Ecobiotic composition capable of preventing and treating redness, signs of skin aging and vascular abnormalities

Abstract

The present invention relates to a cosmetic composition, advantageously an eco-biological cosmetic composition, comprising: - polyglutamic acid or a salt thereof; and - at least one peptide derivative represented by the general formula (I) in which: - R1 represents a hydrogen atom, an acyl radical or an acyloxy radical; and - R2 represents the side chain of an alpha-amino acid chosen from the group consisting of phenylalanine, glutamic acid, arginine, cysteine, methionine, histidine and tyrosine. The present invention also relates to the use of said cosmetic composition for combating skin redness and / or skin aging; to its use for preventing and / or combating cutaneous vascular hyperproliferation and / or cutaneous inflammation and / or rosacea; and to a method for selecting compounds suitable for preventing and / or combating these pathologies.

Description

Technical Field

[0001] This invention relates to the field of cosmetics, and particularly to cosmetic compositions, advantageously eco-biological cosmetic compositions, and their uses for effectively combating skin aging, especially photoaging, aging of skin prone to redness, vascular abnormalities associated with skin aging, and skin inflammation associated with redness, especially redness associated with hypervascularization, skin inflammation, and rosacea. Background Technology

[0002] The skin forms the primary barrier separating an organism from its external environment and comprises three main layers and a superficial layer. From deepest to outermost, these are the subcutaneous tissue, dermis, and epidermis, with the epidermis being colonized by the microbiome and often considered the final "layer of skin." Because the skin constantly interacts with its environment, it is subjected to multiple attacks that disrupt its balance. Various exogenous and endogenous factors can occasionally lead to significant differences in individual levels of skin irritability. Consequently, a growing number of people perceive their skin as prone to redness, often chronically.

[0003] Skin redness, also known as erythema, is a common condition characterized by an abnormal red or pinkish hue of the skin. It can be caused by a variety of factors, such as sun exposure, vascular abnormalities, allergic reactions, irritation, or actually hormonal changes. The chronic form of redness is often referred to as rosacea erythematosus. This is a skin condition characterized by persistent redness, dilated blood vessels, significant hypervascularization of the skin, papules, and inflammatory plaques on the face (particularly the cheeks, chin, nose, and forehead). Whether temporary or chronic, skin redness can be a source of aesthetic distress, discomfort, and even social embarrassment (sometimes leading to withdrawal).

[0004] Excessive vascularization of the skin refers to a condition characterized by an abnormal increase in the number and size of blood vessels. Skin with excessive vascularization is typically more sensitive and reactive, leading to itching, irritation, or even pain. Beyond sensory symptoms, excessive vascularization often has aesthetic implications. Areas of skin with excessive vascularization remain red, and the blood vessels may appear as red lines even when the skin is not inflamed. In some cases, this can affect an individual's self-confidence and quality of life. Furthermore, vascular abnormalities tend to become more prominent with skin aging, particularly due to a gradual decrease in the thickness of the epidermis, the thickness of the dermal extracellular matrix that protects and surrounds blood vessels, and a reduction in the natural biological resources available for skin maintenance, function, and defense.

[0005] In particular, skin redness and / or erythematous acne are caused by a complex set of factors, including age and an individual's overall health. Therefore, it is difficult to propose skin treatments that can act synergistically on the causes of these heterogeneous skin conditions.

[0006] Based on its ecobiological approach, the applicant has identified and acted upon the causes of skin conditions, particularly by modulating the function of key epidermal and dermal regulatory factors to act on multiple aspects simultaneously. In recent years, especially in the skin, PEDF protein has been identified as one of these factors playing a major role in controlling inflammation, skin redness, and especially excessive angiogenesis in the skin.

[0007] PEDF protein, also known as "pigmentary epithelium-derived factor" (i.e., factor derived from pigmentary epithelium), belongs to the group of non-inhibitory serine protease inhibitors (serpins). This 50 kDa protein containing 398 amino acids is a secreted glycoprotein (Filleur et al., 2009), primarily produced by retinoblastoma epithelial cells (Tombran-Tink et al., 2004), but it is also present in other tissues, including the skin (Yan et al., 2018). PEDF protein has diverse functions in the skin. First, it participates in the regulation of cell differentiation and promotes the maturation of keratinocytes, while maintaining a balance between proliferation and cell differentiation in the epidermis (Belkacemi and Zhang, 2016). Furthermore, PEDF protein is known for its anti-inflammatory activity and ability to modulate the skin's immune response. It can inhibit the expression of pro-inflammatory cytokines and reduce the penetration of immune cells into the skin, which helps alleviate inflammatory skin responses (Zamiri et al., 2006). Furthermore, PEDF protein possesses important anti-angiogenic properties; more precisely, PEDF regulates angiogenesis homeostasis by inhibiting VEGF synthesis (Filleur et al., 2009; Yan et al., 2018). Other useful properties of PEDF include its ability to inhibit the expression of metalloproteinases MMP-2 and MMP-9 in human pancreatic cancer cell lines in vitro (Grippo et al., 2012), its ability to inhibit the expression of MMPMT1-MMP (also known as MMP-14) in human chondrosarcoma cell lines in vitro (Tan et al., 2010), and its ability to inhibit ROS (reactive oxygen species) production (Yamagishi et al., 2004; Li and Karin, 1999).

[0008] However, PEDF expression decreases with age, especially from age 30 onwards, for example, this age is positively correlated with the onset of rosacea (Francis et al., 2004).

[0009] In summary, PEDF proteins play a key role in maintaining skin integrity and function by regulating various cellular processes, thereby helping to modulate the skin's immune and inflammatory responses, or in fact, particularly by acting on the main causes of skin redness (such as inflammation and excessive angiogenesis).

[0010] Therefore, EP 2 897 976 proposed the topical application of PEDF-derived peptides to combat skin inflammation and aging. However, formulating PEDF or one of its fragments into cosmetic compositions, especially for topical application, is challenging due to issues with stability, bioavailability, lack of skin penetration, and the maintenance of skin surface bioactivity, as these peptides are rapidly inactivated by the skin microbiota and skin proteases.

[0011] Therefore, there remains an urgent need, particularly based on the principles of ecobiology, to develop (i) compositions that protect and / or restore skin balance to ultimately improve the aesthetic appearance and social life of subjects suffering from skin redness and / or rosacea and / or excessive vascularization and / or skin inflammation and / or aging, especially photoaging and / or vascular abnormalities associated with skin aging, and (ii) methods for identifying and selecting compounds or active ingredients capable of preventing and / or treating said skin redness and / or said rosacea and / or said aging to protect and / or restore skin balance. Summary of the Invention

[0012] Following extensive research, it is commendable that the applicant has unexpectedly and surprisingly discovered a composition comprising a combination of multiple compounds (or active ingredients) that synergistically satisfy the aforementioned needs. Furthermore, it is equally commendable that the applicant has identified an innovative method for selecting said compounds by implementing a surprising PEDF content inhibition step.

[0013] Based on an ecobiological approach to addressing the biological causes of skin conditions, one object of the present invention is to protect and / or restore skin balance by preventing and / or treating skin redness, excessive proliferation of skin blood vessels, skin inflammation and / or rosacea and / or skin aging, particularly vascular abnormalities associated with skin aging (or vascular aging), especially photoaging, while utilizing endogenous mechanisms, particularly by acting on an increase or restoration of endogenous PEDF content.

