WO2023214065A1 - Use of phenylene bis-diphenyltriazine for preserving immune defenses of the skin - Google Patents

Use of phenylene bis-diphenyltriazine for preserving immune defenses of the skin Download PDF

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Publication number
WO2023214065A1
WO2023214065A1 PCT/EP2023/062038 EP2023062038W WO2023214065A1 WO 2023214065 A1 WO2023214065 A1 WO 2023214065A1 EP 2023062038 W EP2023062038 W EP 2023062038W WO 2023214065 A1 WO2023214065 A1 WO 2023214065A1
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composition
skin
bis
use according
triazine
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PCT/EP2023/062038
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French (fr)
Inventor
Carine JACQUES
Pascale BIANCHI
Fabrice LESTIENNE
Hélène DUPLAN
Sandrine BESSOU TOUYA
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Pierre Fabre Dermo-Cosmetique
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Publication of WO2023214065A1 publication Critical patent/WO2023214065A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4966—Triazines or their condensed derivatives
    • 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
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • 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
    • A61Q19/005—Preparations for sensitive skin

Definitions

  • the invention relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine (phenylene bis-diphenyltriazine), as well as a composition comprising it, for its use in the preservation of the skin's immune defenses, in particular the preservation of innate immunity.
  • the skin is much more than an external envelope, it is in fact a real organ necessary for life. It is a site of exchange between the body and the external environment, and is therefore exposed to multiple physical, chemical or microbiological attacks, against which it constitutes the first line of anatomical defense.
  • the skin therefore provides, among other things, a real barrier function.
  • the skin is composed of several types of cells organized in three layers: (i) the hypodermis, the deepest layer, consists of adipose tissue; the dermis, the intermediate and thickest layer, corresponds to supportive connective tissue; and (iii) the epidermis, the superficial layer, which mainly contains keratinocytes.
  • the epidermis is separated from the external environment by the stratum corneum (stratum comeum), a protective barrier rich in comeocytes.
  • stratum corneum stratum comeum
  • the skin is not a simple physical barrier: it also constitutes an immunological barrier, capable of developing innate and adaptive immune responses, which make it possible to defend the host against attacks of various kinds.
  • the cutaneous immune system relies on different resident cells with specific and varied functions depending on their location, recruited specialized cellular players (leukocytes) and soluble mediators (cytokines and chemokines).
  • the dermis is home to fibroblasts, mast cells, macrophages and dendritic cells, which participate directly or indirectly in the immunology of the skin.
  • - Keratinocytes which represent 90% of the epidermal cell population, are important in the development of the immune response due to their number and their capacity to secrete cytokines and antimicrobial peptides.
  • - Langerhans cells are dendritic cells which act as true sentinels of the skin's immune system. They have the capacity to detect antigens which cross the stratum corneum and to migrate to the lymph nodes to present them to T lymphocytes.
  • the skin's immune system can be disrupted by various intrinsic or extrinsic factors, such as aging or UV radiation.
  • UVA and/or UVB ultraviolet radiation
  • visible light in particular high-energy visible blue light
  • infrared damage to macromolecules leading to lesions of the skin.
  • DNA oxidative stress, lipid peroxidation and degradation of the dermal matrix.
  • the skin ecosystem made up of the skin, sebum (hydrolipid film) and microbiota (skin flora), must be studied as a whole to understand how its components interact with each other. and help respond to external stress.
  • the inventors have thus developed a model making it possible to reproduce the complexity of skin physiology, and have demonstrated, in a completely unexpected way, that the phenylene bis-diphenyltriazine sunscreen has the capacity to prevent and/or reduce the alteration of the skin immune system.
  • the present invention therefore relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for its use in the preservation of the immune defenses of the skin.
  • 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine (CAS number: 55514-22-2) also called phenylene bis-diphenyltriazine, is a sunscreen; more particularly an ultra-broad spectrum solar filter capable of filtering the harmful part of the solar spectrum, which includes UV radiation (UVB and UVA), but also high energy visible blue light.
  • UVB and UVA UV radiation
  • the names 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine and phenylene bis-diphenyltriazine are used. indifferently.
  • solar filter designates a substance capable of filtering solar radiation to protect a surface, typically the skin or hair, against the harmful effects of this radiation.
  • UV radiation refers to solar ultraviolet radiation but also to artificial ultraviolet radiation, generated by tanning lamps for example.
  • UVA radiation or simply “UVA”, we mean ultraviolet rays having an X wavelength of between 320 and 400 nm.
  • UVB radiation or simply “UVB”, we mean ultraviolet rays having an X wavelength of between 290 and 320 nm.
  • a solar filter is called a “UVA filter” or “UVB filter” depending on whether it mainly filters UVA or UVB.
  • a so-called “broad band” or “broad spectrum” solar filter filters both UVA and UVB.
  • the term “solar filter”, sometimes abbreviated “filter”, will be used interchangeably, whether it is a filter or a screen.
  • a sunscreen can be “fat-soluble” or “water-soluble”, depending on whether it dissolves more easily in lipids or in water, or even “non-soluble”.
  • a non-soluble sunscreen is typically in particulate form, and can nevertheless be integrated into a sun protection composition, in particular in a dispersed form, in particular hydrodispersed when it is dispersed in an aqueous phase.
  • Phenylene bis-diphenyltriazine is a non-soluble type filter. It is in particular a water-dispersible filter, which is typically in the form of an aqueous dispersion, comprising between 20% and 50%, in particular between 40% and 50% by weight of active material relative to the weight. total dispersion.
  • the process for preparing the aqueous dispersion consists of grinding the insoluble organic filter in the form of particles, using a grinding device and in the presence of a grinding aid.
  • a grinding device can be by example a microbead mill, a vibrating mill or a ball mill.
  • the grinding aid is chosen from the group consisting of anionic, nonionic or amphoteric surfactants, emulsifiers and dispersants such as PPG-l-PEG-9 Lauryl Glycol Ether (Eumulgin® L, marketed by BASF).
  • the size D50 of the phenylene bis-diphenyltriazine particles is between 100 and 1000 nm, more particularly between 100 and 500 nm, even more particularly between 120 and 400 nm, in particular between 120 and 250 nm, in particular between 120 and 200 nm, typically between 150 and 200 nm.
  • size D50 or “median”, we mean the size for which the cumulative function F(D) is equal to 50%, F(D) being defined according to the following relationship: in which: f(D) is the particle size distribution in number, and
  • D is a size class.
  • the D50 value can be determined using a Mastersizer 3000 laser diffraction particle size analyzer using the liquid method.
  • Topical application of 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4] triazine prevents and/or reduces impairment of the immune system cutaneous. It thus makes it possible to protect and preserve skin immunity, particularly innate immunity, particularly with regard to external stress, such as exposure to UV radiation.
  • phenylene bis-diphenyltriazine acts specifically on branched amino acids and other lipid markers by limiting the concentration imbalances of these markers in the irradiated skin. These markers are well known for their involvement in the inflammatory response (see, for example, Ye et al. Front Endocrinol (Lausanne). 2020 Sep 8;11:617; Jang et al., J Neuroinflammation. 2020 Jan 22; 17( 1): 30), which underlines the physiological relevance of the action of phenylene bis-diphenyltriazine.
  • Phenylene bis-diphenyltriazine therefore makes it possible to preserve the immune defenses of the skin, in particular its natural immune defenses, that is to say the immune defenses intrinsically present in the skin of a subject, in particular when it is subjected to aggression, such as exposure to UV radiation.
  • the inventors have also surprisingly demonstrated that phenylene bis-diphenyltriazine acts specifically on arachidonic acid and aromatic amino acids.
  • Arachidonic acid is known as a precursor of metabolites that modulate the immune response. Among these metabolites we can cite prostaglandins, which contribute in particular to the development of several inflammatory manifestations (Jang et al., Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception, J Neuroinflammation. 2020 Jan 22;17(l) :30.). Arachidonic acid is therefore known for its direct effects on inflammation. In the context of the present disclosure, the inventors have surprisingly demonstrated that phenylene bis-diphenyltriazine makes it possible to limit imbalances in the concentration of arachidonic acid induced by UV radiation on the skin, and thus to preserve the skin's immune defenses. of a subject.
  • Aromatic amino acids such as Tryptophan and Phenylalanine are known for their role in the immune response. In particular, their imbalance and overproduction is linked to inflammatory mechanisms (Guenin-Macé et al., Dysregulation of tryptophan catabolism at the hostskin microbiota interface in hidradenitis suppurativa. JCI Insight. 2020 Oct 15;5(20):e 140598; Lian et al., Research progress and perspective in metabolism and metabolomics of psoriasis. Chinese Medical Journal 2020 Dec 20;133(24):p 2976-2986).
  • phenylene bis-diphenyltriazine makes it possible to limit imbalances in the concentration of aromatic amino acids induced by UV radiation on the skin, and thus to preserve the immune defenses of the skin. skin of a subject.
  • the present invention also relates to a method for preventing and/or reducing impairment of the cutaneous immune system, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-( 1,4-phenylene)-bis [1,2,4]triazine.
