M, preferably between 10-4M and 10-6M.

  The camelina oil may be present at a concentration of between 1% and 20%, preferably between 5% and 10%. The present invention also relates to cosmetic compositions for the soothing and regeneration of the dermis comprising tripeptide-1 and camelina oil.

  It has been demonstrated that the combinations described provided rapid attenuation of aggression-related inflammation, facilitated control of tissue repair, and increased the speed of repair of the dermis.

  If the composition of the invention is essentially intended to promote healing and to treat skin attacked by cosmetic or therapeutic skin treatments such as surgical procedures of the skin, laser skin treatments, dermabrasion or peels, it is also intended for the curative and preventive treatment of skin aging.

  The cosmetic, dermatological or pharmaceutical composition may be in the forms which are usually known for this type of administration, that is to say in particular lotions, foams, gels, dispersions, sprays, serums , masks, body milks, ointments, solutions, emulsions, gels, or creams for example, with excipients allowing skin penetration to improve the properties and accessibility of the active ingredient These compositions contain Generally, in addition to the tetrapeptide conjugate according to the present invention, a physiologically acceptable medium, generally based on water or solvent, for example alcohols, ethers or glycols. They may also contain surfactants, preservatives, stabilizing agents, emulsifiers, thickeners, other active ingredients leading to a complementary or possibly synergistic effect, trace elements, essential oils, perfumes, dyes , collagen, chemical or mineral filters, moisturizers, vegetable waters, or thermal waters.

  The present invention is illustrated in the following examples which are not limiting.

  Example 1 Study of tripeptide-1 on the production of ECM proteins by fibroblasts by immunofluorescence.

  ^ Material: fibroblasts of human lineage.

  Protocol: Fibroblasts are cultured in the presence or absence of tripeptide-1 at 10-7M.

  Microscopic study by confocal microscopy. 40 45 - Results: AUGMENTATION% - Type I collagen + 305% - Type II collagen + 105% - Fibronectin + 155% - Laminin + 85% - Elastin + 15% Example 2 Study of the biotransformation of alpha-alpha acid linolenic by the keratinocytes of the skin. Material: keratinocytes of NCTC lineage.

  Protocol: the keratinocytes are brought into contact with the camelina oil for 30 minutes, at a temperature of 37 ° C.

  After incubation, the oil is removed, the cells are rinsed and put back in contact with the culture medium. - Assays take place 3H55H224H (J1), 48H (J2), 72H (J3) on the culture medium (supernatant) and inside the cells after lysis.

  HPLC assay of alpha-linolenic acid and EPA and DHA acids. Results: a) In the supernatant, no trace of alpha-linolenic acid is found 3H. Appearance of EPA and DHA acids after 3 hours of incubation.

  b) The HPLC assay revealed in keratinocyte cells significant amounts of alpha-linolenic acid after 3H incubation and the appearance of EPA acid on D2. Example 3 Study of the biotransformation of alpha-linolenic acid by fibroblasts Material: Fibroblasts of line MRC5.

  Protocol: Same as that described for Example 2.

  HPLC determination of alpha-linolenic acid and EPA and DHA acids. 6 10> Results:

  In the supernatant, alpha-linolenic acid is detected in a smaller amount than the starting amount.

  Appearance of the EPA and DHA acids after 3 hours of incubation, in the supernatant medium.

  EXAMPLE 4 Evaluation of the healing effect of a formulation containing the tripeptide-1 complex and Camelina oil in a skin model maintained in survival.

  In order to evaluate the healing effect, a model of alteration of the skin's repairing abilities was achieved by applying a deiodocorticoid to the surface of the epidermis in order to quantify the stimulation of cell renewal.

  Stimulation of cell turnover was studied by quantification of the mitotic potential of basal cells.

  Material: Fragments of skin of several different donors.