[0014] Therefore, a first object of the present invention relates to a topical composition, advantageously an ecobiological topical composition, comprising:

[0015] - One of polyglutamic acid or its salts; and

[0016] - At least one peptide derivative represented by the following general formula (I):

[0017]

[0018] in:

[0019] - R1 represents a hydrogen atom, an acyl radical, or an acyloxy radical; and

[0020] -R2 represents the side chain of an α-amino acid selected from the group consisting of tryptophan, glutamic acid, arginine, cysteine, methionine, histidine, and tyrosine.

[0021] According to one specific implementation, it is a cosmetic composition, advantageously an eco-biological cosmetic composition, in a form suitable for topical application.

[0022] According to a specific implementation scheme, R2 represents the side chain of an α-amino acid selected from the group consisting of: L-tryptophan, L-glutamic acid, L-arginine, L-cysteine, L-methionine, L-histidine, and L-tyrosine.

[0023] This invention offers several advantages, particularly:

[0024] (i) It allows for the simple use of an effective composition, which can be integrated into routine procedures, wherein the compounds in the composition can work synergistically to prevent and / or treat the aforementioned skin dysfunctions;

[0025] (ii) It respects the living cell communities that make up the skin, which constantly interact with each other and with their environment to maintain the balance of the skin ecosystem;

[0026] (iii) It can be used to protect and / or restore the skin's balance; and

[0027] (iv) It is inexpensive.

[0028] In particular, the present invention is especially capable of:

[0029] -Prevent and / or combat skin redness, and / or;

[0030] -Prevent and / or combat skin aging, especially photoaging; and / or

[0031] -Prevent and / or counteract excessive proliferation of skin blood vessels; and / or

[0032] -Prevention and / or treatment of skin inflammation; and / or

[0033] -Prevention and / or treatment of rosacea; and / or

[0034] - Protect and / or restore the skin's balance; and / or

[0035] -Protection against skin effects associated with UV radiation; and / or

[0036] -Prevent and / or combat vascular abnormalities associated with skin aging; and / or

[0037] -Protection against skin effects related to the environment, especially pollution.

[0038] In the context of this invention, the terms "ecological biological composition," "ecological biological active ingredient," or "ecological biological excipient" refer to compositions, ingredients, or excipients that respect humans, their interactions with the world, and the earth. In other words, this refers to compositions, active ingredients, or (in fact) excipients that respect the homeostasis of the individual, their interactions with the world, and the environment. Specifically, it refers to compositions, active ingredients, or (in fact) excipients that respect the living cellular communities that constitute the skin (i.e., the skin microbiome, keratinocytes, fibroblasts, etc.) and the continuous interactions between these cellular communities and with the environment to maintain the homeostasis / balance of this skin ecosystem.

[0039] In the context of this invention, the term "ecological biological method" refers to a specific method pioneered by the inventors and developed by the applicant, which combines skin biology and ecosystems to help the skin grow in accordance with its natural biology over the long term.

[0040] In the context of this invention, the term "polyglutamic acid and its salts" refers to polymers containing glutamic acid monomers, which are amino acids that exist as components of proteins in all living organisms on Earth.

[0041] In the context of this invention, the terms "inducer" and "PEDF synthesis inducer" are used interchangeably and refer to reagents, treatments, or culture conditions that can initiate a specific reaction or programmed reaction sequence in a biological system, i.e., the production or synthesis (i.e., transcription and / or translation) of PEDF.

[0042] In the context of this invention, the terms "active compound," "active ingredient," and "active element" are used interchangeably to refer to a substance or compound having biological and / or medical properties that constitute the basis of a physiological effect. The active compound, active ingredient, or active element should be distinguished from at least one excipient present in the composition according to the invention.

[0043] In the context of this invention, the term "excipient" refers to a substance or compound that does not possess any biological and / or medical properties. This excipient ensures that the cosmetic formulation produces a specific texture, fragrance, and / or color, and ensures that its shelf life, stability, safety, and expiration date meet specifications. Excipients should be distinguished from at least one active compound, active ingredient, or active element present in the compositions of this invention.

[0044] In the context of this invention, the term "molecular weight (Mw)" refers to the mass average molecular weight (Mw or "molecular weight") of a compound, protein, or another advantageous natural polymer such as polyglutamic acid and its salts.

[0045] In the context of this invention, the expression "composition for skin application" or "composition for topical application" refers to a composition compatible with application to skin, mucous membranes, hair and / or scalp, preferably human skin.

[0046] In the context of this invention, the term "nursing" refers to cosmetic and non-medical care.

[0047] In the context of this invention, the expression "contact with at least one skin cell" refers to any direct exposure (e.g., cultured cells) or indirect exposure (e.g., topical application) to the at least one candidate compound according to the invention. In particular, indirect exposure via topical application can be made on the entire living (advantageously human) skin, on skin explants, on reconstructed epidermis, or on reconstructed skin. Preferably, indirect exposure is made on skin explants, reconstructed epidermis, or reconstructed skin.

[0048] In the context of this invention, the term "skin explant" refers to a biopsy of human skin obtained from surgical waste, comprising the entire epidermis and dermis and / or subcutaneous tissue sections.

[0049] In the context of this invention, the term "skin substitute" refers to reconstructed skin or reconstructed epidermis, preferably human reconstructed skin or reconstructed epidermis, comprising differentiated cells distributed across multiple layers. Specifically, in the context of this invention, the reconstructed skin comprises at least two partitions: a dermal partition and an epidermal partition. These models can be generated by 3D printing or cell differentiation and can include multiple cell types to approximate the full functionality (nervation, immunity, pigmentation, angiogenesis, etc.) of human or animal epidermis as closely as possible. Examples of suitable models of this type are sold by LabSkinCreations, or in fact by Straticell, SkinEthic, Episkin, or Phenion.

[0050] In the context of this invention, the term "reconstructed epidermis" refers to an epidermis generated in vitro using conventional techniques well known to those skilled in the art (e.g., Limat and Hunziker, 2002; Poumay et al., 2004). Advantageously, the keratinocytes used in this epidermis are obtained from the skin of humans suffering from sensitive / rosacea.

[0051] In the context of this invention, the term "reconstructed skin" refers to an epidermal component comprising in vitro generated keratinocytes and a dermal component comprising in vitro generated fibroblasts, integrated into the dermal matrix. The reconstructed skin is commercially available. Advantageously, the keratinocytes and fibroblasts used in this skin can be derived from the skin of sensitive / acne-prone humans, more advantageously from sensitive skin.

[0052] In the context of this invention, the term "skin cell" refers to any cell type that is at least partially present in one of the three layers of the skin: epidermal cells (e.g., keratinocytes, melanocytes, Merkel cells, immune cells such as Langerhans cells, C-fiber nerve endings), dermal cells (e.g., mast cells, vascular smooth muscle cells, specialized myocytes, fibroblasts and immune cells, dermal dendritic cells, fibroblasts, endothelial cells), subcutaneous cells (e.g., adipocytes), nerve cells, and macrophages. Clearly, according to the invention, the expression "skin cell" includes any nerve cell present in the skin as a terminal or fibrous tissue. In particular, the skin cells are fibroblasts or keratinocytes, advantageously of human origin.