  • the present invention relates to a composition
  • a composition comprising 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine and least one cosmetically and/or pharmaceutically acceptable excipient, for the same uses as those presented above.
  • the composition for use according to the invention is in the form of an emulsion.
  • emulsion is meant, within the meaning of the present invention, any type of emulsion obtained by the dispersion of a discontinuous internal phase in a continuous external phase, one of these phases being an aqueous phase and the other being an oily phase.
  • This is, for example, an oil-in-water or water-in-oil or multiple emulsion, preferably an oil-in-water emulsion.
  • emulsions can be more or less fluid and appear in particular in the form of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, or possibly an aerosol, foam or spray, and can also be water resistant.
  • composition for use according to the invention is intended for topical application to the skin.
  • phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the weight. total composition.
  • mass percentages are expressed as a mass percentage of active material relative to the total mass of the composition.
  • phenylene bis-diphenyltriazine can be combined with one or more other solar filters, to constitute a photoprotective system which allows, after application to a surface (skin, hair, etc.), by absorption and/or reflection and/or diffusion mechanisms of UVA and/or UVB radiation, to prevent, or at least limit, bringing said radiation into contact with said surface.
  • the photoprotective system constituting a composition for use according to the invention preferably comprises one or more lipid-soluble UV filters chosen from the following filters (i) to (v):
  • hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (CAS number: 302776-68-7), also called diethylamino hydroxybenzoyl hexyl benzoate or DHHB, marketed by BASF under the name Uvinul A Plus ®.
  • the DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, in particular between 5% and 7%. %, in particular between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition.
  • the BEMT represents between 1% and 4%, in particular between 2% and 4%, in particular between 2% and 3% by weight relative to the total weight of the composition.
  • the BMDBM represents between 1% and 10%, for example between
  • I% and 8% in particular between 1% and 5%, typically between 2% and 4% by weight, relative to the total weight of the composition.
  • EHT ethylhexyl triazone or EHT (chemical name 4-[[4,6-bis[[4-(2-ethylhexoxy-oxomethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino acid) benzoic 2-ethylhexyl ester; CAS number: 88122-99-00), marketed by BASF under the name Uvinul T 150®.
  • the EHT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3.5% and 4.5% by weight relative to to the total weight of the composition.
  • diethylhexyl butamido triazone or DBT chemical name 4,4'-[[6-[[4-[[(1,1 - dimethylethyl)amino]carbonyl]phenyl]amino]-l,3,5-triazine- 2,4-diyl]diimino]bis-, bis(2-ethylhexyl)benzoate; CAS number: 154702-15-5
  • CAS number: 154702-15-5 marketed by 3V Sigma under the name Uvasorb HEB®.
  • the DBT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3.5% and 4.5% by weight relative to the total weight of the composition.
  • the photoprotective system constituting a composition for use according to the invention may comprise one or more additional particulate organic UV filters, in addition to phenylene bis-diphenyltriazine, chosen from the following filters (vi) and (vii):
  • methylene bis-benzotriazolyl tetramethylbutylphenol (chemical name: 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol; n ° CAS: 103597-45-1) also called MBBT, marketed by BASF under the name Tinosorb M®.
  • MBBT is typically in the form of an aqueous dispersion, comprising between 40% and 60%, typically 50% by weight of active material relative to the total weight of the dispersion.
  • the MBBT represents between 1% and 7%, typically 2% and 6%, in particular between 2% and 5%, in particular between 3% and 4% by weight relative to the total weight of the composition. .
  • the size D50 of the MBBT particles is between 50 nm and 250 nm, in particular between 60 nm and 150 nm.
  • TBPT is typically in the form of an aqueous dispersion, comprising between 40% and 60%, typically 50% by weight of active material relative to the total weight of the dispersion.
  • the TBPT represents between 1% and 7%, in particular between 2% and 7%, in particular between 2% and 6% by weight relative to the total weight of the composition.
  • the size D50 of the TBPT particles is between 50 nm and 250 nm, in particular between 80 nm and 150 nm.
  • the composition for use according to the invention does not comprise ethylhexyl salicylate, octocrylene, ethylhexyl methoxycinnamate, isoamyl methoxylcinnamate, homosalate, para-aminobenzoic acid (PABA ), octyl dimethyl PABA, 3-methylbenzylidene camphor, 4-methylbenzylidene camphor, benzophenone-3 and/or benzophenone-4.
  • PABA para-aminobenzoic acid
  • octyl dimethyl PABA 3-methylbenzylidene camphor
  • 4-methylbenzylidene camphor benzophenone-3 and/or benzophenone-4.
  • composition for use according to the invention does not comprise any water-soluble fiber.
  • water-soluble filters are, generally speaking, more easily assimilated by marine organisms than fat-soluble or non-soluble filters. Consequently, the Applicant's choice of using only liposoluble or particulate filters, in particular hydrodispersed, makes it possible to minimize the impact of the composition according to the invention on the marine environment.
  • the composition for use according to the invention comprises one or more particulate inorganic filters, such as titanium dioxide (TiCfi) or zinc oxide (ZnO).
  • particulate inorganic filters such as titanium dioxide (TiCfi) or zinc oxide (ZnO).
  • the particulate inorganic filter(s) possibly present in the composition according to the invention typically have a particle size D50 of between 15 nm and 150 nm.
  • composition for use according to the invention does not comprise any particulate inorganic filter.
  • the total number of UV filters present in the composition is less than or equal to 5, preferably less than or equal to 4, and all of the UV filters present in the composition composition represent between 4% and 25% by weight, in particular between 6% and 20% by weight, in particular between 7% and 18% by weight, typically between 8% and 17% by weight, relative to the total weight of the composition .
  • the photoprotective system consists of:
  • (d) corresponds to ethylhexyl triazone.
  • the phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the weight.
  • total composition DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, for example between 5% and 7%, in particular between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition
  • the BEMT represents between 1% and 4%, in particular between 2% and 4%, in particular between 2% and 3% by weight of the composition relative to the total weight of the composition
  • the EHT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3, 5% and 4.5% by weight relative to the total weight of the composition.
  • the term "cosmetically and/or pharmaceutically acceptable” is intended to mean that which is useful in the preparation of a composition which can have a cosmetic and/or pharmaceutical application, and which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for human cosmetic or pharmaceutical use.
  • pharmaceutically and/or cosmetically acceptable excipient is meant any cosmetically and/or pharmaceutically acceptable adjuvant allowing the manufacture, conservation or administration of the composition.
  • compositions for use according to the invention may thus comprise conventional pharmaceutical or dermatological adjuvants chosen in particular from liquid lipophilic compounds, emulsifiers, consistency agents, water retention agents, texture agents, opacifiers. , coloring pigments, anti-foaming agents, perfumes, preservatives, polymers, fillers, sequestrants, bactericides, odor absorbers, alkalizing or acidifying agents, surfactants, free radical scavengers, vitamins, alpha-hydroxy acids, active agents (in particular softeners, moisturizing agents, antioxidants) or any other ingredient usually used for the manufacture of anti- solar.
  • conventional pharmaceutical or dermatological adjuvants chosen in particular from liquid lipophilic compounds, emulsifiers, consistency agents, water retention agents, texture agents, opacifiers. , coloring pigments, anti-foaming agents, perfumes, preservatives, polymers, fillers, sequestrants, bactericides, odor absorbers, alkalizing or acidifying agents, surfactants
  • the composition may thus comprise a liquid lipophilic compound or a combination of several liquid lipophilic compounds, typically a liquid lipophilic emollient or a combination of liquid lipophilic emollients, in particular a liquid fatty substance or a combination of liquid fatty substances.
  • a liquid lipophilic compound or a combination of several liquid lipophilic compounds typically a liquid lipophilic emollient or a combination of liquid lipophilic emollients, in particular a liquid fatty substance or a combination of liquid fatty substances.
  • liquid lipophilic compound we mean a compound which has an affinity for non-polar substances such as lipids, and is in liquid form in particular for a temperature between 5°C and room temperature (between 20°C and 25°C). It typically comprises one or more polar chemical function(s) chosen from the ester (-CO2-), alcohol (-OH), ether (-O-), carbonate (-OCO2-) and acid functions.
  • carboxylic acid (-CO2H), and one or more lipophilic group(s), that is to say one or more aliphatic and/or aromatic hydrocarbon group(s), in particular one or more several saturated or unsaturated hydrocarbon chain(s), linear or branched, comprising between 6 and 20 carbon atoms, for example between 7 and 18 carbon atoms, in particular between 8 and 16 carbon atoms, a II can be chosen in particular from C12-C15 alkyl benzoate, caprylic/capric triglycerides, dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl t
  • liquid lipophilic emollient(s) are chosen in particular from C12-C15 alkyl benzoate, caprylic/capric triglycerides and dicaprylyl carbonate.
  • the composition for use according to the invention does not comprise diisopropyl sebacate, diethylhexyl succinate, isopropyl myristate and/or dibutyl adipate.
