Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9706—Algae
  • A61K8/9717—Rhodophycota or Rhodophyta [red algae], e.g. Porphyra
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/02—Algae
  • A61K36/04—Rhodophycota or rhodophyta (red algae), e.g. Porphyra
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/06—Fungi, e.g. yeasts
  • A61K36/062—Ascomycota
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/42—Cucurbitaceae (Cucumber family)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/75—Rutaceae (Rue family)
  • A61K36/752—Citrus, e.g. lime, orange or lemon
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9728—Fungi, e.g. yeasts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• the present invention relates to the use in a cosmetic composition of an activator of autophagy of skin cells as a cosmetic active ingredient.
• the invention also relates to cosmetic compositions comprising at least one autophagic activator for skin cells as a cosmetic active ingredient and a cosmetic process for detoxifying the skin and / or for preventing or combating cutaneous aging, comprising: topical application to the skin of such compositions.
• the skin, organ of contact with the environment, is constantly subjected to external and internal aggression, which threatens its balance and modifies its appearance.
• UV radiation ultraviolet
• various cutaneous manifestations such as actinic erythema, solar elastosis or the premature appearance of the effects of skin aging: the skin becomes loose, deeply wrinkled, rough, dry, strewn with hypopigmented or hyperpigmented spots and dilated vessels.
• These manifestations which reflect profound structural changes in the skin tissue, are unsightly and unsightly and many people tend to want to fade them. This is why the objective of the present invention is to provide an effective means for protecting the skin against the aggressions likely to alter its proper functioning and its appearance, and to fight against the resulting manifestations.
• the present invention proposes using as a cosmetic active ingredient in a cosmetic composition at least one activator of the autophagy of skin cells, in particular keratinocytes and fibroblasts.
• the use of at least one autophagic activator for cutaneous cells makes it possible to fight against the accumulation of deleterious molecules in the cutaneous cells produced in the event of stress and thus to fight against the resulting manifestations.
• the invention relates to the use in a cosmetic composition of at least one autophagic activator of skin cells, in particular keratinocytes and / or fibroblasts, as an active ingredient, for detoxifying skin cells. , fight against aging of the skin, restructure the skin, moisturize and protect the stratum corneum, increase cell renewal, protect cells from the harmful effects of UVA and UVB radiation and limit inflammation phenomena.
• the invention relates to the use in a cosmetic composition of at least one activator of autophagy of skin cells, as an active ingredient for detoxifying skin cells and / or to fight against skin aging.
• a cosmetic composition of at least one activator of autophagy of skin cells as an active ingredient for detoxifying skin cells and / or to fight against skin aging.
• the use according to the invention makes it possible to increase the elimination of damaged molecules, to detoxify the skin and to limit skin aging. Indeed, under certain conditions, especially with age and overexposure to the sun, the skin cells are no longer able to evacuate the molecules damaged by radiation and various stresses. The cells are engorged by these damaged molecules and by free radicals.
• the cosmetic use of autophagic activators of cutaneous cells according to the invention It helps to limit this cellular engorgement and to rid the cells of deleterious and useless elements that hinder its optimal functioning by accumulating.
• the invention also relates to a cosmetic composition for topical application to the skin comprising, in a physiologically acceptable medium, an effective amount of at least one autophagic activator for cutaneous cells chosen from active principles derived from Lithothamnium calcareum, Melilotus off icinalis. , Citrus limonum, Candida saitoana, Lens culinaris, Averrhoa carambola, Momordica charantia, Yarrowia lipolytica and at least one cosmetic adjuvant.
• the autophagic activator of the cutaneous cells is present in an amount of between 0.1 and 15% by weight relative to the total weight of the composition.
• the invention also relates to a cosmetic process for detoxifying the skin and / or for preventing or combating cutaneous aging, comprising the topical application to the skin of a composition comprising at least one activator of the autophagy of the skin. skin cells.
• a cosmetic process for detoxifying the skin and / or for preventing or combating cutaneous aging comprising the topical application to the skin of a composition comprising at least one activator of the autophagy of the skin. skin cells.