[0053] In the context of this invention, the terms "reference value," "normal value," "normal," "standard," "usual value," or "reference biological sample" are used interchangeably to refer to the value or average of a parameter (e.g., gene expression, particularly at the mRNA level, etc.) obtained from one or more subjects, and represent the baseline state of the expected measurement; in contrast to "value tested," "test value," "candidate compound" value, or "test biological sample." Reference values ​​and test values ​​are obtained by performing the same detection, quantification, identification, and other methods.

[0054] In the context of this invention, the terms "content", "amount" and "level" are used interchangeably.

[0055] In the context of this invention, the terms "PEDF protein" and "PEDF" are used interchangeably.

[0056] In the context of this invention, the expression "endogenous skin content of PEDF and / or nucleic acid encoding thereof" or "content of PEDF and / or PEDF-encoded nucleic acid" refers to the level present in skin cells and / or extracellular media after secretion by the skin cells under normal conditions, particularly under normal culture conditions, without inducing or eliminating PEDF expression.

[0057] In the context of this invention, the terms "extracellular space," "extracellular matrix," "extracellular medium," or "supernatant" refer to the space outside the cell. This space is considered to be outside the plasma membrane. This term is the opposite of "intracellular," which refers to the interior of the cell.

[0058] In the context of this invention, the term "variation in expression" refers to overexpression or underexpression of a gene. Specifically, the term "overexpression" means an increase in gene expression relative to a reference value; the term "underexpression" means a decrease in gene expression relative to a reference value.

[0059] The term "encoding" (or "coding for") is used interchangeably to refer to the inherent characteristic of a specific nucleotide sequence in a polynucleotide (such as a gene, cDNA, or mRNA) that serves as a template for the synthesis of a polypeptide with a defined amino acid sequence and the resulting biological characteristics. Therefore, if the transcription and translation of the mRNA corresponding to a gene produces a protein in a cell or another biological system, then that gene encodes that protein. Both the coding strand (whose nucleotide sequence is identical to the mRNA sequence and is typically described in sequence listings and databases) and the non-coding strand (which serves as a template for gene or cDNA transcription) can be referred to as the protein or another product encoding that gene or cDNA.

[0060] In the context of this invention, the term "bioactive derivative" refers to isomers, fragments, or modified forms of isomers or fragments, particularly those grafted covalently modified with organic groups (such as octanoyl, stearoyl, palmitoyl fatty chains, or actually through acetylation, methylation, etc.). Such derivatives may exhibit bioactivity similar to or even superior to that of the protein from which they originate.

[0061] In the context of this invention, all embodiments described below can be combined.

[0062] According to one specific embodiment, the molecular weight (Mw) of at least one polyglutamic acid or its salt according to the invention is from 0.1 MDa to 20 MDa, advantageously from 1 MDa to 5 MDa.

[0063] According to another specific embodiment, the molecular weight (Mw) of at least one polyglutamic acid or its salt according to the invention is from 0.01 kDa to 10 kDa, advantageously from 0.1 kDa to 5 kDa.

[0064] According to another specific embodiment, one of the at least one polyglutamic acid or its salt according to the invention is poly-γ-glutamic acid, advantageously a potassium salt of poly-γ-glutamic acid.

[0065] Specifically, polyglutamic acid or one of its salts corresponds to the following INCI names: polyglutamic acid, sodium polyglutamate, natto gum, or hydrolyzed poly-γ-glutamic acid potassium.

[0066] According to the present invention, one of the at least one polyglutamic acid or its salt is synthetic, plant or microbial in origin, such as poly-γ-glutamic acid synthesized by Bacillus subtilis subsp. Chungkookjang or other similar bacterial strains.

[0067] Specifically, at least one polyglutamic acid or salt thereof according to the invention corresponds to the following starting materials: AminoPGALE®-301 sold by Toyobo Co. LTD; AquaMax™ HM sold by CP Kelco; sodium polyglutamate sold by Vedan Biotechnology Corporation; TEGO® Cosmo PGA sold by Evonik Nutrition & Care GmbH; or Gamma-Max or specifically Gamma-Oligo sold by Rahn Corporation. Preferably, it is a Gamma-Oligo starting material sold by Rahn Corporation.

[0068] According to one specific embodiment, the at least one peptide derivative is selected from the group consisting of α-L-glutamyltryptamine, L-tryptamine and L-methionyltryptamine.

[0069] Advantageously, the at least one peptide derivative is α-L-glutamyltryptamine, preferably α-L-glutamyltryptamine corresponding to CAS No. 478273-36-8 ((4S)-4-amino-5-[[2-(1H-indol-3-yl)ethyl]amino]-5-oxovalerate) and / or INCI name glutamylaminoethylindole.

[0070] Specifically, the at least one peptide derivative corresponds to GLISTIN, a cosmetic starting material sold by EXSYMOL under the name INCI (glutamylaminoethylindole (and) propylene glycol (and) water).

[0071] According to one specific embodiment, the weight ratio of at least one peptide derivative and one of polyglutamic acid or its salt in the composition of the present invention is from 1:200 to 1:10, advantageously from 1:100 to 1:30.

[0072] According to one specific embodiment, the composition of the present invention comprises:

[0073] - One of polyglutamic acid or its salts, comprising 0.001% to 10% of the total weight of the composition, advantageously 0.01% to 5%, preferably 0.1% to 2%; and / or

[0074] - At least one peptide derivative, comprising 0.00001% to 10% of the total weight of the composition, preferably 0.0001% to 1%.

[0075] Advantageously, the compositions according to the invention, individually or in combination, have the following additional technical features:

[0076] - The compositions according to the invention further comprise at least one additional compound selected from the group consisting of: glycyrrhetinic acid, a derivative or salt of the acid; hyaluronic acid or one of its salts or one of its derivatives; psoralen; dipotassium glycyrrhizate; acetyl dipeptide-1 cetyl ester; squalane; jojoba oil; fructooligosaccharides; rhamnose; mannitol; xylitol; ectoine; and mixtures thereof;

[0077] - The composition according to the invention comprises glycyrrhetinic acid, a derivative of the acid, or a salt thereof, preferably accounting for 0.01% to 2% of the total weight of the composition, advantageously accounting for 0.1% to 1% of the total weight of the composition;

[0078] - The composition according to the invention comprises hyaluronic acid or one of its salts or one of its derivatives, advantageously wherein:

[0079] Hyaluronic acid is in the form of an acid or salt, especially a sodium, potassium, or magnesium salt, with sodium salt being preferred.

[0080] The molecular weight (Mw) of hyaluronic acid or one of its salts is from 0.1 kDa to 2 MDa, preferably from 400 to 600 kDa or from 0.1 to 5 kDa;

[0081] Hyaluronic acid or one of its salts accounts for 0.0001% to 10% of the total weight of the composition, advantageously 0.001% to 2% of the total weight of the composition, and more advantageously 0.01% to 1% of the total weight of the composition;

[0082] Hyaluronic acid or one of its salts corresponds to the starting material BIOSODIUM HYALURONATEMMW sold by DKSH, which corresponds to the INCI name sodium hyaluronate.