  • it does not include dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2- ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isononoate, butylene glycol, dicaprylate/dicaprate, octyldodecanol
  • the composition may further comprise a polyol miscible with water at room temperature (approximately 25°C), in particular chosen from polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having 2 to 6 carbon atoms, such as glycerin; glycol derivatives such as propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol; glycol ethers such as C1-C4 alkyl ethers of mono-, di- or tri-propylene glycol, C1-C4 alkyl ethers of mono-, di- or tri-ethylene glycol and mixtures thereof .
  • polyol miscible with water at room temperature approximately 25°C
  • polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having 2 to 6 carbon atoms, such as glycerin;
  • the composition may also comprise one or more anionic, cationic and nonionic emulsifiers chosen from glucose derivatives such as cetearyl glucoside, arachidyl glucoside, lauryl glucoside, polyglyceryl-3 methylglucose distearate and methyl glucose sesquistearate; sucrose derivatives such as sucrose polystearate and sucrose palmitate; glycerides of fatty acids such as glyceryl stearate, glyceryl oleate and glyceryl stearate citrate; glutamic acid derivatives such as sodium stearoyl glutamate; sulfosuccinic acid derivatives such as disodium cetearyl sulfosuccinate and sodium dioctyl sulfosuccinate; phosphoric acid derivatives such as potassium cetyl phosphate; polyglyceryl fatty acid esters such as polyglyceryl-3-diisostearate and polygly
  • the emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.
  • composition for use according to the invention does not comprise an ethoxylated emulsifier and/or comprising a PEG chain.
  • the composition does not include sorbitol derivatives such as polysorbate-n and PEG-10 sorbitan laurate; fatty alcohol and fatty acid polyglycol ethers such as ceteareth-20, beheneth-25, steareth-2 and PEG-100 stearate; and organomodified oxyalkenylated silicone/polysiloxane/polyalkyl/polyether copolymers and derivatives.
  • sorbitol derivatives such as polysorbate-n and PEG-10 sorbitan laurate
  • fatty alcohol and fatty acid polyglycol ethers such as ceteareth-20, beheneth-25, steareth-2 and PEG-100 stearate
  • organomodified oxyalkenylated silicone/polysiloxane/polyalkyl/polyether copolymers and derivatives organomodified oxyalkenylated silicone/polysiloxane/polyalkyl/polyether cop
  • the composition may also comprise one or more consistency agents in solid form chosen from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyl stearate; THE polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; cellulose derivatives such as hydroxypropylcellulose; waxes such as beeswax, carnauba wax, microcrystalline wax, ceresin, and ozocerite; polyacrylates or homopolymers of crosslinked acrylic acids or polyacrylamides such as carbomers, acrylate copolymers, crosslinked acrylate/(Cio-C3o)alkylacrylate copolymers, acrylate/behenethyl-25 methacrylate copolymers; and silicate derivatives such as magnesium silicates.
  • fatty alcohols such as cetyl alcohol, cet
  • the composition for use according to the invention comprises one or more consistency agents chosen from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyl stearate; polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; and cellulose derivatives such as hydroxypropylcellulose.
  • fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol
  • fatty acids such as stearic acid
  • fatty acid esters such as myristyl stearate
  • polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan
  • cellulose derivatives such as hydroxypropylcellulose.
  • the composition does not include a consistency agent chosen from acrylates and their derivatives.
  • the composition may also comprise one or more water retention agents chosen from a copolymer of N-vinylpyrrolidone (VP) and eicosene (INCI: VP/eicosen copolymer), a crosslinked polymer of trimethylpentanediol, adipic acid and glycerol (INCI: trimethylpentanediol/adipic acid/glycerin crosspolymer), polyamide 3 (INCI), a copolymer of acrylate and octylacrylamide (INCI: acrylates/octylacrylamide copolymer), and triacontanyl PVP (INCI).
  • VP N-vinylpyrrolidone
  • INCI eicosene
  • a crosslinked polymer of trimethylpentanediol, adipic acid and glycerol INCI: trimethylpentanediol/adipic acid/glycerin crosspoly
  • the composition for use according to the invention comprises VP/eicosene copolymer as a water retention agent.
  • composition may also comprise one or more texturing agents in the form of powders, in particular chosen from ingredients of the starch family, such as rice, corn and tapioca starches; talcs and cellulose derivatives such as microcrystalline cellulose.
  • the composition for use according to the invention does not comprise a texturing agent chosen from nylon derivatives and polymethyl methacrylate (PMMA).
  • a texturing agent chosen from nylon derivatives and polymethyl methacrylate (PMMA).
  • the composition may also comprise coloring pigments, in particular chosen from CI77891, CI77491, CI77492 and CI77499 (INCI designations).
  • the composition for use according to the invention comprises a quantity of C1-C4 alcohols, such as ethanol and isopropanol, less than or equal to 4% by weight, preferably less than or equal to 2% by weight, in particular less than or equal to 1% by weight, in particular less than or equal to 0.5% by weight, relative to the total weight of the composition.
  • the composition is free of ethanol and isopropanol.
  • the composition for use according to the invention comprises a quantity of volatile ingredients less than or equal to 5% by weight, preferably less than or equal to 2% by weight, in particular less than or equal to 1% by weight, in particular less than or equal to 0.5% by weight, relative to the total weight of the composition.
  • volatile ingredients is meant, within the meaning of the present invention, non-alcoholic volatile organic or inorganic compounds such as esters, silicones or volatile alkanes, characterized by a flash point below 60°C.
  • flash point flash point (denoted PE), we mean, within the meaning of the present invention, the minimum temperature at which a combustible substance emits vapors in sufficient concentration to form a gaseous mixture with the ambient air which ignites on contact.
  • a substance with a PE such as 23°C ⁇ PE ⁇ 60°C belongs to the category 3 “lowly flammable”.
  • volatile esters we can notably cite isohexyl neopentanoate.
  • volatile silicones we can notably cite cyclopentasiloxane.
  • volatile alkanes we can notably cite isohexadecane.
  • composition for use according to the invention is devoid of volatile ingredients within the meaning of the present invention.
  • the composition may also comprise alkalizing or acidifying agents, and more particularly acids and bases making it possible to adjust the pH zone of said composition.
  • the bases can be mineral (soda, potash, ammonia, etc.) or organic, such as mono-, dion triethanolamine, aminomethylpropanediol, N-methyl-glucamine, basic amino acids such as arginine and lysine, and their mixtures.
  • Acids can be mineral (hydrochloric acid, etc.) or organic, such as lactic acid and citric acid.
  • composition for use according to the invention may further comprise additional active agents chosen in particular from moisturizing agents, desquamating agents, improving the barrier function, depigmenting agents, anti-oxidant agents, dermocontracting agents, anti-glycation agents, agents stimulating the synthesis of dermal and/or epidermal macromolecules and/or preventing their degradation, agents stimulating the proliferation of fibroblasts or keratinocytes and/or the differentiation of keratinocytes, NO synthase inhibitors, agents increasing the activity of the sebaceous gland, tensing agents, liporestructuring agents, slimming agents, agents promoting skin microcirculation, agents soothing and/or irritant agents, sebo-regulators or anti-seborrheic agents, astringent agents, healing agents, anti-inflammatory agents, anti-acne agents, and mixtures thereof.
  • additional active agents chosen in particular from moisturizing agents, desquamating agents, improving the barrier function, depigmenting agents, anti-oxidant agents, derm
  • composition for use according to the invention is silicone-free.
  • the composition for use according to the invention comprises one or more antioxidants, typically chosen from vitamin E and its derivatives.
  • the composition for use according to the invention comprises one or more compounds chosen from tocopherols, tocotrienols and their derivatives.
  • tocopherols or “tocotrienols” is meant the compounds a-, P-, y- and ô-tocopherol or tocotrienol.
  • the term “tocopherol” usually refers to a-tocopherol.
  • ester derivatives such as tocopheryl acetate
  • glycosylated derivatives such as tocopheryl glucoside (INCI: tocopheryl glucoside).
  • the composition for use according to the invention comprises one or more antioxidants chosen from tocopherol and its derivatives, in particular from tocopherol, tocopherol glycoside and mixtures thereof, in an amount typically between 0 .01% and 1% by weight relative to the total weight of the composition.
  • the inventors have developed a model of reconstructed human epidermis (RHE) colonized by skin microbiota and sebum from donors in order to reproduce the complexity of the skin ecosystem. This model comes closer to the reality of skin physiology and makes it possible to study the interactions between the skin and the microbiota.
  • RHE reconstructed human epidermis
  • the epidermis was reconstructed from skin excisions from cosmetic surgery according to the method described by Frankart et al. (Frankart et al., Exp. Dermatol. 2012, 21(11), 871-875). Briefly, the cells (keratinocytes) were isolated from skin excisions, then cultured before being seeded on culture inserts immersed in culture medium then the culture inserts are placed at the air/liquid interface in an incubator at 37°C in a humidified atmosphere with 5% CO2, to form the stratum corneum.