• the present invention therefore relates to the use in a cosmetic composition of an activator of autophagy, as a cosmetic active ingredient.
• Autophagy is a mechanism for recycling and detoxifying constituents and cellular organelles.
• autophagy can regulate, repair and eliminate long-lived proteins in cells, thus ensuring control during the differentiation and aging of human skin.
• the mechanism of autophagy comprises four stages: the initiation, the formation of an initial vacuole, called autophagosome, which sequesters the cytoplasmic material, the maturation of the autophagosome in vacuole degraded and fusion with the lysosome, until the degradation of the sequestered material.
• a skin cell autophagic activator useful according to the invention may be an active ingredient having a stimulating activity for the expression of MAP-LC3 (microtubule-associated membrane protein) microtubule-associated membrane proteins. and / or ATG5-12 ("Autophagy-related genes", autophagy genes) of skin cells.
• MAP-LC3 microtubule-associated membrane protein
• ATG5-12 Autophagy-related genes
• the first step of autophagy is the formation of a multimembrane structure, called phagophore, whose origin remains unknown. This structure extends to form the autophagosome that sequesters the cytoplasmic material. The autophagosome fuses with the lysosome and its contents are then degraded by the lysosomal enzymes. During the formation of the autophagosome, ATG proteins are recruited from the cytoplasm and transitably associate with the autophagosomal membrane. This process involves mainly three protein complexes: the class III PI (3) K associated with the Bécline 1 protein and two conjugation systems.
• the early event in the induction of autophagosome formation is the production of phosphatidyl inositol 3-phosphate by the Bécline 1-PI (3) K class III complex which allows the recruitment of the first ATG12-ATG5 conjugation system , also noted ATG5-12.
• the latter allows the conjugation of phosphatidyl ethanolamine (PE) to the MAP-LC3 protein to form the MAP-LC3-PE conjugate, which is then recruited to the autophagosomal membrane.
• PE phosphatidyl ethanolamine
• YATG5-12 is precursor to MAP-LC3 and phosphatidyl ethanolamine (PE) conjugation.
• Map-LC3 are 15kDa proteins found in mammals. They are involved in the formation of autophagosome membranes. There are two forms: a cystolic form the LC3-I and a form bound to the LC3-II membrane.
• Map-LC3 are first cleaved, directly after their synthesis, at their C-terminal part to give the LC3-I cystolic form. During autophagy, LC3-I is converted to LC3-II, and proteins associate with autophagic vacuoles.
• an active ingredient exhibiting an activity stimulating the expression of MAP-LC3 and / or AT65-12 of the cells of the skin makes it possible to stimulate the formation of the autophagosome and therefore to stimulate the formation of the autophagosome. autophagy of the skin cells.
• an activator of skin cell autophagy useful according to the invention may be an active ingredient inhibiting the activation of phosphorylated mTOR.
• MTOR mammalian target of rapamycin
• mammalian rapamycin target is a molecule involved in the initiation of autophagosome formation and acts as a sensor for ATP and regulating amino acids. the balance between nutrient availability and cell growth.
• mTOR When the amount of nutrients is sufficient, mTOR is phosphorylated on the 2448 seine and transmits a positive signal activating cell growth and inhibiting autophagy. In the opposite case, that is to say in conditions of nutritional deprivation or starvation, this phosphorylation disappears in favor of a phosphorylation of threonine 2446, which allows the lifting of the inhibition of autophagy. The mechanism of autophagy is therefore initiated when there is dephosphorylation of mTOR on serine 2448.
• a stimulator of the autophagic activity of cutaneous cells useful according to the invention may be an active ingredient having a stimulating activity for the expression of p53 protein, AMPK and / or DRAM.
• the p53 protein is a major stress protein, capable in particular of: activating DRAM (Damage Regulated Autophagy Modulator) protein, a protein directly involved in the initiation of the mechanism of autophagy, and
• AMPK protein kinase
• the cosmetic use of an active ingredient having an activity stimulating the expression of the phosphorylated p53 protein, DRAM and / or AMPK of the skin cells makes it possible to promote the initiation of autophagy , to mobilize the formation of autophagosomes and thus to stimulate the autophagy of skin cells.