[0083] The composition according to the invention further comprises a bioactive system, which, on the one hand, binds to a stable form in aqueous solution of a nucleotide selected from ATP (adenosine triphosphate), Gp4G (guanosine tetraphosphate), and Ap4A (adenosine tetraphosphate); and on the other hand, binds to at least one biomimetic peptide comprising up to six amino acids, said biomimetic peptide mimicking a skin polypeptide or skin protein, or a biomolecule that is an agonist or antagonist of said peptide or protein. This bioactive system can be used to catalyze the metabolic activities of skin cells, while simultaneously achieving cosmetic or therapeutic effects on the skin through the use of the biomimetic peptide. The latter can be selected to obtain desired effects, such as effects of inhibiting neurogenic stimulation, depigmentation activity, inhibition of any intolerance or sensitization, etc.

[0084] In the bioactive system according to the invention, advantageously, the nucleotide accounts for at most 10% of the total weight of the composition, preferably from 0.001% to 5% of the total weight of the composition; and the biomimetic peptide accounts for 0.001% to 1% of the total weight of the composition;

[0085] - The compositions according to the invention comprise compounds that contribute to internal protection through some action, which may include: DNA protection, reduction of UV-induced immunosuppression, free radical scavenging, or a combination of these actions;

[0086] - The compositions according to the invention comprise free radical scavengers that maintain cell structure, such as vitamin E and / or its fat-soluble or water-soluble derivatives, particularly tocotrienols and / or tocopherols, which advantageously constitute 0.001% to 10% of the total weight of the composition, more advantageously 0.02% to 2% of the total weight of the composition, preferably 0.04%;

[0087] - The composition according to the invention further comprises at least one compound selected from the group consisting of: fructooligosaccharides, boldo extract, carnosine, adenosine, creatinine and creatine;

[0088] - The composition according to the invention comprises *Peumus boldus* or an extract of *Peumus boldus*. *Peumus boldus* is a tree from the Monimiaceae family, whose leaf extract induces the synthesis of defensins and cathelicidin. Advantageously, the *Peumus boldus* extract comprises 0.0001% to 10% of the total weight of the composition, more advantageously 0.001% to 2% of the total weight of the composition, and preferably 0.01% to 1% of the total weight of the composition;

[0089] The Bordeaux tree extract in the composition according to the invention advantageously corresponds to the starting material MP BETAPUR PGF sold by BASF, which corresponds to the INCI name water (and) butylene glycol (and) Bordeaux leaf extract (and) pentane glycol (and) xanthan gum.

[0090] - The composition according to the invention comprises adenosine, advantageously accounting for 0.0001% to 5% of the total weight of the composition, more advantageously accounting for 0.001% to 1% of the total weight of the composition, preferably 0.01% to 0.05%;

[0091] The adenosine in the composition according to the invention is advantageously in a non-phosphorylated form, more advantageously in powder form, and can correspond to the INCI name adenosine sold by PHARMA WALDHOF.

[0092] - The composition according to the invention comprises carnosine, advantageously in the form of 0.001% to 5% of the total weight of the composition, more advantageously in the form of 0.01% to 1%;

[0093] The carnosine in the composition according to the invention is preferably in a purified or highly purified form, advantageously obtained by chemical synthesis, and can be the starting material Kopsine, which is sold by KUMAR ORGANIC PRODUCTS LTD and corresponds to the INCI name carnosine.

[0094] - The composition according to the invention comprises creatinine, which advantageously accounts for 0.001% to 5% of the total weight of the composition, and more advantageously accounts for 0.01% to 1% of the total weight of the composition;

[0095] The creatinine in the compositions according to the invention is advantageously in a purified or highly purified form, more advantageously obtained by chemical synthesis, and can be the starting material TEGO COSMO C 250 sold by EVONIK, corresponding to the INCI name METHYLHYDANTOIN-2-IMIDE.

[0096] - The composition according to the invention comprises fructo-oligosaccharide, also known as oligofructose or FOS, which advantageously accounts for 0.001% to 10% of the total weight of the composition, preferably 0.01% to 5% of the total weight of the composition;

[0097] The FOS in the compositions according to the invention is advantageously in a purified or highly purified form and may correspond to the starting material fructooligosaccharides sold by SHAANXI BOLIN BIOTECHNOLOGY CO, which corresponds to the INCI name fructooligosaccharides.

[0098] - The composition according to the invention further comprises peptide extracts from soybeans and / or wheat, which advantageously account for 0.01% to 20% of the total weight of the composition, more advantageously 0.1% to 10%;

[0099] The peptide extracts from soybeans and wheat in the compositions according to the invention advantageously have a weight ratio between 80 / 20 and 20 / 80, more advantageously between 70 / 30 and 30 / 70, and preferably equal to 60 / 40;

[0100] The peptide extracts derived from soybeans and / or wheat in the compositions according to the present invention preferably do not contain synthetic GHK tripeptide (glycyl-histyl-lysine; INCI: tripeptide-1).

[0101] The soybean peptide extract in the composition according to the invention can be an extract identified by CAS number 68607-88-5; advantageously, it corresponds to the INCI name hydrolyzed soy protein.

[0102] The wheat peptide extract in the composition according to the invention can be an extract identified by CAS number 70084-87-6; advantageously, it corresponds to the INCI name hydrolyzed wheat protein.

[0103] - The composition according to the invention comprises at least one branched hydrogenated glucose homopolymer containing α (1-4) and α (1-6) bonds, which advantageously accounts for 0.001% to 2% by weight of the composition, more advantageously 0.01% to 0.5%;

[0104] - The branched hydrogenated glucose homopolymer containing α (1-4) and α (1-6) bonds in the composition according to the invention advantageously corresponds to the INCI name hydrogenated starch hydrolysate, more advantageously corresponds to the starting material MG-60 sold by HAYASHIBARA, and corresponds to the INCI name maltooligosylglutamate & hydrogenated starch hydrolysate.

[0105] - The composition according to the invention comprises at least one hybrid of glucose and trehalose, advantageously maltodextrose glucoside, more advantageously accounting for 0.001% to 2% by weight of the composition, and more advantageously accounting for 0.01% to 0.5%.

[0106] According to one specific embodiment, the composition according to the invention is an acceptable galen formulation suitable for cosmetic use, i.e., compatible with skin, mucous membranes, hair, and scalp.

[0107] In particular, the composition is in the form of a galenol formulation suitable for skin application and / or topical application.

[0108] Therefore, the compositions according to the invention can be in the form of aqueous solutions, hydroalcoholic solutions, organic solutions, or oily solutions; suspending or dispersing agents or serums in solvents or fats; vesicular dispersants; or water-in-oil (W / O) emulsions, oil-in-water (O / W) emulsions, or multiple emulsions such as water-in-oil-in-water (W / O / W) emulsions. The emulsions can have greater or lesser thicknesses and are in the form of creams or lotions; the compositions of the invention can also be in the form of ointments, gels, solid rods, pastes, or solid anhydrous products, foaming agents (especially aerosols), two-phase compositions, or even sprayable compositions.