  • Sebum is collected from the foreheads of 10 volunteers without apparent skin pathology using a standard collection kit. Each collection tube is then washed 3 times with hexane to extract the sebum. The extracts are then combined and the solvent is evaporated under vacuum. The mass of the sebum collected is controlled (e.g. 1,100 mg for a preparation) then the sebum is taken up in 20 ml of hexane. 100 vials of sebum are made with 9 mg of substance per vial and packaged under argon. For the deposition of sebum on the reconstructed epidermis, the vials are then taken up with 250 ⁇ L of absolute ethanol (Fischer Scientific, Illkirch, France) then diluted 1/20 in physiological serum.
  • absolute ethanol Fisher Scientific, Illkirch, France
  • the microbiota is collected from 18 volunteers without apparent skin pathology using a swab soaked in physiological serum (Fischer Scientific, Illkirch, France) containing 0.1% by volume of Triton X-100 (Fischer Scientific, Illkirch, France). ). The swab is rubbed energetically on the donor's forehead for 40 seconds. Each swab is then placed in a tube to be centrifuged. After centrifugation, a colorless liquid is recovered (approximately 60 pL) and its volume is adjusted to 120 pL with physiological saline. Each microbiota is then mixed with the sebum in order to be able to produce the deposit.
  • the sebum/microbiota mixture (22 pL) is deposited on the surface of the reconstructed human epidermis and spread using a finger cot.
  • the reconstructed human epidermis thus obtained are incubated at 32°C, 5% CO2, 60% humidity for 24 hours.
  • the reconstructed epidermis are irradiated by simulated solar radiation using a Suntest CPS+ chamber (ATLAS Material Testing Technology BV, Moussy le Neuf, France) equipped with an NXE 1500 xenon lamp, and equipped with a UV filter to eliminate the lengths waves less than 290 nm.
  • the irradiance in the UV spectra is approximately 70 W/m 2 from 290 to 400 nm.
  • the skin models are exposed to a single acute UV dose of 16.5 J/cm 2 (approximately 45 min) and the irradiation chamber is maintained at 37°C using ice-cold water and a flow of air.
  • Formulation A or B is applied at a dose of 2 mg/cm 2 to the surface of the reconstructed epidermis. After irradiation with the total solar spectrum (up to 790 nm), the model is maintained in culture for 24 hours at 32°C and 60% humidity.
  • the surface of the reconstructed epidermis is washed twice with 100 ⁇ L of physiological serum, and then dried with a cotton swab. This step aims to recover the skin microbiota as well as the hydrolipidic film.
  • the reconstructed epidermis are separated from the insert and are weighed in order to standardize the results obtained with the metabolomic approach.
  • the reconstructed epidermis is crushed and 108 samples are extracted. Briefly, samples are ground in 2 x ImL of acetonitrile/water 1/9 (v:v) with fastprep using Lysing Matrix M tubes, 6 cycles of 20 seconds at force 4, with 2 min on ice between each cycle . A volume of 800 pL of each sample was evaporated to dryness with a SpeedVac then normalized in 220 pL of D2O. The samples were analyzed by NMR then mass spectrometry.
  • 1H NMR spectra are obtained at 300 K on a Bruker Avance III HD 600 MHz NMR spectrometer (Bruker Biospin, Rheinstetten, Germany), operating at 600.13 MHz for the resonance frequency 1H, using a 5 mm reverse sensing 1H-13C-15N-31P cryoprobe attached to a Cryoplatform (the preamplification unit).
  • 1H NMR spectra are acquired using the NOESY 1D experiment with pre-saturation for water removal (noesyprld), with a mixing time of 100 ms.
  • samples are transferred from NMR tubes to UHPLC vials.
  • the samples are centrifuged at 9000 g for 5 min.
  • a volume of 10 pL is then injected into the ACQUITY UHPLC system from Waters (Manchester, UK), using water/methanol/acetic acid 95/5/0.1 (v:v:v) as mobile phase A and methanol/acetic acid 100/0.1 (v:v) as mobile phase B, at a flow rate of 0.3 mL/min.
  • the following gradient is used: 0-30 min: 0% to 100% B, 30-34 min: 100% B.
  • the separation is carried out at 30°C with a Hypersil Gold C18 column (100 x 2.1 mm , 1.9 pm) from Thermo Scientific (Les Ulis, France).
  • the following electrospray parameters are applied: capillary voltage of 0.5 kV, sampling cone voltage of 30 V, source temperature of 120 °C, desolvation temperature of 350 °C, cone gas flow rate of 50 L/h and desolvation gas flow rate of 600 L/h in positive mode; capillary voltage of 0.5 kV, sampling cone voltage of 30 V, source temperature of 120 °C, desolvation temperature of 550 °C, cone gas flow rate of 30 L/h and gas flow rate of desolvation of 600 L/h in negative mode.
  • High-resolution mass spectra are acquired with a Synapt G2-Si mass spectrometer from Waters (Manchester, UK), between m/z 50 and 800 in sensitivity and centroid modes. Samples are analyzed randomly, and a QC sample, corresponding to a pool of all samples, is analyzed 11 times along the sequence.
  • the structural identifications of the discriminating metabolites are carried out on an LTQ Orbitrap XL mass spectrometer (Thermo Scientific, Les Ulis, France) coupled to a U3000 liquid chromatography system (Thermo Scientific, Les Ulis, France).
  • Data are normalized to allow quantification of signals detected in multiple samples.
  • Principal component analysis is first applied to check the validity of the acquisition, to detect potential outliers and internal clusters.
  • Multivariate analyzes are carried out using SIMCA vl5 software (Umetrics, Umeâ, Sweden).
  • the mixOmics package (Rohart et al., 2017) is used to perform multilevel analyses.
  • the analysis pipeline includes mapping metabolomics data to an organism's specific metabolic network, then applying graph-based methods and advanced visualization tools to improve data analysis.
  • BCAAs aromatic amino acids and their metabolites play an important role in the immune response.
  • Arachidonic acid and its metabolites are well known as modulators of immune responses.
  • the following table shows the concentrations of arachidonic acid in the reconstructed epidermis, determined by liquid chromatography - mass spectrometry (LC/MS).
  • UV radiation induces a significant decrease in the concentration of arachidonic acid in the reconstructed epidermis.
  • Topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to maintain a level of arachidonic acid equivalent to a control group, despite exposure to UV radiation.

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Abstract

The present invention relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine, or a composition comprising same, for use in preserving the immune defenses of the skin, in particular preserving innate immunity.

Description

UTILISATION DE LA PHÉNYLÈNE BIS-DIPHÉNYLTRIAZINE POUR LA PRÉSERVATION DES DÉFENSES IMMUNITAIRES DE LA PEAU USE OF PHENYLENE BIS-DIPHENYLTRIAZINE FOR THE PRESERVATION OF SKIN IMMUNE DEFENSES
Domaine de T invention Field of invention
L’invention concerne la 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine (phénylène bis- diphényltriazine), ainsi qu’une composition la comprenant, pour son utilisation dans la préservation des défenses immunitaires de la peau, en particulier la préservation de l’immunité innée. The invention relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine (phenylene bis-diphenyltriazine), as well as a composition comprising it, for its use in the preservation of the skin's immune defenses, in particular the preservation of innate immunity.
Contexte technique Technical background
La peau est bien plus qu’une enveloppe externe, elle est en effet un véritable organe nécessaire à la vie. Elle est un terrain d’échange entre le corps et l’environnement extérieur, et est de ce fait exposée à de multiples agressions physiques, chimiques ou microbiologiques, vis-à-vis desquelles elle constitue la première ligne de défense anatomique. La peau assure donc, entre autres, une véritable fonction barrière. The skin is much more than an external envelope, it is in fact a real organ necessary for life. It is a site of exchange between the body and the external environment, and is therefore exposed to multiple physical, chemical or microbiological attacks, against which it constitutes the first line of anatomical defense. The skin therefore provides, among other things, a real barrier function.
La peau est composée de plusieurs types de cellules organisés en trois couches : (i) l’hypoderme, la couche la plus profonde, consiste en un tissu adipeux ; le derme, la couche intermédiaire et la plus épaisse, correspond à un tissu conjonctif de soutien ; et (iii) l’épiderme, la couche superficielle, qui comporte principalement des kératinocytes. L’épiderme est séparé de l’environnement extérieur par la couche cornée (stratum comeum), barrière de protection riche en coméocytes. La peau n’est cependant pas une simple barrière physique : elle constitue en effet également une barrière immunologique, capable de développer des réponses immunitaires innée et adaptative, qui permettent de défendre l’hôte contre des agressions de natures diverses. The skin is composed of several types of cells organized in three layers: (i) the hypodermis, the deepest layer, consists of adipose tissue; the dermis, the intermediate and thickest layer, corresponds to supportive connective tissue; and (iii) the epidermis, the superficial layer, which mainly contains keratinocytes. The epidermis is separated from the external environment by the stratum corneum (stratum comeum), a protective barrier rich in comeocytes. However, the skin is not a simple physical barrier: it also constitutes an immunological barrier, capable of developing innate and adaptive immune responses, which make it possible to defend the host against attacks of various kinds.
