FR3106057A1 - Cosmetic composition comprising extracts of Padina Pavonica to improve healing of the skin - Google Patents

Abstract

The present invention relates to the cosmetic use of extracts of Padina Pavonica for improving the healing of the skin, as well as a cosmetic composition for improving the healing of the skin comprising extracts of Padina Pavonica, and a method of cosmetic care for improving cicatrization comprising a step of applying to an area of the skin a composition according to the invention.

Description

Cosmetic composition comprising extracts of Padina Pavonica to improve healing of the skin

FIELD OF THE INVENTION

The present invention relates to the cosmetic use of extracts of Padina Pavonica for improving the healing of the skin, as well as a cosmetic composition for improving the healing of the skin comprising extracts of Padina Pavonica, and a cosmetic care method for improving the healing comprising a step of applying a composition according to the invention to an area of the skin.

STATE OF THE ART

Environmental factors are closely linked to increased inflammation and disease risk. However, inflammatory mechanisms depend on the type and intensity of stressors.

Inflammatory skin disorders affect more than 35 million Americans and are the most common problem in dermatology. It is estimated that about 15% of human cancers are linked to infection and chronic inflammation.

Skin inflammation can be characterized as acute or chronic. Acute inflammation can result from exposure to UV rays, ionizing radiation, allergens, or contact with chemical irritants (soaps, hair dyes, etc.) while chronic inflammation results from a sustained inflammatory response to cellular mediation at the level of the skin itself. This chronic inflammation can cause significant and serious tissue diseases like dermatitis, rosacea, seborrheic dermatitis and psoriasis.

In fact, inflammation is the response of the immune system to harmful stimuli, such as pathogens, damaged cells, toxic compounds or even irradiation (Medzhitov R. 2010 - Cell 140: 771-776). It works by eliminating harmful stimuli and initiating the healing process (Ferrero-Miliani L et al. 2007- Clin. Exp. Immunol. 147: 227-235). Therefore, inflammation is a vital defense mechanism for health.

In the skin, inflammation is characterized by redness, warmth, pain, swelling and loss of tissue function. Its response is the coordinated activation of signaling pathways to regulate levels of inflammatory mediators to maintain tissue homeostasis, repair damaged tissue, and heal the wound. Primary inflammatory stimuli, including cytokines, coordinate these cellular functions through a complex web of interactions. The NF-KB signaling pathway is activated and plays an important role in the inflammatory immune response, survival and apoptosis processes, and is also strongly suspected of accelerating skin aging (Adler A.S. et al. 2007 - Genes Dev 21: 3244-3257; Tilstra J.S. et al. 2011 - Aging Dis. 2: 449-465).

A number of studies suggest a link between stress and delayed wound healing with important implications in the context of surgery and natural wounds. Stress can affect healing progression through multiple immune and neuroendocrine pathways with important implications in the context of surgery and among chronically ill populations (Christian et al. 2006 - Neuroimmunomodulation 13(5-6): 337-346 .doi:10.1159/000104862).

Stress is also associated with slower or delayed wound healing in stressed older people, adults with leg injuries and surgical patients (Marucha P.T. et al. 1998 - Psychosom. Med. 60(3): 362-365; Ebrecht M. et al 2004 - Psychoneuroendocrinology 29: 798-809). Wound healing is severely affected by age-related effects, such as skin dryness, roughness, pigmentation alterations, wrinkles. More marked aging is associated with increased inflammation, delayed epithelialization and matrix breakdown.

It is therefore important to support the skin's ability to manage inflammation and heal wounds quickly and effectively in order to maintain good health, especially during aging skin.

There is therefore a continuing need to improve the healing of the skin.

Surprisingly, the Applicant demonstrated that extracts of Padina Pavonica had an effect on all stages of skin healing.

It is for this purpose proposed, according to a first aspect of the invention, the cosmetic use of extracts of Padina Pavonica to improve the healing of the skin.