[0109] The galenal formulation of the composition and its preparation method, as well as the corresponding excipients suitable for the compositions of the present invention, can be selected by those skilled in the art based on their general knowledge according to the type of composition sought. In particular, the composition may include any fats conventionally used in the cosmetics field. Fats of oils and waxes of plant, mineral, animal, and / or synthetic origin are particularly noteworthy. The oils may be volatile or non-volatile. Synthetic esters and ethers, fatty alcohols, and fatty acids may also be mentioned. The composition may also contain an aqueous medium, an aqueous alcoholic medium containing alcohols (such as ethanol or isopropanol), or an organic medium containing common organic solvents (such as C1-6 alcohols (especially ethanol and isopropanol), glycols (such as propylene glycol), and ketones). Obviously, those skilled in the art will carefully select such or these optional adjuvants or excipients, and / or their amounts, so that the advantageous properties of the compositions according to the invention are not or substantially not altered by the contemplated addition. The composition may contain at least one conventional emulsifier, selected from amphoteric, anionic, cationic, or nonionic emulsifiers, used alone or as a mixture. It may be particularly advantageous that the compositions of the present invention are formulated in a sprayable manner. For example, this can be achieved by formulating a specific emulsion containing a specific combination of excipients.

[0110] Another object of the present invention relates to the advantageous ecobiological and / or cosmetic use of the compositions according to the invention to stimulate, improve, restore or increase the expression of genes encoding PEDF proteins and / or the production or synthesis of PEDF proteins.

[0111] In other words, the present invention also envisions:

[0112] - The composition according to the invention as described above is advantageously an ecobiological composition for stimulating the expression of a gene encoding a PEDF protein and / or the synthesis of a PEDF protein; and / or

[0113] - The composition according to the invention is advantageously an ecobiological composition for use in the preparation of a medicament for stimulating the expression of a gene encoding a PEDF protein and / or the synthesis of a PEDF protein; and / or

[0114] - A method for stimulating the expression of a gene encoding a PEDF protein and / or the synthesis of a PEDF protein, comprising the application, preferably local application, of a composition according to the invention, advantageously an ecobiological composition.

[0115] Another object of the present invention relates to the advantageous ecobiological use of the compositions according to the invention for the prevention and / or treatment of conditions or symptoms associated with PEDF deficiency and / or reduced PEDF levels relative to reference values.

[0116] In other words, the present invention also envisions:

[0117] - The compositions according to the invention are advantageously ecobiological compositions for the prevention and / or treatment of conditions or symptoms associated with PEDF deficiency and / or decreased PEDF levels relative to reference values; and / or

[0118] - The composition according to the invention is advantageously an ecobiological composition for use in the preparation of a medicament for the prevention and / or treatment of conditions or symptoms associated with PEDF deficiency and / or decreased PEDF levels relative to reference values; and / or

[0119] - Methods for the prevention and / or treatment of conditions or symptoms associated with PEDF deficiency and / or reduced PEDF levels relative to reference values, including the application, advantageously topical application of compositions according to the invention, advantageously ecobiological compositions.

[0120] Another object of the invention relates to the advantageous ecobiological use of the compositions according to the invention for the prevention and / or counteraction of skin aging (advantageously photoaging) and / or vascular aging (i.e. vascular abnormalities associated with skin aging).

[0121] In the context of this invention, the terms "vascular abnormalities associated with skin aging" and "vascular aging" are used interchangeably, particularly referring to the loss of elasticity in an individual's blood vessels.

[0122] In other words, the present invention also envisions:

[0123] - The compositions according to the invention are advantageously ecobiological compositions for preventing and / or combating skin aging (advantageously photoaging) and / or vascular aging; and / or

[0124] - The composition according to the invention is advantageously an ecobiological composition for use in the preparation of a medicament for preventing and / or combating skin aging (advantageously photoaging) and / or vascular aging; and / or

[0125] - Methods for preventing and / or combating skin aging (advantageously photoaging) and / or vascular aging, including the application, advantageously topical application, of compositions according to the invention, advantageously ecobiological compositions.

[0126] Another object of the present invention relates to the use of the compositions according to the invention for cosmetic, non-therapeutic, and advantageous ecobiological purposes for the prevention and / or counteraction of skin redness.

[0127] In other words, the present invention also envisions:

[0128] - The compositions according to the invention are advantageously ecobiological compositions for preventing and / or combating skin redness; and / or

[0129] - The compositions according to the invention are advantageously ecobiological compositions for use in the preparation of medicaments for the prevention and / or treatment of skin redness; and / or

[0130] - Methods for preventing and / or combating skin redness, including the application, advantageously topical application of the composition according to the invention, advantageously being an ecobiological composition.

[0131] Another object of the present invention relates to the use of the compositions according to the invention for the prevention and / or treatment of excessive proliferation of skin blood vessels, advantageously for ecobiological use.

[0132] In other words, the present invention also envisions:

[0133] - The compositions according to the invention are advantageously ecobiological compositions for the prevention and / or treatment of excessive vascularization of the skin; and / or

[0134] - The compositions according to the invention are advantageously ecobiological compositions for use in the preparation of medicaments for the prevention and / or treatment of excessive vascularization of the skin; and / or

[0135] - Methods for preventing and / or treating excessive proliferation of skin blood vessels, including the application, advantageously topical application of the composition according to the invention, advantageously an ecobiological composition.

[0136] Another object of the present invention relates to the use of the compositions according to the invention for the prevention and / or treatment of skin inflammation, advantageously for ecobiological use.

[0137] In other words, the present invention also envisions:

[0138] - The compositions according to the invention are advantageously ecobiological compositions for the prevention and / or treatment of skin inflammation;

[0139] - The compositions according to the invention are advantageously ecobiological compositions for use in the preparation of medicaments for the prevention and / or combating of skin inflammation; and / or

[0140] - Methods for preventing and / or treating skin inflammation, including the application, advantageously topical application of the composition according to the invention, advantageously an ecobiological composition.

[0141] Another object of the present invention relates to the use of the compositions according to the invention for the prevention and / or treatment of rosacea, advantageously for ecobiological and / or cosmetic uses.

[0142] In other words, the present invention also envisions:

[0143] - The composition according to the invention is advantageously an ecobiological composition for the prevention and / or treatment of rosacea;

[0144] - The compositions according to the invention are advantageously ecobiological compositions for the preparation of medicaments for the prevention and / or treatment of rosacea; and / or

[0145] - Methods of preventing and / or treating rosacea, including the application, advantageously topical application of the composition according to the invention, advantageously an ecobiological composition.

[0146] Furthermore, the applicant has identified, in an innovative and unexpected manner, the synthesis of PEDF as a target (i) by exposure to UV, particularly UVA, which is reduced or inhibited; and then (ii) by the increase or restoration of the active ingredient contained in the composition of the present invention, thereby prompting the applicant to develop an innovative, simple and robust method according to the present invention.

[0147] Therefore, according to another aspect, the present invention relates to a method for selecting a compound or a mixture of compounds, advantageously an in vitro or ex vivo method, comprising the following steps:

[0148] a) Measure the content of PEDF protein (pigment epithelium-derived factor) and / or PEDF-encoded nucleic acid in at least one skin cell and / or extracellular space, referred to as the reference value;

[0149] b) Inhibit PEDF synthesis by exposure to ultraviolet (UV) radiation;

[0150] c) Contact the compound or mixture of compounds with the skin cells;

[0151] d) Measure the content of PEDF protein and / or PEDF-encoded nucleic acid in the skin cells and / or extracellular space, referred to as the "candidate compound" value;

[0152] e) Compare the “candidate compound” value obtained in step d) with the reference value obtained in step a);

[0153] f) When an increase in the content of PEDF and / or PEDF-encoded nucleic acid is observed in step e), select the compound or a mixture of compounds.