  Protocol: The skin fragments are kept alive for 4 days with the application of a class II dermocorticoid to OJ and JI. The formulation was applied daily from D1 to D4. Result: Immunohistochemical analysis of cell proliferation. 0/0 Control skin 12 6.2 Skin + dermocorticoid (control skin) 7.5 2.5 NS: p = 0.075 Skin + dermocorticoid + Formula containing 11.7 3.2 the complex ~ p = 0.02 #: difference statistically significant compared with the dermocorticoid alteration model (Student paired test, p <0.05).

  The healing effect was demonstrated by obtaining a statistically significant restoration of the mitotic index of the epithelium after experimental alteration of the skin. EXAMPLE 5 Evaluation of the Moisturizing and Restructuring Effect of a Formulation Containing the Tripeptide-1 Complex and Camelina Oil in a Skin Model Maintained in Survival

  40 The moisturizing and restructuring effect was analyzed after performing a model of skin barrier alteration by sodium lauryl sulphate (LSS) responsible for an insensible loss of water accompanied by alteration of the expression of the skin. involucrin.

  Evaluation of the expression of involucrine will make it possible to quantify the protection provided by the formulation at the level of the stratum corneum and the stimulation of its metabolism at the level of the keratinocytes of the skin. 7 25 35

  ^ Material: Fragments of skin of several different donors.

  Protocol: The skin fragments are kept alive for 4 days with 2 topical applications of 1% LSS at OJ and J1. The formulation was applied daily from D1 to D4.

  Immunohistochemical evaluation of involucrine expression. Score Intensity Score Topography Skin control 2,4 + 0,8 2 + 0,8 Skin + LSS (skin control) 1,4 + 1,2 1,7 + 1,5 * p = 0,04 Skin + LSS + formula 3.09 1 containing the complex ~ p = 0.003 *: statistically significant difference with respect to the control skin (Student paired test, p = <0.05). #: statistically significant difference from LSS-altered skin (Student's paired test, p <0.005).

  The moisturizing and restructuring effect was visualized and quantified after the LSS cutaneous barrier alteration model was carried out, by demonstrating an increase in involucrine at the level of the epidermis.

  The increase of this expression testifies to the protection provided by the complex, but also to the stimulation of the metabolism of the cells of the upper part of the epithelium.

  Example 6 Evaluation of the soothing effect of a formulation containing the tripeptide-1 complex and Camelina oil in a skin model maintained in survival.

  The soothing effect was analyzed after completion on the skin of an experimental burn model (application of an agarose gel at 80 ° C.).

  The soothing activity was studied by analyzing the limitation of both the destruction of the epidermis (corresponding to the extension of the burn) and the vascular dilatation. Material: Fragments of skin from several different donors.

  Protocol: The skin fragments are kept alive for 4 days.

  The experimental model of alteration is obtained by burning after application of an agarose gel at 85 ° C on D0. The formulation was applied daily until D4.

  Results: 1) Histological analysis of cellular alterations in the epidermis (% of damaged cells)% Skin + burn (control skin) 24.1 25.1 Skin + burn + formula containing complex 15.8 11.6 2) Histological analysis of dilatation of vessels (area of dilated vessels in m2) m2 Skin Control 171.6 38.9 Skin + burn (control skin) 270.8 56.9 * p = 0.00005 Skin + burn + formula comprising 197.8 78.1 complex # p = 0.003 *: statistically significant difference from control skin (Student paired test, p <0.05). : statistically significant difference from skin control impaired by burning (Student paired test, p <0.05). 3) Histological analysis of dilatation of the vessels (% dilated vessels) 0/0 Skin Control 87.6 8.85 Skin + burn (control skin) 99.3 + 1.2 * p = 0.0004 Skin + burn + formulation containing 91,25 + 8.2 complex ≠ p = 0.02 *: statistically significant difference compared to the control skin (Student's paired test, p <0.05): statistically significant difference compared to control skin impaired by burning (Student paired test, p <0.05)

  4) Histological analysis of the edema (score) Score Skin Control 1.73 0.34 Skin + burn (control skin) 2.26 0.64 * p = 0.036 Skin + burn + Universkin Gel Cream 1.88 + 0, 78 *: statistically significant difference from control skin (Student paired test, p <0.05). The soothing effect was significantly quantified after skin-imaging of an experimental burn model by demonstrating the limitation of the dilation of the capillaries of the skin.