Padina pavonica is a brown alga also called Peacock tail or padina, widely distributed in warm temperate zones to tropical zones in Europe, Atlantic Ocean, Adriatic Sea, Mediterranean Sea, South America and Central America, Asia (India, Taiwan, Japan , Indonesia), Australia and New Zealand. This algae consists of an erect thallus divided into whitish to brownish-brown fan-shaped fronds, and attached to the substrate by a rhizoidal holdfast. Concentric capillary bands 1-2 mm wide occur every 2.5-3 mm on both sides of the thallus but are more prominent on the dorsal side (Carter P.W. 1927 - An. Bot. 41: 139-159). Frond growth is initiated by an entire marginal row of meristematic cells in an involuting apical fold directed towards the inner surface of the thallus. The apical tip of the fronds is rolled up towards the ventral part of the thallus. It can reach up to 15 cm in length in summer. Padina's life cycle is isomorphic haplodiplontic. The thallus breaks off each winter and regrows in the spring. This algae is one of only two calcified brown algae known today, the second being Newhousia imbricata (Silberfeld T. et al. 2013 - J. Phycol. 49: 130-142; Johnson V.R. et al. 2012 - Global Change Biol. 18: 2792-2803).

This seaweed contains proteins, lipids, fatty acids, fibers, pigments (including chlorophyll c1, c2, fucoxanthin, fucoxanthol, flavoxanthin and diatoxanthin), terpenes, sterols (fucosterol would be the main sterol ), as well as polysaccharides, such as alginates, fucoidanes and cellulose. The yield of alginate extraction would reach 66.72% with 9.7% uronic acid only (Abid M.D. et al. 2019- Trends J. Sc. Res. 4 (2): 62-67.)

By extracts of Padina Pavonica are understood in particular extracts which comprise a certain number of potentially active species.

By extracts of Padina Pavonica are understood in particular aqueous extracts or ethanolic extract or acetonic extract of Padina. Preferably the extract is based on paraffin (for example marketed under the active name HPS3 from ALBAN MULLER located at 8, rue Charles Pathe-94300 Vincennes-France), vegetable oil of Simmondsia chinensis (for example marketed under the name Padinami from ALBAN MULLER) or glycerine (for example marketed under the name Protectami from ALBAN MULLER and Neurodermine from Matriscience). Preferably, the Padina Pavonica extract is Alban Muller's HPS3.

The exact content, concentration and amount of Padina Pavonica extract used may vary from application to application as described above, namely, the ability to achieve a statistically significant improvement in a measure described here compared to a witness.

A person skilled in the art can easily find in his general knowledge a process for obtaining such an extract of Padina Pavonica. It could, for example, be extracts from the whole thalli of Padina Pavonica under cold pressure for 4 hours followed by ultrafiltration to calibrate the extract, then after checking the specifications, filtration in a sterile room under a laminar flow hood.

Those skilled in the art may also refer to the process as described in patent document FR2743723, pages 3 and 4 of which are given below:

PREPARATION OF THE EXTRACT

The extract is prepared by drying the plant after harvest, if possible away from light, to keep its pharmacological properties intact (…). We proceeded to dry the crushed or raw plants, by ventilation without heating and we thus obtained a plant material of dark brown color on which the white streaks of calcium carbonate contrast sharply (…).

The ratio used is 1 gram of dry plant matter for 5 ml of solvent (…). The most convenient solvents to use are ethanol, hexane, cyclohexane, chloroform, dichloromethane, heptane, ethyl acetate, acetone. Most organic solvents are however suitable, alone or in combination. Moreover, although more difficult to implement, aqueous extraction in an ammoniacal medium gives satisfactory results. To produce the extract, it is not necessary to macerate the materials in the chosen solvent, it is possible to continuously pass the solvent over the powder (percolation). Simply adjust the flow rate and concentrate the extract to obtain a chosen activity solution.

The extracts obtained with organic solvents are often difficult to handle (evaporation, hydration, risk of deflagration, etc.), it is therefore desirable to fix them on one or more solid supports such as an absorbent organic polymer such as, for example, cellulose, minerals or absorbent mineral compositions or adsorbents (colloidal silica, etc.), more inert products such as paraffins, polyethylene glycols (PEG), propylene glycols, polyvinylpyrrolidone, etc. All low-oxygen inert supports may be suitable (…).