[0154] Step a) of the present invention includes measuring the content of PEDF protein and / or PEDF-encoded nucleic acid in at least one skin cell and / or extracellular space, the content representing a baseline state of the intended measurement, rather than "the value tested", "the test value", "the test biological sample", or "the candidate compound value".

[0155] Reference values ​​and test values ​​are obtained by performing the same detection, quantification, and identification methods. Advantageously, the content is measured at the protein level by ELISA, immunohistochemistry, colorimetry, or Western blotting, and / or at the nucleic acid level by in situ hybridization, northern blotting, sequencing, or RT-PCR (more advantageously, RT-qPCR).

[0156] According to one specific implementation, step b) includes suppressing the expression of genes encoding PEDF and / or the production of PEDF mRNA and / or the synthesis of PEDF protein.

[0157] According to the invention, step c) of contacting the compound or mixture of compounds with the skin cells is performed for at least 1 minute, or at least 30 minutes, and up to 120 hours.

[0158] According to one specific implementation, exposure to UV in step b) includes exposure to UVA and / or UVB and / or the full spectrum, through the entire solar spectrum. Advantageously, this is:

[0159] - Exposure to UVA, preferably at 750 W / m², with a surface energy of 7.5 J / cm² to 80 J / cm²; or

[0160] - Exposure to the full solar spectrum, preferably at 750 W / m 2 The surface energy is 7.5 J / cm. 2 Up to 80 J / cm 2 .

[0161] Exposure to UV can be performed using any method known to those skilled in the art, such as using the Suntest XLS+ instrument (Atlas France).

[0162] According to an implementation scheme that can be combined with the foregoing implementation scheme, step b) is preferably carried out under the following culture conditions for at least 30 minutes and at most 72 hours: 37°C, 5% CO2 and / or saturated humidity.

[0163] According to one embodiment, when the method of the present invention is an ex vivo method, the contact in step c) can be achieved by locally applying the compound or a mixture of compounds to a skin explant, reconstructed epidermis, or reconstructed skin.

[0164] According to an alternative embodiment, when the method of the present invention is an in vitro method, the contact in step c) can be carried out by adding cells to the culture medium, advantageously adding keratinocytes, fibroblasts or melanocytes.

[0165] According to one specific embodiment, between steps a) and b), the method of the invention further includes the step of contacting the compound or mixture of compounds with the skin cells, advantageously for at least 1 minute, or even at least 30 minutes and up to 120 hours. Advantageously, after the step of contacting the compound or mixture of compounds with the skin cells, and before implementing inhibition of PEDF synthesis by exposure to UV, the culture medium is changed so that it does not contain the compound or mixture of compounds upon exposure to UV.

[0166] The amount of PEDF protein and / or the nucleic acid (preferably mRNA) encoding it can be measured using any method known to those skilled in the art.

[0167] Advantageously, quantification of expressed PEDF protein can be performed via immunohistochemistry on cell sections; by Western blotting; or, it can be performed by an ELISA assay, for example, an ELISA assay on the supernatant of cell cultures or cell extracts, by interpolating the optical density value of the sample to a calibration curve obtained with a series of dilutions of recombinant human PEDF protein (e.g., from 0.1 ng / mL to 10 ng / mL). In practice, viability assays using MTT, known to those skilled in the art, can be performed on cell pads. PEDF assays are only used when cell viability is greater than 80% and are correlated with this cell viability value.

[0168] The content of messenger ribonucleic acid (mRNA) encoding PEDF can be measured by in situ hybridization of cell sections; by northern hybridization; or practically by RT-qPCR. Advantageously, total RNA is extracted from tissues, for example using a commercially available kit (such as the QIAGEN Rneasy Plus Mini). Total RNA analysis can be performed after extraction to provide the quantity and quality of RNA in the cell extract; this step can be performed using kits such as Bioanalyzer and RNA 6000 Nano. cDNA is generated using the QuantiTect Reverse Transcription Kit (QIAGEN), followed by real-time quantitative PCR at each treatment time, for example using the QuantiFast SYBR Green PCR Kit (QIAGEN), and the expression of housekeeping genes (e.g., GAPDH) as controls and the expression of PEDF using specific primers are monitored.

[0169] Therefore, according to a specific implementation scheme, the PEDF content is measured by ELISA, by immunohistochemistry of cell sections, or by Western blotting; the content of messenger ribonucleic acid (mRNA) encoding PEDF is measured by immunohistochemistry, in situ hybridization of cell sections, northern blotting, sequencing, or RT-PCR, preferably RT-qPCR.

[0170] According to one specific implementation, the candidate compound is neither the PEDF protein nor one of its bioactive derivatives.

[0171] According to another aspect, the present invention relates to a topical composition, advantageously an ecobiological topical composition, comprising at least one compound or a mixture of compounds selected by means of the method of the present invention described above.

[0172] According to one specific embodiment, the composition is in the form of a galenol formulation, which is suitable for topical use and is advantageously cosmetically acceptable, i.e., compatible with skin, mucous membranes, hair, and scalp.

[0173] In particular, the composition is in the form of a galenol formulation suitable for skin application.

[0174] Therefore, the compositions of the present invention are present in one of the galen formulations as described above.

[0175] Another object of the invention relates to the use of the composition, advantageously for ecobiological purposes, comprising at least one compound or mixture of compounds selected by the method according to the invention, for:

[0176] - Stimulate, improve, or substantially increase the expression of genes encoding PEDF proteins and / or the synthesis of PEDF proteins; and / or

[0177] -Prevention and / or treatment of conditions or symptoms associated with PEDF deficiency and / or decreased PEDF levels relative to reference values; and / or

[0178] -Prevent and / or combat skin aging (favorably photoaging) and / or vascular aging; and / or

[0179] -Prevention and / or treatment of excessive skin angiogenesis; and / or

[0180] -Prevention and / or treatment of skin inflammation; and / or

[0181] -Prevention and / or treatment of rosacea.

[0182] The following non-limiting embodiments form an integral part of this invention, and any feature that is novel relative to the prior art is claimed in its own right and as a general means. Attached Figure Description

[0183] [ Figure 1 [Evaluate the effects of PGA and L-GAEI, alone or in combination, on PEDF synthesis, which was induced in normal human fibroblasts (NHF) or normal human keratinocytes (NHK) exposed to 30 J / cm³.] 2 The energy density was measured after UVA. Results were obtained from experiments with 3 wells under each condition. Statistical tests were performed for the "untreated, unirradiated" condition (significance: *: p < 0.05; **: p < 0.01; ***: p < 0.001). Detailed Implementation

[0184] The percentages given in the table below are given as a percentage of the product weight to the total weight of the composition.

[0185] Example 1: Cosmetic composition - O / W emulsion as defined in this invention

[0186] Table 1 describes the compositions according to the present invention.

[0187] [Table 1]

[0188]

[0189]

[0190] Example 2: Cosmetic composition - gel as defined in this invention

[0191] Table 2 describes the compositions according to the present invention.