Le système immunitaire cutané repose sur différentes cellules résidentes pourvues de fonctions spécifiques et variées selon leur localisation, des acteurs cellulaires spécialisés recrutés (leucocytes) et des médiateurs solubles (cytokines et chimiokines). The cutaneous immune system relies on different resident cells with specific and varied functions depending on their location, recruited specialized cellular players (leukocytes) and soluble mediators (cytokines and chemokines).
Le derme abrite notamment des fibroblastes, des mastocytes, des macrophages et des cellules dendritiques, qui participent de manière directe ou indirecte à l’immunologie de la peau. The dermis is home to fibroblasts, mast cells, macrophages and dendritic cells, which participate directly or indirectly in the immunology of the skin.
Au sein de l’épiderme, deux types de cellules jouent un rôle majeur dans l’immunité cutanée, qu’elle soit innée ou adaptative. Within the epidermis, two types of cells play a major role in skin immunity, whether innate or adaptive.
- Les kératinocytes, qui représentent 90 % de la population cellulaire épidermique, sont importants dans le développement de la réponse immunitaire de par leur nombre et leur capacité à sécréter des cytokines et des peptides antimicrobiens. - Les cellules de Langerhans, sont des cellules dendritiques qui font office de véritables sentinelles du système immunitaire cutanée. Elles ont en effet la capacité de détecter les antigènes qui franchissent la couche cornée et de migrer jusqu’aux ganglions lymphatiques pour les présenter aux lymphocytes T. - Keratinocytes, which represent 90% of the epidermal cell population, are important in the development of the immune response due to their number and their capacity to secrete cytokines and antimicrobial peptides. - Langerhans cells are dendritic cells which act as true sentinels of the skin's immune system. They have the capacity to detect antigens which cross the stratum corneum and to migrate to the lymph nodes to present them to T lymphocytes.
Le système immunitaire cutané peut être perturbé par différents facteurs intrinsèques ou extrinsèques, tels que le vieillissement ou les rayonnements UV. The skin's immune system can be disrupted by various intrinsic or extrinsic factors, such as aging or UV radiation.
Le domaine de la photoprotection reste un enjeu majeur de santé public pour prévenir les dommages cutanés d’une surexposition solaire. Les altérations de la peau sont majoritairement induites par les radiations ultraviolettes (UVA et/ou UVB), mais aussi par la lumière visible, notamment la lumière bleue haute énergie visible, et les infrarouges via des dommages sur les macromolécules entraînant des lésions de l’ADN, du stress oxydatif, la peroxydation lipidique et une dégradation de la matrice dermique. The field of photoprotection remains a major public health issue to prevent skin damage from overexposure to the sun. Skin changes are mainly induced by ultraviolet radiation (UVA and/or UVB), but also by visible light, in particular high-energy visible blue light, and infrared via damage to macromolecules leading to lesions of the skin. DNA, oxidative stress, lipid peroxidation and degradation of the dermal matrix.
Pour évaluer l’impact de l’exposition au soleil, l’écosystème cutané, constitué de la peau, du sébum (film hydrolipidique) et du microbiote (flore cutanée), doit être étudié dans son ensemble pour comprendre comment ses composantes interagissent entre elles et contribuent à répondre au stress externe. Les inventeurs ont ainsi développé un modèle permettant de reproduire la complexité de la physiologie cutanée, et ont mis en évidence, de façon tout à fait inattendue, que le filtre solaire phénylène bis-diphényltriazine a la capacité de prévenir et/ou diminuer l’altération du système immunitaire cutané. To assess the impact of exposure to the sun, the skin ecosystem, made up of the skin, sebum (hydrolipid film) and microbiota (skin flora), must be studied as a whole to understand how its components interact with each other. and help respond to external stress. The inventors have thus developed a model making it possible to reproduce the complexity of skin physiology, and have demonstrated, in a completely unexpected way, that the phenylene bis-diphenyltriazine sunscreen has the capacity to prevent and/or reduce the alteration of the skin immune system.
Description de l’invention Description of the invention
La présente invention concerne donc la 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine pour son utilisation dans la préservation des défenses immunitaires de la peau. The present invention therefore relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for its use in the preservation of the immune defenses of the skin.
La 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine, (n° CAS : 55514-22-2) également appelée phénylène bis-diphényltriazine, est un filtre solaire ; plus particulièrement un filtre solaire à spectre ultra large capable de filtrer la partie nocive du spectre solaire, laquelle inclut le rayonnement UV (UVB et UVA), mais également la lumière bleue haute énergie visible. Dans la suite de la description, les appellations 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine et phénylène bis-diphényltriazine sont utilisées indifféremment. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine, (CAS number: 55514-22-2) also called phenylene bis-diphenyltriazine, is a sunscreen; more particularly an ultra-broad spectrum solar filter capable of filtering the harmful part of the solar spectrum, which includes UV radiation (UVB and UVA), but also high energy visible blue light. In the remainder of the description, the names 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine and phenylene bis-diphenyltriazine are used. indifferently.
Le terme « filtre solaire » désigne une substance capable de filtrer les rayonnements solaires pour protéger une surface, typiquement la peau ou les cheveux, contre les effets nocifs de ces radiations.The term “solar filter” designates a substance capable of filtering solar radiation to protect a surface, typically the skin or hair, against the harmful effects of this radiation.
Le terme « rayonnement ultraviolet » ou « rayonnement UV », communément abrégé « UV », désigne le rayonnement ultraviolet solaire mais également le rayonnement ultraviolet artificiel, généré par des lampes de bronzage par exemple. The term “ultraviolet radiation” or “UV radiation”, commonly abbreviated “UV”, refers to solar ultraviolet radiation but also to artificial ultraviolet radiation, generated by tanning lamps for example.
Par « rayonnement UVA » ou simplement « UVA », on entend désigner les rayons ultraviolets ayant une longueur d’onde X comprise entre 320 et 400 nm. By “UVA radiation” or simply “UVA”, we mean ultraviolet rays having an X wavelength of between 320 and 400 nm.
Par « rayonnement UVB » ou simplement « UVB », on entend désigner les rayons ultraviolets ayant une longueur d’onde X comprise entre 290 et 320 nm. By “UVB radiation” or simply “UVB”, we mean ultraviolet rays having an X wavelength of between 290 and 320 nm.
Un filtre solaire est qualifié de « filtre UVA » ou « filtre UVB » selon qu’il filtre majoritairement les UVA ou les UVB. A solar filter is called a “UVA filter” or “UVB filter” depending on whether it mainly filters UVA or UVB.
Un filtre solaire dit « large bande » ou encore « large spectre » filtre à la fois les UVA et les UVB. A so-called “broad band” or “broad spectrum” solar filter filters both UVA and UVB.
Selon le mécanisme de filtration du rayonnement, c’est-à-dire selon que le rayonnement est absorbé et/ou réfléchi, voire diffusé par le filtre solaire, on distingue, en toute rigueur : Depending on the radiation filtration mechanism, that is to say whether the radiation is absorbed and/or reflected, or even diffused by the solar filter, we strictly distinguish:
- les filtres stricto sensu, qui majoritairement absorbent le rayonnement, et - filters stricto sensu, which mainly absorb the radiation, and
- les écrans, qui absorbent et réfléchissent le rayonnement. - screens, which absorb and reflect radiation.
Toutefois, dans la suite de la description, on utilisera indifféremment le terme « filtre solaire », parfois abrégé « filtre », qu’il s’agisse d’un filtre ou d’un écran. However, in the remainder of the description, the term “solar filter”, sometimes abbreviated “filter”, will be used interchangeably, whether it is a filter or a screen.
Un filtre solaire peut être « liposoluble » ou « hydrosoluble », selon qu’il se solubilise plus facilement dans les lipides ou dans l’eau, ou encore « non soluble ». Un filtre solaire non soluble se présente typiquement sous forme particulaire, et peut néanmoins être intégré dans une composition de protection solaire, notamment sous une forme dispersée, en particulier hydrodispersée lorsqu’il est dispersé dans une phase aqueuse. A sunscreen can be “fat-soluble” or “water-soluble”, depending on whether it dissolves more easily in lipids or in water, or even “non-soluble”. A non-soluble sunscreen is typically in particulate form, and can nevertheless be integrated into a sun protection composition, in particular in a dispersed form, in particular hydrodispersed when it is dispersed in an aqueous phase.
Ua phénylène bis-diphényltriazine est un filtre de type non soluble. Il s’agit en particulier d’un filtre hydrodispersible, qui se présente typiquement sous la forme d’une dispersion aqueuse, comprenant entre 20 % et 50 %, en particulier entre 40 % et 50 % en poids de matière active par rapport au poids totale de la dispersion. Phenylene bis-diphenyltriazine is a non-soluble type filter. It is in particular a water-dispersible filter, which is typically in the form of an aqueous dispersion, comprising between 20% and 50%, in particular between 40% and 50% by weight of active material relative to the weight. total dispersion.