By way of example, the extract used in the present invention is obtained by maceration of 1 g of dry plant material in 5 ml of pure ethanol for 12 hours.

Skin wound healing is a complex series of reactions and interactions involving the re-epithelialization of cellular structures and missing tissue layers through four overlapping phases, namely hemostasis, inflammation, cell proliferation and remodeling. . The success of the last phase strongly depends on the previous phases. Chemokines are involved in all stages of wound healing, playing a key role in orchestrating this sequence through the regulation of angiogenesis and the recruitment of inflammatory cells that secrete cytokines and growth factors to promote wound healing. Chemokines are small chemotactic cytokines (8-12 kDa) divided into different groups depending on the location and number of cysteine residues at the N-terminus. An imbalance in the chemokinetic environment can alter the wound healing process and lead to prolonged healing or excessive scar formation. Many factors can interfere with one or more phases of this process, causing poor healing or impaired healing (Rees P.A. et al. 2015- Advound Wound Care 4 (11) -DOI: 10.1089/wound.2014.0568). In addition, dysregulated expression of cytokines in the skin can weaken the barrier function and thus worsen the inflammatory response (Kai H. et al. 2013 Int. J. Mol. Sci. 14, 6720-6745, doi:10.3390/ijms14046720 ).

Hemostasis is the first step in wound healing, during which a clot forms to prevent further blood loss. This involves the immediate activation of the coagulation cascade to allow the formation of a clot which occurs to prevent blood loss. This clot serves as a scaffold for arriving cells, for example neutrophils, monocytes and endothelial cells. The clot and surrounding wound tissues release pro-inflammatory cytokines and growth factors such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), fibroblast growth factor ( FGF) and epidermal growth factor (EGF). CXCL4 is the predominant chemokine released alongside CXCL1, CXCL4, CXCL5, CXCL5, CXCL7, CXCL8, CXCL12, CCL2, CCL3, and CCL5.

Once the bleeding is controlled, the inflammatory cells migrate into the wound (chemotaxis) and promote the inflammatory phase, characterized by the sequential infiltration of neutrophils, macrophages and lymphocytes. This inflammatory response serves to jump-start healing, as inflammation stabilizes the wound by removing contaminating debris and controlling microbial invasion, and then inflammation creates an environment conducive to tissue repair. This phase requires the recruitment of an influx of neutrophils for infection control and the accumulation of macrophages to initiate repair by a myriad of chemokines and inflammatory cytokines from the blood clot and injured cells at the edges of the wound. The main purpose of chemokines in this phase is to recruit these cells to remove dead cells, debris and foreign bodies from the wound and to promote the release of pro-angiogenic molecules to facilitate cell migration, proliferation and differentiation. . This inflammatory phase is mediated by the pro-angiogenic chemokines CXCL1, CXCL2, CXCL3, CXCL3, CXCL5, CXCL6, CXCL7 and CXCL8 and their receptors CXCR1 and CXCR2.

The third healing phase is the cell proliferation phase, characterized by an increased number of endothelial cells, keratinocytes, fibroblasts and macrophages. It is a key process. Macrophages begin to initiate tissue repair by producing enzymes such as hyaluronidase, elastase, and collagenase, which break down hyaluronic acid, elastin, and connective tissue collagen. In doing so, they prepare the extracellular matrix for tissue growth and synthesize and release multiple growth and regulatory factors essential for coordinating the formation of new tissue. This phase includes fibroplasia and angiogenesis. Fibroplasia is the process resulting from the deposition of ECM proteins including collagens, proteoglycans and fibronectin by fibroblasts. It depends on the success of angiogenesis, in which chemokines play a key regulatory role. CXCL10 and CXCL11 can play a crucial role in this phase, as well as CXCL8 which can reduce the number of fibroblasts by stimulating differentiation into myofibroblasts. Angiogenesis is vital for rebuilding wound microvasculature during the proliferative phase of healing to restore nutrient supply to regenerative tissues and prevent sustained tissue hypoxia. Regulation depends on a dual balance of angiogenic and angiostatic factors. The CXC subfamily has a major role in the regulation of angiogenesis, in particular CCL11 and CCL16 which have a direct positive effect and CXCR2 which mediates endothelial cell chemotaxis. CXCL16 acts as a mediator of the innate immune reactivities of epidermal keratinocytes. It regulates its own receptor, increases cell proliferation, stimulates cell migration in wound healing.