[0192] [Table 2]

[0193]

[0194] Example 3: In vitro evaluation of the effect of the composition according to the present invention on PEDF synthesis

[0195] 1. Research Objectives

[0196] The aim of this study is to (i) demonstrate that exposure to UV, particularly UVA, reduces PEDF synthesis; and (ii) determine the ability of two cosmetic active ingredients, alone or in combination, to induce PEDF synthesis after inducing inhibition of PEDF synthesis through exposure to UVA.

[0197] It should be noted that inhibitors of PEDF gene expression and / or PEDF synthesis can be used to identify candidate compounds (or active ingredients) capable of inducing the production and / or increased content of PEDF and / or PEDF-encoded nucleic acids. In other words, after the step of inhibiting the production of PEDF and / or PEDF-encoded nucleic acids, candidate compounds that induce an increase in the content of PEDF and / or PEDF-encoded nucleic acids are classified as compounds according to the purposes of the present invention, preferably ecobiological compounds, i.e., suitable for the prevention and / or treatment of aging and / or excessive skin angiogenesis and / or skin inflammation and / or rosacea, as described above.

[0198] 2. Materials and Methods

[0199] 2.1. Cell Culture

[0200] Normal human fibroblasts (NHF) from Lonza (France) were used in this study. Cells were seeded at a rate of 15,000 cells / well in 96-well plates using complete medium (DMEM + 10% FBS + 1% penicillin-streptomycin or P / S). After incubation for 24 hours, the cells were pre-incubated for 24 hours at 37°C and 5% CO2 with an active ingredient diluted in DMEM + 1% P / S. Next, the medium was replaced with irradiated medium (Ca-free HBSS) and treated with 30 J / cm² water. 2Surface energy of UVA (750 W / m 2 Cells cultured under Suntest XLS+ (Atlas FRANCE) irradiation were incubated for 24 hours after irradiation with the active ingredient of this invention. The culture supernatant was collected and stored at -80 °C, and then used to quantify the PEDF content in the culture medium by ELISA. Cell viability was evaluated on cell pads using an MTT assay to normalize the PEDF results to the MTT.

[0201] 2.2. Active ingredients tested

[0202] The active ingredients tested are listed in Table 3 below.

[0203] [Table 3]

[0204]

[0205] 2.3. Tested PEDF synthesis inhibitors

[0206] Surprisingly, the applicant demonstrated that exposure to UVA can inhibit the synthesis of PEDF and / or PEDF-encoded nucleic acids (see point 1 above). Therefore, at 30 J / cm²... 2 Up to 750 W / m 2 The surface can be exposed to UVA.

[0207] 2.4. PEDF in culture supernatant was determined by ELISA.

[0208] PEDF in the supernatant was quantified by an ELISA assay using an enzyme-linked immunosorbent assay kit (Human Serpin F1 / PEDF DuoSet ELISA, product number: DY1177-05, R&D Systems, France) and the manufacturer's recommended reagents. Optical density (OD) was read at 450 nm using a spectrophotometer. PEDF concentration was calculated based on a standard curve (39 pg / mL to 2500 pg / mL) established using recombinant human PEDF protein. Results are expressed as PEDF / well in pg / mL. Cell viability was assessed using the MTT assay on cell pads. PEDF assays were only performed when cell viability was greater than 80% and correlated with this cell viability value.

[0209] 2.5. MTT assay

[0210] The principle of this assay is based on the use of a tetrazolium salt, MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), which is reduced to formazan by the mitochondrial enzyme succinate dehydrogenase in living cells. The amount of formazan produced is proportional to the metabolic activity of the cells. This insoluble purple compound must be dissolved in DMSO to allow for spectrophotometric determination at 540 nm.

[0211] 2.6. Statistical Analysis

[0212] Quantitative analyses are expressed as mean ± standard deviation. Statistical significance was determined by Student's t-test. Differences were considered statistically significant starting from p < 0.05. (NS: p > 0.05; *: p < 0.05; **: p < 0.01; ***: p < 0.001).

[0213] 3. Results and Conclusions

[0214] The results are as follows Figure 1 As shown.

[0215] It can be seen that:

[0216] - "Untreated, unirradiated" conditions represent the percentage of PEDF synthesis without stress;

[0217] - The "untreated, irradiated" conditions arbitrarily represent 100% PEDF synthesis under stress.

[0218] - PGA tested at 0.005% and 0.0025% did not provide any significant protection against UVA stress-induced inhibition of PEDF synthesis, i.e., PEDF synthesis was -0.9% and +2% for PGA 0.005% and PGA 0.0025%, respectively (calculated based on raw data).

[0219] - L-GAEI tested at 0.0001% and 0.00005% did not provide any significant protection against UVA stress-induced inhibition of PEDF synthesis; that is, for L-GAEI 0.0001% and L-GAEI 0.00005%, PEDF synthesis was -6.5% and +2.5%, respectively (calculated based on raw data).

[0220] The two doses of the PGA+L-GAEI combination significantly protected against PEDF synthesis after UVA stress, with PEDF synthesis increasing by 27% and 36% for PGA 0.005% + L-GAEI 0.0001% and PGA 0.0025% + L-GAEI 0.00005%, respectively.

[0221] The synergistic effect between the two active substances (in this case, polyglutamic acid or one of its salts as defined in claim 1 (i.e., PGA) and a peptide derivative of general formula (I) (i.e., L-GAEI)) and mixtures thereof) was calculated by comparing test results measuring the potency of the two active substances. The Colby formula (Tammes, 1964; Schuldt, P. H and Lammont 1962) was then used.

[0222] If the measured efficacy of the mixture is greater than the efficacy expected according to the Colby formula, a synergistic effect exists. If it is lower than the expected value, an antagonistic effect exists. Furthermore, if they are equal, there is no interaction between the two substances.

[0223] Colby's formula: E = X+Y - (X×Y) / 100

[0224] Regarding the condition "PGA (0.005%) alone or in combination with L-GAEI (0.0001%)":

[0225] Where X = the effect of compound (or active ingredient) PGA on PEDF synthesis at the test dose (0.005%), i.e., 99.1% of PEDF synthesis.

[0226] Where Y = the effect of compound (or active ingredient) L-GAEI on PEDF synthesis at the test dose (0.0001%), i.e., 93.5% of PEDF synthesis.

[0227] Where E = the expected effect of active ingredients PGA and L-GAEI at doses of 0.005% and 0.0001%, respectively, without synergistic effect = (99.1+93.5) - [(99.1*93.5) / 100] = 99.94%.

[0228] The observed potency of the composition was 127%, which is significantly higher than 99.94% (the expected potency of the composition).

[0229] Regarding the condition "PGA (0.0025%) alone or in combination with L-GAEI (0.00005%)":

[0230] Where X = the effect of compound (or active ingredient) PGA on PEDF synthesis at the test dose (0.0025%), i.e., 102% PEDF synthesis.

[0231] Where Y = the effect of compound (or active ingredient) L-GAEI on PEDF synthesis at the test dose (0.00005%), i.e., 102.5% PEDF synthesis.

[0232] Where E = the expected effect of active ingredients PGA and L-GAEI at doses of 0.0025% and 0.00005%, respectively, without synergistic effect = (102+102.5) - [(102*102.5) / 100] = 99.95%.

[0233] The observed potency of the composition was 136%, which is significantly higher than 99.95% (the expected potency of the composition).