  The limitation of the destruction of the epidermis (corresponding to the extension of the burn) was observed more moderately and not significantly.

Example 7: Oily emulsion OIL PHASE% BY WEIGHT - Montanov 68 5% - Camelina oil 5% - Vaseline oil 3% - Isopropyl palmitate 7% AQUEOUS PHASE - Glycerin 5% - Sepigel 305 0.3% - Preservative 0 , 5% -Tripeptide-1 10 ppm - Water qs 100% Example 8 CREAM GEL% A - Dow Corning 9040 6% - Camelina oil 2% - Regu -Seb 3% Sepigel 305 3% B - Water 82% -Glycerin 4 % - Tripeptide-1 5 ppm 11

Claims (10)

  1) Cosmetic, dermatological or pharmaceutical composition for the care of skin attacked by cosmetic, cosmetic or therapeutic treatments such as surgical procedures, laser treatments, dermabrasion, peels, comprising in a physiologically acceptable medium at least: a) A peptide corresponding to the general formula AX-Gly-His-Lys-Y (II) - in which A may represent a hydrogen or a radical corresponding to a monocarboxylic acid of general formula R-COOH in which R represents a C 1 -C 11 aliphatic radical - in which X may be a bond or lysine, arginine, ornithine, Y is OH or NH 2. associated with (b) An oil having an α-linolenic acid content greater than 15% and an omega-6 acid to omega-3 ratio of less than or equal to 5 (I)   2) Cosmetic, dermatological or pharmaceutical composition for skin care attacked by cosmetic, dermatological or therapeutic treatments such as surgical procedures, laser treatments, dermabrasion, peels, comprising in a physiologically acceptable medium at least. 1) The peptide of formula H-Gly-His-Lys-OH associated with 2) Camelina oil.   3) Compositions according to claims 1) and 2) characterized in that they contain from 10 "8M to 10-2M by weight of peptide of the general formula (II) and from 1% to 20% of an oil as defined in claim 1).   4) Compositions according to claims 1) and 2) characterized in that they contain 10-4M to 10-6M by weight of peptide of formula H-Gly-His-Lys-OH and 5% to 10% of 35 camel oil.   5) Use of a peptide corresponding to the general formula (II) associated with an oil corresponding to the general definition (I) for the preparation of a cosmetic, dermatological or pharmaceutical composition intended for cutaneous tissue repair.   6) Use of the peptide of formula H-Gly-His-Lys-OH associated with camelina oil for the preparation of a cosmetic, dermatological or pharmaceutical composition intended for skin tissue repair. 45   7) Use of the peptide of formula H-Gly-His-Lys-OH associated with camelina oil for the preparation of a cosmetic, dermatological or pharmaceutical composition intended to soothe weakened skin by surgical treatments, laser treatments , peelings. 50   8) Use of the peptide of formula H-Gly-His-Lys-OH associated with camelina oil for the preparation of a cosmetic, dermatological or pharmaceutical composition intended to promote the healing of weakened skin by surgical treatments, treatments by laser, peels. 40   9) Use of the peptide of formula H-Gly-His-Lys-OH associated with camelina oil for the preparation of a cosmetic, dermatological or pharmaceutical composition intended to promote the restructuring and regeneration of the skin weakened by treatments surgical, laser treatments, peels.   10) Cosmetic treatment method in that a cosmetic composition comprising at least one peptide associated with an oil according to any one of Claims 1 to 4 is applied to the skin.