Once macrophages start producing these growth factors, the restorative part of healing really begins and the final stage of healing begins. Late healing is the remodeling stage in which fibroblasts reorganize the collagen matrix to promote scar formation and create a more stable seal. The extracellular matrix is broken down by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs), allowing regression of neovascularization and deposition of type I collagen. Matrix metalloproteinases (MMPs) play an important role in wound healing. Their activity is mainly regulated in vivo by endogenous tissue inhibitors of metalloproteinases (TIMPs). Loss of MMP regulation is a feature of chronic wounds and contributes to healing failure (Caley M.P. et al. 2015. Adv. Wound Care 4: 225-234). Re-epithelialization also involves the migration and proliferation of keratinocytes, followed by differentiation to regenerate the epidermis during wound closure. CXCL1 and CXCL8 are involved in keratinocyte migration through their interactions with CXCR2. The PLAUR gene is also involved in the migration of re-epithelializing keratinocytes (Rømer J. et al. 1994 - J. Invest. Dermatol. 102: 519-522).

Preferably, said extracts of Padina Pavonica are extracts from the thalli of Padina Pavonica.

According to a second aspect, the invention relates to a cosmetic composition for improving the healing of the skin comprising extracts of Padina Pavonica.

Preferably, said extracts of Padina Pavonica are extracts from the thalli of Padina Pavonica.

Preferably, said composition comprises from 0.01 to 10% by weight of the composition of Padina Pavonica extracts, preferably from 0.5 to 6%, even more preferably 3%.

Preferably, said composition also comprises at least one other cosmetically acceptable compound, preferably chosen from agents making it possible to improve the formation and/or maturation of the stratum corneum, agents promoting healing, soothing agents, restructuring agents , regenerating agents, revitalizing agents, sun filters, anti-wrinkle agents, moisturizing agents, anti-aging agents, surfactants, fatty substances, organic solvents, solubilizing agents, thickening and gelling agents, smoothing agents, agents reinforcing firmness, elasticity and/or the barrier effect of the skin, antioxidants, opacifiers, stabilizing agents, foaming agents, perfumes, ionic or non-ionic emulsifiers, fillers, sequestrants and chelators, perfumes, filters, essential oils, coloring materials, pigments, hydrophilic or lipophilic active agents, lipid vesicles encapsulating one or more active agents and/or preservatives.

The composition according to the invention may also contain the usual adjuvants in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers, filters , pigments, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the fields considered, and for example from 0.01 to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase, into the lipid vesicles and/or into the nanoparticles.

Preferably, said cosmetic composition comprises 1,3 propanediol.

Preferably, said cosmetic composition comprises between 0.1 and 10% by weight, preferably between 1 and 5%, more preferably between 2 and 4%, particularly preferably approximately 3% by weight, of a composition called "active" comprising between 15 and 50%, preferably between 30 and 40%, even more preferably about 32% by weight of extracts of Padina Pavonica, between 10 and 30% by weight, preferably 20% of 1 ,3 propanediol, and QSP water.

Preferably, the cosmetic composition according to the invention comprises from 0.01 to 10% by weight of the composition of extracts of Padina Pavonica, preferably from 0.50 to 3%, even more preferably between 0.9 and 1%, particularly preferably about 0.96%.

Thus, if the cosmetic composition comprises 3% of an active composition comprising 32% by weight of extracts of Padina Pavonica, then the cosmetic composition comprises 0.96% of extracts of Padina Pavonica.

Even more preferably, said composition further comprises at least one preservative, preferably chosen from phenoxyethanol or a mixture of water, potassium sorbate and sodium benzoate.

The mixture of water, potassium sorbate and sodium benzoate is marketed under the trade name Microcare SB.