[0234] These data demonstrate the synergistic effect between components PGA and L-GAEI in the compositions according to the present invention.

[0235] At the tested concentrations, the individual active ingredients PGA and L-GAEI did not have a significant positive effect on the amount of PEDF. The combination of these active ingredients PGA and L-GAEI had a significant synergistic effect on the amount of PEDF, and therefore also a significant synergistic effect on the expression and / or synthesis of PEDF.

[0236] References

[0237] Belkacemi, L., and Zhang, SX(2016).Anti-tumor effects of pigmentepithelium-derived factor (PEDF): implication for cancer therapy.A mini-review.J. Exp.Clin.Cancer Res.CR 35, 4.

[0238] Filleur, S., Nelius, T., de Riese, W., and Kennedy, RC (2009). Characterization of PEDF: A multi-functional serpin family protein. J. Cell. Biochem. 106, 769–775.

[0239] Francis, MK, Appel, S., Meyer, C., Balin, SJ, Balin, AK, andCristofalo, VJ (2004). Loss of EPC-1 / PEDF expression during skin aging invivo.J. Invest.Dermatol.122, 1096–1105.

[0240] Grippo, J.O., Simring, M., Coleman, T.A.(2012).Abfraction, abrasion,biocorrosion, and the enigma of noncarious cervical lesions: a 20-yearperspective.J Esthet Restor Dent.24(1), 10-23.

[0241] Li and Karin (1999).Is NF-kappaB the sensor of oxidative stress?FASEBJ. 13(10), 1137-43.

[0242] Limat and Hunziker (2002).Use of epidermal equivalents generated fromfollicular outer root sheath cells in vitro and for autologous grafting ofchronic wounds.Cells Tissues Organs 172(2), 79-85.

[0243] Poumay, Y., Dupont, F., S Marcoux, S., Leclercq-Smekens, M., Hérin,M., Coquette, A. (2004).A simple reconstructed human epidermis: preparationof the culture model and utilization in in vitro studies.Arch DermatolRes.296(5), 203-11.

[0244] Tan, K.T., Zheng, G., Hsu, T.T., Wang, Y., Lee, V.W.S., Tian, X.,Wang, Y., Cao, Q., Wang, Y., Harris, D.C.H.(2010).Macrophage matrixmetalloproteinase-9 mediates epithelial-mesenchymal transition in vitro inmurine renal tubular cells.Am. J. Pathol.176(3), 1256-70.

[0245] Tombran-Tink, J., Lara, N., Apricio, S.E., Potluri, P., Gee, S., Ma,J.-X., Chader, G., and Barnstable, C.J.(2004).Retinoic acid and dexamethasoneregulate the expression of PEDF in retinal and endothelial cells.Exp.EyeRes.78, 945–955.

[0246] Yamagishi, S.I., Inagaki, Y., Nakamura, K., Abe, R., Shimizu, T.,Yoshimura, A. Imaizum, T. (2004).Pigment epithelium-derived factor inhibitsTNF-a-induced interleukin-6 expression in endothelial cells by suppressingNADPH oxidase-mediated reactive oxygen species generation.J.Mol.Cell.Cardio.37, 497-506.

[0247] Yan, B.-X., Zheng, Y.-X., Li, W., Chen, J.-Q., Zhou, J., Cai, S.-Q.,Zheng, M., and Man, X.-Y. (2018).Comparative expression of PEDF and VEGF inhuman epidermal.Discov Med.25(136):47-56.

[0248] Zamiri, P., Masli, S., Streilein, J.W., and Taylor, A.W.(2006).Pigment epithelial growth factor suppresses inflammation by modulatingmacrophage activation.Invest.Ophthalmol.Vis. Sci.47, 3912–3918.

Claims

1. A topical composition, advantageously an ecobiological topical composition, comprising: - One of polyglutamic acid or its salts; and - At least one peptide derivative represented by the following general formula (I): in: -R1 represents a hydrogen atom, an acyl radical, or an acyloxy radical; and -R2 represents the side chain of an α-amino acid selected from the group consisting of tryptophan, glutamic acid, arginine, cysteine, methionine, histidine, and tyrosine.

2. The composition according to claim 1, characterized in that... The molecular weight (Mw) of the polyglutamic acid or one of its salts is from 0.01 kDa to 10 kDa, advantageously from 0.1 kDa to 5 kDa.

3. The composition according to claim 1 or 2, characterized in that... One of the polyglutamic acid or its salts is poly-γ-glutamic acid, advantageously a potassium salt of poly-γ-glutamic acid.

4. The composition according to any one of the preceding claims, characterized in that... The at least one peptide derivative is selected from the group consisting of α-L-glutamyltryptamine, L-tryptamine and L-methionyltryptamine, with α-L-glutamyltryptamine being the most advantageous.

5. The composition according to any one of the preceding claims, characterized in that: -The polyglutamic acid or one of its salts corresponds to the following INCI names: polyglutamic acid, sodium polyglutamate, natto gum, or hydrolyzed poly-γ-glutamic acid potassium; and / or - The at least one peptide derivative is α-L-glutamyltryptamine, which corresponds to CAS No. 478273-36-8 ((4S)-4-amino-5-[[2-(lH-indol-3-yl)ethyl]amino]-5-oxovalerate) and / or corresponds to INCI name glutamylaminoethylindole.

6. The composition according to any one of the preceding claims, characterized in that... The weight ratio of the at least one peptide derivative and one of polyglutamic acid or its salt is 1:200 to 1:10, advantageously 1:100 to 1:

30.

7. The composition according to any one of the preceding claims, characterized in that: - The polyglutamic acid or one of its salts accounts for 0.001% to 10% of the total weight of the composition, advantageously 0.01% to 5%, preferably 0.1% to 2%; and / or - The at least one peptide derivative accounts for 0.00001% to 10% of the total weight of the composition, advantageously 0.0001% to 1%.

8. The non-medical use of the composition according to any one of claims 1 to 7 for combating skin redness and / or skin aging.

9. The composition according to any one of claims 1 to 7, for prevention and / or treatment: - Excessive proliferation of blood vessels in the skin; and / or - Skin inflammation; and / or - Acne vulgaris.

10. An in vitro or extracellular method for selecting a compound or a mixture of compounds, comprising the following steps: a) Measure the content of PEDF protein (pigment epithelium-derived factor) and / or PEDF-encoded nucleic acid in at least one skin cell and / or extracellular space, referred to as the reference value; b) Inhibit PEDF synthesis by exposure to ultraviolet (UV) radiation; c) Contact the compound or mixture of compounds with the skin cells; d) Measure the content of PEDF protein and / or PEDF-encoded nucleic acid in the skin cells and / or extracellular space, referred to as the "candidate compound" value; e) Compare the "candidate compound" value obtained in step d) with the reference value obtained in step a); f) When an increase in the content of PEDF and / or PEDF-encoded nucleic acid is observed in step e), select the compound or a mixture of compounds.

11. The method according to claim 10, characterized in that... The exposure to UV was obtained through the following: - Exposure to UVA, preferably at 750 W / m², with a surface energy of 7.5 J / cm² to 80 J / cm²; or - Exposure to the full solar spectrum, preferably at 750 W / m 2 The surface energy is 7.5 J / cm. 2 Up to 80 J / cm 2 .

Images