• the cellular consequence of an activation of the mechanism of autophagy by an active principle having a stimulating activity of the expression of MAP-LC3, ATG5-12, phosphorylated p53 protein, DRAM and / or AMPK and or having a phosphorylated mTOR inhibitory activity is a better detoxification of cells, that is to say a decrease in reactive oxygen species and degenerate macromolecules blocked in cutaneous cells.
• the stimulator of the autophagic activity of cutaneous cells useful according to the invention is an active ingredient derived from at least one plant, an alga or a yeast.
• the autophagy activator is an active ingredient derived from at least one algae of the genus Lithothamnium calcareum, or from a plant chosen from Melilotus officinalis, Citrus limonum, Lens culinaris, Averrhoa carambola, Momordica charantia or a yeast selected from Candida saitoana and Yarrowia lipolytica.
• the autophagic activator of cutaneous cells is capable of being selected by a test carried out on cutaneous cell cultures comprising the following steps: - culture of cutaneous cells, keratinocytes or fibroblasts, in a suitable culture medium,
• DRAM and / or AMPK by said cells and comparison of the results with those obtained on cultures of cutaneous cells not treated with the extract to be tested. If there is an increase in the expression of MAP-LC3, of ATG5-l2 phosphorylated protein p53, DRAM protein and / or AMPK I 1, and / or a decrease in phosphorylated mTOR, then the principle tested active can be used in a cosmetic composition as an activator of autophagy of skin cells.
• the protocol consists in submitting normal human HaCaT keratinocytes or keratinocytes to nutrient stress, that is to say to an absence of growth factors, for a certain time and to evaluate the expression of several markers of autophagy during cellular recovery.
• the protocol is as follows:
• the cells are cultured for several times (from 0.5h to 24h) in a state of nutritional stress, after these times of cultures in a state of nutritive stress, withdrawal of the non-nutritive culture medium and replacement with complete culture medium, and finally evaluation of the autophagy state of the cutaneous cells by evaluation of the expression of MAP-LC3 , AT65-12 complex, phosphorylated mTOR, phosphorylated p53, DRAM and phosphorylated AMPK after cell recovery.
• MAP-LC3 after nutritional stress It is possible to evaluate the autophagy of cutaneous cells by visualizing the expression of the MAP-LC3 protein by immunofluorescent labeling.
• the expression of MAP-LC3 was evaluated on skin cell cultures of HaCaT lines and on normal human keratinocytes after different contact times of nutrient stress.
• the immunolabeling results being qualitative, several levels of expression of MAP-LC3 were defined:
• This marking is observable from 1 hour and up to 3 hours of starvation.
• the conditions of nutritive stress thus make it possible to induce a phenomenon of the autophagic type, visualized by the expression ATG5-12.
• phosphorylated mTOR expression was evaluated on skin cell cultures of HaCaT lines and on normal human keratinocytes after different culture times under nutrient stress.
• the expression of phosphorylated mTOR is presented in the table below in percentage relative to the control (without nutritional stress).
• This experiment showed a clear decrease of the phosphorylated mTOR protein visible as early as 8 hours of deprivation, in cutaneous skin cell cultures subjected to starvation.
• the conditions of nutritive stress thus make it possible to induce autophagy on cutaneous cell cultures, visualized by the decrease in the expression of phosphorylated mTOR.
• the evaluation of the expression of the phosphorylated p53 protein was evaluated on skin cell cultures of HaCaT lines and on normal human keratinocytes after different culture times in a state of nutritional stress.
• the expression of phosphorylated p53 is presented in the table below in percentage relative to the control (without nutritional stress).
• This experiment showed a clear increase in the expression of the phosphorylated p53 protein visible as early as 1 hour, in starved cell cultures.
• the conditions of nutritive stress thus make it possible to induce an autophagic type phenomenon on cutaneous cell cultures, visualized by the increase in the expression of the phosphorylated p53 protein.
• This experiment showed a marked increase in the expression of the DRAM protein after 0.5 hour of culture in a state of nutritional stress.