Preferably, said cosmetic composition is formulated in the form of a cream, an ointment, an ointment, a mask, a serum, a milk, a lotion, a paste, a foam, an aerosol, a stick, a shampoo, a conditioner, patches, an aqueous hydroalcoholic or oily solution, an oil-in-water emulsion or water-in-oil or multiple, of an aqueous or oily gel, of a liquid, pasty or solid anhydrous product, and/or of a dispersion of oil in an aqueous phase using spherules, these spherules which may be polymeric nanoparticles such as nanospheres and nanocapsules or lipid vesicles of the ionic and/or non-ionic type.

Preferably, said composition increases the expression of at least one gene chosen from CCL5, CXCL5, CCL2, CXCL8, CXCL1, CXCL6, CXCR2, CCL2, CXCL3, CXCL16, CXCL11, CXCL10, MMP9, MMP1, TIMP2, PLAUR, CSF2, TNF, and/or reduced MMP2 expression.

According to a third aspect, the invention relates to a cosmetic care process for improving healing comprising a step of applying a composition according to the invention to an area of the skin.

Preferably, an amount of 0.1 to 50 mg/cm2, preferably 0.25 to 2.5 mg/cm2, of cosmetic composition according to the invention is applied to the area of the skin.

Preferably, the cosmetic composition according to the invention is applied once or twice a day, preferably twice a day, for at least 7 days, preferably at least 15 days, more preferably at least one month, from particularly preferably at least 2 months, and more particularly preferably at least 3 months. Very particularly preferably, the cosmetic composition is applied in the process according to the invention twice a day for at least 3 months.

Preferably according to the invention, said area of the skin is the face, the neck and/or the décolleté.

Examples:

Example 1: Full Genome Transcriptome Analysis

Method

In order to better characterize the effects of the composition on the skin cells, normal human keratinocytes were cultured in vitro in the presence or in the absence of the extract according to the invention in order to evaluate the cytotoxic doses.

Then, the complete gene expression profile of the genome was established. It was carried out using Affymetrix DNA chips that identify and characterize a large number of genes and pathways that are upregulated or downregulated under specific conditions.

The dose tested was 3% (no cytotoxic dose) applied for 24 hours (n=3).

The data was analyzed in the "StratiCell Skin Knowledge" database.

Results

The results provide in-depth knowledge on the mechanisms of action of the composition according to the invention.

The data was annotated at two levels of analysis:

• The individual analysis was carried out according to the definition of the Affymetrix probe in order to select the genes expressed differentially between the cultures treated or not with the active ingredient for a fold-change (FC >1 (positive regulation) or < 1 ( negative regulation) for a p-value P < 0.05.

When keratinocytes were cultured in the presence of 3% of the composition according to the invention for 24 hours, the expression of 3363 genes was found to be modulated, significantly for a p-value of P<0.05.

These data correspond to 1528 upregulated genes (increase between 1.x and 4.5x) and 1835 downregulated genes (decrease between 1.2x and 7x). When the fold-change is set to x2, 269 genes are up-regulated and 111 genes down-regulated.

These data prove the high potential of the composition on wound healing.

• Analysis of functional groups of genes particularly relevant to skin biology completed the first analysis.

Thematic analysis of these selected genes through Straticell's proprietary skin database revealed the importance of genes relevant to wound healing.

Example 2: Impact on healing and its different stages by transcriptomic analysis.

The extracts according to the invention induce the overexpression of various chemokines which will allow the recruitment of inflammatory cells and the promotion of angiogenesis (Table 1).

Table 1: Overexpression of chemokines involved in the first phase of wound healing.

(Table 1]

The release of CCL2 and CCL5 by macrophages promotes the migration of more macrophages to the wound.

This becomes important once the fibrin clot has formed, allowing the recruitment of inflammatory cells to initiate the next phase of wound healing.

The extracts according to the invention induce the expression of several chemokines and of their CXCR2 receptor during the inflammatory phase of healing (Table 2).

Table 2: Overexpression of chemokines involved in the second phase of wound healing.

CXCL8 and CXCL1 play a major role in the recruitment of inflammatory cells. The chemokines CCL2 and CCL3 induce the increase of macrophages.