Avantageusement, le procédé de préparation de la dispersion aqueuse consiste en un broyage du filtre organique insoluble sous forme de particules, à l’aide d’un appareil de broyage et en présence d’un adjuvant de broyage. Classiquement, des procédés de broyage en voie humide sont utilisés (broyage humide, malaxage par voie humide) et l’adjuvant de broyage permet une meilleure dispersion des particules. Ces techniques sont bien connues de l’homme de l’art. U’appareil de broyage peut être par exemple un broyeur à microbilles, un broyeur vibrant ou un broyeur à boulets. En fonction du procédé de broyage, l’adjuvant de broyage est choisi dans le groupe constitué des tensioactifs anioniques, non ioniques ou amphotères, des émulsifiants et des dispersants tel que le PPG-l-PEG-9 Lauryl Glycol Ether (Eumulgin® L, commercialisée par BASF). Advantageously, the process for preparing the aqueous dispersion consists of grinding the insoluble organic filter in the form of particles, using a grinding device and in the presence of a grinding aid. Conventionally, wet grinding processes are used (wet grinding, wet kneading) and the grinding aid allows better dispersion of the particles. These techniques are well known to those skilled in the art. The grinding device can be by example a microbead mill, a vibrating mill or a ball mill. Depending on the grinding process, the grinding aid is chosen from the group consisting of anionic, nonionic or amphoteric surfactants, emulsifiers and dispersants such as PPG-l-PEG-9 Lauryl Glycol Ether (Eumulgin® L, marketed by BASF).
Dans un mode de réalisation particulier, la taille D50 des particules de phénylène bis-diphényltriazine est comprise entre 100 et l OOO nm, plus particulièrement entre 100 et 500 nm, encore plus particulièrement entre 120 et 400 nm, notamment entre 120 et 250 nm, en particulier entre 120 et 200 nm, typiquement entre 150 et 200 nm. In a particular embodiment, the size D50 of the phenylene bis-diphenyltriazine particles is between 100 and 1000 nm, more particularly between 100 and 500 nm, even more particularly between 120 and 400 nm, in particular between 120 and 250 nm, in particular between 120 and 200 nm, typically between 150 and 200 nm.
Par « taille D50 » ou « médiane », on entend désigner la taille pour laquelle la fonction cumulative F(D) est égale à 50 %, F(D) étant définie selon la relation suivante :
Figure imgf000005_0001
dans laquelle : f(D) est la distribution de tailles des particules en nombre, et By “size D50” or “median”, we mean the size for which the cumulative function F(D) is equal to 50%, F(D) being defined according to the following relationship:
Figure imgf000005_0001
in which: f(D) is the particle size distribution in number, and
D est une classe de taille. D is a size class.
La valeur de la D50 peut être déterminée à l’aide d’un granulomètre à diffraction laser Mastersizer 3000 en voie liquide. The D50 value can be determined using a Mastersizer 3000 laser diffraction particle size analyzer using the liquid method.
L’application topique de 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4] triazine prévient et/ou diminue l’altération du système immunitaire cutané. Elle permet ainsi de protéger et préserver l’immunité cutanée, notamment l’immunité innée, en particulier vis-à-vis d’un stress externe, telle qu’une exposition aux rayonnements UV. En particulier, les inventeurs ont démontré de manière surprenante que la phénylène bis-diphényltriazine agit de façon spécifique sur les acides aminés ramifiés et d’autres marqueurs lipidiques en limitant les déséquilibres de concentration de ces marqueurs dans la peau irradiée. Ces marqueurs sont bien connus pour leur implication dans la réponse inflammatoire (voir, par exemple, Ye et al. Front Endocrinol (Lausanne). 2020 Sep 8;11:617 ; Jang et al., J Neuroinflammation. 2020 Jan 22; 17(1): 30), ce qui souligne la pertinence physiologique de l’action de la phénylène bis-diphényltriazine. Topical application of 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4] triazine prevents and/or reduces impairment of the immune system cutaneous. It thus makes it possible to protect and preserve skin immunity, particularly innate immunity, particularly with regard to external stress, such as exposure to UV radiation. In particular, the inventors have surprisingly demonstrated that phenylene bis-diphenyltriazine acts specifically on branched amino acids and other lipid markers by limiting the concentration imbalances of these markers in the irradiated skin. These markers are well known for their involvement in the inflammatory response (see, for example, Ye et al. Front Endocrinol (Lausanne). 2020 Sep 8;11:617; Jang et al., J Neuroinflammation. 2020 Jan 22; 17( 1): 30), which underlines the physiological relevance of the action of phenylene bis-diphenyltriazine.
La phénylène bis-diphényltriazine permet donc de préserver les défenses immunitaires de la peau, en particulier ses défenses immunitaires naturelles, c’est-à-dire les défenses immunitaires intrinsèquement présentes dans la peau d’un sujet, en particulier lorsque celle-ci est soumise à une agression, telle qu’une exposition aux rayonnements UV. Les inventeurs ont aussi démontré de manière surprenante que la phénylène bis-diphényltriazine agit de façon spécifique sur l’acide arachidonique et les acides aminés aromatiques. Phenylene bis-diphenyltriazine therefore makes it possible to preserve the immune defenses of the skin, in particular its natural immune defenses, that is to say the immune defenses intrinsically present in the skin of a subject, in particular when it is subjected to aggression, such as exposure to UV radiation. The inventors have also surprisingly demonstrated that phenylene bis-diphenyltriazine acts specifically on arachidonic acid and aromatic amino acids.
L’acide arachidonique est connu comme précurseur de métabolites modulateurs de la réponse immunitaire. Parmi ces métabolites on peut citer les prostaglandines, qui contribuent notamment au développement de plusieurs manifestations inflammatoire (Jang et al., Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception, J Neuroinflammation. 2020 Jan 22;17(l):30.). L’acide arachidonique est donc connu pour ses effets directs sur l’inflammation. Dans le cadre de la présente divulgation, les inventeurs ont démontré de façon surprenante que la phénylène bis-diphényltriazine permet de limiter les déséquilibres de concentration en acide arachidonique induit par des rayonnements UV sur la peau, et ainsi de préserver les défenses immunitaires de la peau d’un sujet. Arachidonic acid is known as a precursor of metabolites that modulate the immune response. Among these metabolites we can cite prostaglandins, which contribute in particular to the development of several inflammatory manifestations (Jang et al., Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception, J Neuroinflammation. 2020 Jan 22;17(l) :30.). Arachidonic acid is therefore known for its direct effects on inflammation. In the context of the present disclosure, the inventors have surprisingly demonstrated that phenylene bis-diphenyltriazine makes it possible to limit imbalances in the concentration of arachidonic acid induced by UV radiation on the skin, and thus to preserve the skin's immune defenses. of a subject.
Les acides aminés aromatiques (tels que le Tryptophane et la Phénylalanine) sont connus pour leur rôle dans la réponse immunitaire. En particulier, leur déséquilibre et surproduction est en lien avec les mécanismes inflammatoires (Guenin-Macé et al., Dysrégulation of tryptophan catabolism at the hostskin microbiota interface in hidradenitis suppurativa. JCI Insight. 2020 Oct 15;5(20):e 140598 ; Lian et al., Research progress and perspective in metabolism and metabolomics of psoriasis. Chinese Medical Journal 2020 Dec 20;133(24):p 2976-2986). Dans le cadre de la présente divulgation, les inventeurs ont démontré de façon surprenante que la phénylène bis-diphényltriazine permet de limiter les déséquilibres de concentration en acides aminés aromatiques induit par des rayonnements UV sur la peau, et ainsi de préserver les défenses immunitaires de la peau d’un sujet. Aromatic amino acids (such as Tryptophan and Phenylalanine) are known for their role in the immune response. In particular, their imbalance and overproduction is linked to inflammatory mechanisms (Guenin-Macé et al., Dysregulation of tryptophan catabolism at the hostskin microbiota interface in hidradenitis suppurativa. JCI Insight. 2020 Oct 15;5(20):e 140598; Lian et al., Research progress and perspective in metabolism and metabolomics of psoriasis. Chinese Medical Journal 2020 Dec 20;133(24):p 2976-2986). In the context of the present disclosure, the inventors have surprisingly demonstrated that phenylene bis-diphenyltriazine makes it possible to limit imbalances in the concentration of aromatic amino acids induced by UV radiation on the skin, and thus to preserve the immune defenses of the skin. skin of a subject.
La présente invention concerne également une méthode pour prévenir et/ou diminuer l’altération du système immunitaire cutané, comprenant l’application topique d’une quantité efficace de 5,6,5 ’,6’- tétraphényl-3 ,3 ’ -( 1 ,4-phénylène)-bis [ 1 ,2,4]triazine . The present invention also relates to a method for preventing and/or reducing impairment of the cutaneous immune system, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-( 1,4-phenylene)-bis [1,2,4]triazine.