• the expression of the DRAM protein becomes maximal after 1.5 hours of culture in a state of nutritional stress. This coincides with the kinetics of expression of the p53 protein which reaches its maximum after one hour of nutrient stress.
• the conditions of nutritive stress thus make it possible to induce an autophagic type phenomenon on skin cell cultures, visualized by the increase of the expression of the DRAM protein.
• autophagy is possible, as in the case of nutritional stress, by the evaluation of different proteins such as MAP-LC3, the ATG5-12 complex, the phosphorylated mTOR protein, the phosphorylated p53 protein, the DRAM protein or the phosphorylated AMPK protein.
• autophagic expression of cutaneous cells was investigated by analyzing the expression of MAP-LC3, phosphorylated p53 protein and DRAM protein in stressed skin cell cultures.
• the operating protocol is as follows: - cell cultures for 24 hours in complete culture medium
• MAP-LC3 expression was analyzed under these moderate stress conditions (125 ⁇ M and 250 ⁇ M of hydrogen peroxide HzOz) on HaCaT keratinocyte cultures and on normal human keratinocytes.
• the immunolabeling results being qualitative, several levels of AT65-12 expression were defined:
• MAP-LC3 at the level of the cytoplasm of the cells from 0.5 hour of recovery which becomes maximum after 1.5 hours, then decreases from 2 hours of recovery.
• the conditions of nutritive and oxidative stress thus make it possible to induce a phenomenon of the autophagic type, visualized by the increase of the expression of MAP-LC3 in the cutaneous cells.
• DRAM protein It is also possible to evaluate the autophagy of stressed skin cells by visualizing the expression of the DRAM protein by Western Blott. The evaluation of DRAM expression was therefore analyzed under these conditions of moderate stress with 125 ⁇ M of HzO 2 , on HaCaT keratinocyte cultures and on normal human keratinocytes. The expression of DRAM is presented in the following table in percentage relative to the control (without stress).
• so-called young skin cells show an increase in MAP-LC3 expression when subjected to moderate oxidative stress (125, 250, see 400 ⁇ M). When subjected to significant oxidative stress (600 and 1000 ⁇ m), they are placed in apoptosis. The so-called aged skin cells do not exhibit the same increase in MAP-LC3 expression when subjected to the same moderate oxidative stress.
• the screening is carried out according to the protocol of nutritive and oxidative stress presented in point 2.1, starting from active ingredients derived from plants, algae or yeasts.
• the evaluation of the effect of active principles on cutaneous skin autophagy was performed by analyzing the expression of the MAP-LC3 protein in skin cell cultures subjected to nutritive and oxidative stress.
• the test protocol is as follows: - cell cultures for 24 hours in complete culture medium,
• the main active ingredients are:
• the invention also covers cosmetic compositions including at least one active ingredient acting on the autophagy of cutaneous cells in different galenic forms, adapted for topical administration to the skin.
• compositions may especially be in the form of creams, oil-in-water emulsions, water-in-oil emulsions, multiple emulsions, solutions, suspensions or powders. They can be more or less fluid and have the appearance of a cream, a lotion, a milk, a serum, an ointment, a gel, a paste or a foam, or in solid form.
• compositions contain between 0.01 and 15% by weight of active principle (s) acting on autophagy cutaneous cells according to the present invention, preferably between 1% and 4%.
• active principle s
• Expert cream a composition containing between 0.01 and 15% by weight of active principle (s) acting on autophagy cutaneous cells according to the present invention, preferably between 1% and 4%.
• An example of a cream comprising an active ingredient extracted from lemon as presented in point 4 may have the following composition:
• An example of a cream comprising an active ingredient extracted from Lithothamnium as presented in point 4 can have the following composition:
• Night cream An example of a cream comprising an active ingredient extracted from Melilothus as presented in point 4, may have the following composition: A. Water QSP 100% Carbopol ETD 2020 (Noveon) 0.4%
• An example of a cream comprising an active ingredient extracted from Candida saitoana as presented in point 4 may have the following composition: A. Water QSP 100%

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