The extracts according to the invention also induce several major chemokines controlling the processes of the third phase of wound healing (Table 3).

Table 3: Overexpression of chemokines involved in the third phase of wound healing.

The extracts according to the invention are also capable of acting on the final phase of healing (Table 4).

Table 4: Effect on the expression of genes involved in the last phase of wound healing.

The extracts according to the invention induce the genes coding for MMP9 and MMP1. The family of matrix metalloproteinases comprises around twenty members, each of which has its own specificity in terms of substrates to be degraded within the matrix of the dermis and their role in healing. MMP9 (or gelatinase B) and MMP1 (collagenase-1) are listed in the literature to be expressed specifically by keratinocytes at the edge of a wound and promote migration and re-epithelialization. In addition, the extract reduces the expression of the MMP2 gene (gelatinase A, whose function is similar to MMP9). MMP-2 and MMP-9 may be important in detaching keratinocytes from the basement membrane prior to lateral movement early in epithelial wound healing, and MMP-2 and MMP-9 are transiently observed in epidermal cells soon after injury (Salo T et al. 1991 - J. Biol. Chem. 1991; 266: 1143; 1994 - Lab. Invest. 70: 176). It is indeed important that the damaged tissues are eliminated before the reconstruction of new tissues.

The observed induction of TIMP-2 (tissue inhibitor of metalloproteinase 2) is consistent with the reduction of MMP2.

The extracts according to the invention also induce the expression of the PLAUR gene and other genes involved in the healing process (Table 5).

Table 5: Effect on the expression of genes involved in the last phase of wound healing.

TNF can modulate macrophage function to stimulate angiogenesis. It also acts at the start of the wound healing process.

The CSF2 gene which codes for a cytokine controlling the production, differentiation and function of granulacts is also increased.

Due to the effective activity of chemokines which play a major role in all stages of wound healing, the extracts according to the invention make it possible to act on the mediators of the normal healing cascade and prevent the alterations caused by the stress, thereby reducing host susceptibility to infection.

Claims (6)

Composition comprising aqueous or ethanolic or acetonic extracts of Padina Pavonica for its use in improving the healing of the skin. Composition for use according to the preceding claim, characterized in that the said extracts of Padina Pavonica are extracts of the thalli of Padina Pavonica. Composition for use according to claims 1 and 2, characterized in that said composition comprises from 0.01 to 10% by weight of the composition of Padina Pavonica extracts, preferably from 0.5 to 6%, even more preferably between 0.9 and 1%, particularly preferably 0.96%. Composition for use according to any one of Claims 1 to 3, characterized in that the said composition also comprises at least one other cosmetically acceptable compound, preferably chosen from agents which make it possible to improve the formation and/or the maturation of the stratum corneum , healing agents, soothing agents, restructuring agents, regenerating agents, revitalizing agents, sun filters, anti-wrinkle agents, moisturizing agents, anti-aging agents, surfactants, fatty substances, organic solvents, solubilizing agents, thickening and gelling agents, smoothing agents, agents enhancing the firmness, elasticity and/or the barrier effect of the skin, antioxidants, opacifiers, stabilizing agents, foaming agents, perfumes, ionic or non-ionic emulsifiers, fillers, sequestrants and chelators, perfumes, filters, essential oils, coloring materials, pigments, hydrophilic or lipophilic active agents, lipid vesicles encapsulating one or more active agents and /or curators. Composition for use according to any one of claims 1 to 4, characterized in that said composition comprises 1,3 propanediol. Composition for use according to any one of Claims 1 to 5, characterized in that the said composition is formulated in the form of a cream, an ointment, an ointment, a mask, a serum, a milk, a lotion, a paste, a mousse, an aerosol, a stick, a shampoo, a conditioner, patches, an aqueous hydroalcoholic solution or oily, of an oil-in-water or water-in-oil or multiple emulsion, of an aqueous or oily gel, of an anhydrous liquid, pasty or solid product, and/or of an oil dispersion in an aqueous phase using spherules, these spherules possibly being polymeric nanoparticles such as nanospheres and nanocapsules or lipid vesicles of the ionic and/or non-ionic type.