Elle concerne en outre méthode pour préserver les défenses immunitaires de la peau, en particulier ses défenses immunitaires naturelles, et donc une méthode pour préserver l’immunité cutanée, notamment l’immunité innée, comprenant l’application topique d’une quantité efficace de 5,6,5’,6’-tétraphényl- 3 ,3 ’ -( 1 ,4-phénylène)-bis [ 1 ,2,4]triazine . It further relates to a method for preserving the skin's immune defenses, in particular its natural immune defenses, and therefore a method for preserving skin immunity, in particular innate immunity, comprising the topical application of an effective quantity of 5 ,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine.
Selon un autre aspect, la présente invention concerne une composition comprenant de la 5,6,5 ’,6’- tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine et au moins un excipient cosmétiquement et/ou pharmaceutiquement acceptable, pour les mêmes utilisations que celles présentées ci-dessus. According to another aspect, the present invention relates to a composition comprising 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine and least one cosmetically and/or pharmaceutically acceptable excipient, for the same uses as those presented above.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention est sous forme d’émulsion. Par « émulsion », on entend, au sens de la présente invention, tout type d’émulsion obtenue par la dispersion d’une phase interne discontinue dans une phase externe continue, l’une de ces phases étant une phase aqueuse et l’autre étant une phase huileuse. Il s’agit, par exemple, d’une émulsion huile-dans- eau ou eau-dans-huile ou multiple, de préférence d’une émulsion huile-dans-eau. In a particular embodiment, the composition for use according to the invention is in the form of an emulsion. By “emulsion” is meant, within the meaning of the present invention, any type of emulsion obtained by the dispersion of a discontinuous internal phase in a continuous external phase, one of these phases being an aqueous phase and the other being an oily phase. This is, for example, an oil-in-water or water-in-oil or multiple emulsion, preferably an oil-in-water emulsion.
Ces émulsions peuvent être plus ou moins fluides et se présenter notamment sous la forme d’une crème blanche ou colorée, d’une pommade, d’un lait, d’une lotion, d’un sérum, d’une pâte, ou éventuellement d’un aérosol, d’une mousse ou d’un spray, et peuvent également être résistantes à l’eau. These emulsions can be more or less fluid and appear in particular in the form of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, or possibly an aerosol, foam or spray, and can also be water resistant.
La composition pour une utilisation selon l’invention est destinée à une application topique sur la peau. The composition for use according to the invention is intended for topical application to the skin.
Dans un mode de réalisation particulier, la phénylène bis-diphényltriazine représente entre 1 % et 5 %, notamment entre 2 % et 5 %, en particulier entre 2 % et 4 %, typiquement entre 3 % et 4 % en poids par rapport au poids total de la composition. In a particular embodiment, phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the weight. total composition.
Il est entendu que ces pourcentages massiques, ainsi que l’ensemble de ceux indiqués dans la description, sont exprimés en pourcentage de masse de matière active par rapport à la masse total de la composition. It is understood that these mass percentages, as well as all of those indicated in the description, are expressed as a mass percentage of active material relative to the total mass of the composition.
Dans la composition pour une utilisation selon la présente invention, la phénylène bis-diphényltriazine peut être associée à un ou plusieurs autres fdtres solaires, pour constituer un système photoprotecteur qui permet, après application sur une surface (peau, cheveux, etc.), par des mécanismes d’absorption et/ou de réflexion et/ou de diffusion du rayonnement UVA et/ou UVB, d’empêcher, ou du moins de limiter, la mise en contact dudit rayonnement avec ladite surface. In the composition for use according to the present invention, phenylene bis-diphenyltriazine can be combined with one or more other solar filters, to constitute a photoprotective system which allows, after application to a surface (skin, hair, etc.), by absorption and/or reflection and/or diffusion mechanisms of UVA and/or UVB radiation, to prevent, or at least limit, bringing said radiation into contact with said surface.
Le système photoprotecteur constitutif d’une composition pour une utilisation selon l’invention comprend de préférence un ou plusieurs fdtre) UV liposolubles choisis parmi les fdtres (i) à (v) suivants : The photoprotective system constituting a composition for use according to the invention preferably comprises one or more lipid-soluble UV filters chosen from the following filters (i) to (v):
(i) hexyl 2-[4-(diéthylamino)-2-hydroxybenzoyl]benzoate (n° CAS : 302776-68-7), également appelé diéthylamino hydroxybenzoyl hexyl benzoate ou DHHB, commercialisé par BASF sous le nom d’Uvinul A Plus®. (i) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (CAS number: 302776-68-7), also called diethylamino hydroxybenzoyl hexyl benzoate or DHHB, marketed by BASF under the name Uvinul A Plus ®.
Il s’agit d’un fdtre UVA liposoluble, ayant une longueur d’onde d’absorption maximale Àmax égale à 354 nm. Dans un mode de réalisation particulier, le DHHB représente entre 1 % et 10 %, par exemple entre 3 % et 10 %, en particulier entre 4 % et 9 %, typiquement entre 5 % et 8 %, en particulier entre 5 % et 7 %, notamment entre 6 % et 7 % ou avantageusement entre 5 % et 6 % en poids, par rapport au poids total de la composition. It is a lipid-soluble UVA filter, having a maximum absorption wavelength Àmax equal to 354 nm. In a particular embodiment, the DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, in particular between 5% and 7%. %, in particular between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition.
(ii) 2,4-bis[4-(2-éthylhexyloxy)-2-hydroxyphényl]-6-(4-méthoxyphényl)-l,3,5-triazine (n° CAS : 187393-00-6), également appelée bis-éthylhexyloxyphenol méthoxyphenyl triazine ou BEMT, commercialisée par BASF sous le nom de Tinosorb S®. (ii) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine (CAS No: 187393-00-6), also called bis-ethylhexyloxyphenol methoxyphenyl triazine or BEMT, marketed by BASF under the name Tinosorb S®.
Il s’agit d’un filtre large bande liposoluble, ayant deux pics d’absorption à 310 nm et 340 nm. It is a lipid-soluble broadband filter, having two absorption peaks at 310 nm and 340 nm.
Dans un mode de réalisation particulier, la BEMT représente entre 1 % et 4 %, notamment entre 2 % et 4 %, en particulier entre 2 % et 3 % en poids par rapport au poids total de la composition. In a particular embodiment, the BEMT represents between 1% and 4%, in particular between 2% and 4%, in particular between 2% and 3% by weight relative to the total weight of the composition.
(iii) 4-tert-butyl-4-méthoxydibenzoylmethane ou butyl méthoxydibenzoylméthane (nom chimique : l,4-(l,l-diméthyléthyl)phényl-3-(4-méthoxyphényl)- 1,3 -propanedione ; n° CAS : 70356-09-1), également appelé avobenzone ou BMDBM, commercialisé notamment par DSM sous le nom de Parsol 1789®. (iii) 4-tert-butyl-4-methoxydibenzoylmethane or butyl methoxydibenzoylmethane (chemical name: 1,4-(l,l-dimethylethyl)phenyl-3-(4-methoxyphenyl)-1,3-propanedione; CAS No: 70356-09-1), also called avobenzone or BMDBM, marketed in particular by DSM under the name Parsol 1789®.
Il s’agit d’un filtre UVA liposoluble, ayant une longueur d’onde d’absorption maximale Àmax égale à 357 nm. It is a fat-soluble UVA filter, having a maximum absorption wavelength Àmax equal to 357 nm.
Dans un mode de réalisation particulier, le BMDBM représente entre 1 % et 10 %, par exemple entreIn a particular embodiment, the BMDBM represents between 1% and 10%, for example between
I % et 8 %, en particulier entre 1 % et 5 %, typiquement entre 2 % et 4 % en poids, par rapport au poids total de la composition. I% and 8%, in particular between 1% and 5%, typically between 2% and 4% by weight, relative to the total weight of the composition.
(iv) éthylhexyl triazone ou EHT (nom chimique acide 4-[[4,6-bis[[4-(2-éthylhexoxy- oxométhyl)phényl]amino]-l,3,5-triazin-2-yl]amino]benzoïque 2-éthylhexyl ester ; n° CAS : 88122-99- 00), commercialisée par BASF sous le nom d’Uvinul T 150®. (iv) ethylhexyl triazone or EHT (chemical name 4-[[4,6-bis[[4-(2-ethylhexoxy-oxomethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino acid) benzoic 2-ethylhexyl ester; CAS number: 88122-99-00), marketed by BASF under the name Uvinul T 150®.
II s’agit d’un filtre UVB liposoluble, ayant une longueur d’onde d’absorption maximale Àmax égale à 314 nm. It is a fat-soluble UVB filter, having a maximum absorption wavelength Àmax equal to 314 nm.
Dans un mode de réalisation particulier, l’EHT représente entre 1 % et 6 %, typiquement entre 2 % et 5 %, notamment entre 3 % et 5 %, en particulier entre 3,5 % et 4,5 % en poids par rapport au poids total de la composition. (v) diéthylhexyl butamido triazone ou DBT (nom chimique 4,4'-[[6-[[4-[[( 1 , 1 - diméthyléthyl)amino]carbonyl]phényl]amino]-l,3,5-triazine-2,4-diyl]diimino]bis-, bis(2- éthylhexyl)benzoate ; n° CAS : 154702-15-5), commercialisée par 3V Sigma sous le nom d’Uvasorb HEB®. In a particular embodiment, the EHT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3.5% and 4.5% by weight relative to to the total weight of the composition. (v) diethylhexyl butamido triazone or DBT (chemical name 4,4'-[[6-[[4-[[(1,1 - dimethylethyl)amino]carbonyl]phenyl]amino]-l,3,5-triazine- 2,4-diyl]diimino]bis-, bis(2-ethylhexyl)benzoate; CAS number: 154702-15-5), marketed by 3V Sigma under the name Uvasorb HEB®.
Il s’agit d’un fdtre UVB liposoluble, ayant une longueur d’onde d’absorption maximale Àmax égale à 310 nm. It is a lipid-soluble UVB filter, having a maximum absorption wavelength Àmax equal to 310 nm.
Dans un mode de réalisation particulier, la DBT représente entre 1 % et 6 %, typiquement entre 2 % et 5 %, notamment entre 3 % et 5 %, en particulier entre 3,5 % et 4,5 % en poids par rapport au poids total de la composition. In a particular embodiment, the DBT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3.5% and 4.5% by weight relative to the total weight of the composition.
Le système photoprotecteur constitutif d’une composition pour une utilisation selon l’invention peut comprendre un ou plusieurs fdtres UV organiques particulaires additionnels, en plus de la phénylène bis-diphényltriazine, choisis parmi les fdtres (vi) et (vii) suivants : The photoprotective system constituting a composition for use according to the invention may comprise one or more additional particulate organic UV filters, in addition to phenylene bis-diphenyltriazine, chosen from the following filters (vi) and (vii):
(vi) méthylène bis-benzotriazolyl tétraméthylbutylphenol (nom chimique : 2,2’-méthylène-bis-(6-(2H- benzotriazol-2-yl)-4-(l,l,3,3-tetraméthylbutyl)phénol ; n° CAS : 103597-45-1) également appelé MBBT, commercialisé par BASF sous le nom de Tinosorb M®. (vi) methylene bis-benzotriazolyl tetramethylbutylphenol (chemical name: 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol; n ° CAS: 103597-45-1) also called MBBT, marketed by BASF under the name Tinosorb M®.
Il s’agit d’un fdtre large bande, ayant deux pics d’absorption à 306 nm et 348 nm, de type non soluble. It is a broadband filter, having two absorption peaks at 306 nm and 348 nm, of non-soluble type.
Le MBBT se présente typiquement sous la forme d’une dispersion aqueuse, comprenant entre 40 % et 60 %, typiquement 50 % en poids de matière active par rapport au poids totale de la dispersion. MBBT is typically in the form of an aqueous dispersion, comprising between 40% and 60%, typically 50% by weight of active material relative to the total weight of the dispersion.
Dans un mode de réalisation particulier, le MBBT représente entre 1 % et 7 %, typiquement 2 % et 6 %, notamment entre 2 % et 5 %, en particulier entre 3 % et 4 % en poids par rapport au poids total de la composition. In a particular embodiment, the MBBT represents between 1% and 7%, typically 2% and 6%, in particular between 2% and 5%, in particular between 3% and 4% by weight relative to the total weight of the composition. .
Dans un mode de réalisation particulier, la taille D50 des particules de MBBT est comprise entre 50 nm et 250 nm, en particulier entre 60 nm et 150 nm. In a particular embodiment, the size D50 of the MBBT particles is between 50 nm and 250 nm, in particular between 60 nm and 150 nm.
(vii) 2,4,6-tris(biphényl-4-yl)-l,3,5-triazine (n° CAS : 31274-51-8) également tris-biphényl triazine ou TBPT, commercialisé par BASF sous le nom de Tinosorb A2B®. (vii) 2,4,6-tris(biphenyl-4-yl)-l,3,5-triazine (CAS number: 31274-51-8) also tris-biphenyl triazine or TBPT, marketed by BASF under the name of Tinosorb A2B®.
Il s’agit d’un fdtre essentiellement UVB, ayant une longueur d’onde d’absorption maximale Àmax égale à 310 nm, de type non soluble. La TBPT se présente typiquement sous la forme d’une dispersion aqueuse, comprenant entre 40 % et 60 %, typiquement 50 % en poids de matière active par rapport au poids totale de la dispersion. It is an essentially UVB filter, having a maximum absorption wavelength Àmax equal to 310 nm, of non-soluble type. TBPT is typically in the form of an aqueous dispersion, comprising between 40% and 60%, typically 50% by weight of active material relative to the total weight of the dispersion.
Dans un mode de réalisation particulier, la TBPT représente entre 1 % et 7 %, en particulier entre 2 % et 7 %, notamment entre 2 % et 6 % en poids par rapport au poids total de la composition. In a particular embodiment, the TBPT represents between 1% and 7%, in particular between 2% and 7%, in particular between 2% and 6% by weight relative to the total weight of the composition.
Dans un mode de réalisation particulier, la taille D50 des particules de TBPT est comprise entre 50 nm et 250 nm, en particulier entre 80 nm et 150 nm. In a particular embodiment, the size D50 of the TBPT particles is between 50 nm and 250 nm, in particular between 80 nm and 150 nm.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend pas d’éthylhexyl salicylate, d’octocrylène, d’éthylhexyl méthoxycinnamate, d’isoamyl méthoxylcinnamate, d’homosalate, d’acide para-aminobenzoïque (PABA), d’octyl diméthyl PABA, de 3-méthylbenzylidène camphor, de 4-méthylbenzylidène camphor, de benzophénone-3 et/ou de benzophénone-4. In a particular embodiment, the composition for use according to the invention does not comprise ethylhexyl salicylate, octocrylene, ethylhexyl methoxycinnamate, isoamyl methoxylcinnamate, homosalate, para-aminobenzoic acid (PABA ), octyl dimethyl PABA, 3-methylbenzylidene camphor, 4-methylbenzylidene camphor, benzophenone-3 and/or benzophenone-4.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend aucun fdtre hydrosoluble. In a particular embodiment, the composition for use according to the invention does not comprise any water-soluble fiber.
L’absence de fdtres hydrosolubles est particulièrement avantageuse, en cela que les filtres hydrosolubles sont, de manière générale, plus facilement assimilables par les organismes marins que les filtres liposolubles ou non solubles. Par conséquent, le choix de la Demanderesse consistant à recourir uniquement à des filtres liposolubles ou particulaires, notamment hydrodispersés, permet de minimiser l’impact de la composition selon l’invention sur le milieu marin. The absence of water-soluble filters is particularly advantageous, in that water-soluble filters are, generally speaking, more easily assimilated by marine organisms than fat-soluble or non-soluble filters. Consequently, the Applicant's choice of using only liposoluble or particulate filters, in particular hydrodispersed, makes it possible to minimize the impact of the composition according to the invention on the marine environment.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention, comprend un ou plusieurs filtres inorganiques particulaires, tel que du dioxyde de titane (TiCfi) ou de l’oxyde de zinc (ZnO). In a particular embodiment, the composition for use according to the invention comprises one or more particulate inorganic filters, such as titanium dioxide (TiCfi) or zinc oxide (ZnO).
Le ou les filtres inorganiques particulaires éventuellement présent dans la composition selon l’invention ont typiquement une taille D50 de particule comprise entre 15 nm et 150 nm. The particulate inorganic filter(s) possibly present in the composition according to the invention typically have a particle size D50 of between 15 nm and 150 nm.
Dans un autre mode de de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend aucun filtre inorganique particulaire. In another particular embodiment, the composition for use according to the invention does not comprise any particulate inorganic filter.
Dans un mode de réalisation particulier, le nombre total de filtres UV présents dans la composition est inférieur ou égal à 5, de préférence inférieur ou égal à 4, et l’ensemble des filtres UV présents dans la composition représentent entre 4 % et 25 % en poids, en particulier entre 6 % et 20 % en poids, notamment entre 7 % et 18 % en poids, typiquement entre 8 % et 17 % en poids, par rapport au poids total de la composition. In a particular embodiment, the total number of UV filters present in the composition is less than or equal to 5, preferably less than or equal to 4, and all of the UV filters present in the composition composition represent between 4% and 25% by weight, in particular between 6% and 20% by weight, in particular between 7% and 18% by weight, typically between 8% and 17% by weight, relative to the total weight of the composition .
Dans un mode de réalisation avantageux, le système photoprotecteur est constitué de : In an advantageous embodiment, the photoprotective system consists of:
(a) 5 ,6,5 ’ ,6 ’ -tétraphényl-3 ,3 ’ -( 1 ,4-phénylène)-bis [ 1 ,2,4]triazine, (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine,
(b) 2,4-bis[4-(2-éthylhexyloxy)-2-hydroxyphényl]-6-(4-méthoxyphényl)-l,3,5-triazine, (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine,
(c) hexyl 2-[4-(diéthylamino)-2-hydroxybenzoyl]benzoate, et (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and
(d) éthylhexyl triazone ou diéthylhexyl butamido triazone. (d) ethylhexyl triazone or diethylhexyl butamido triazone.
En particulier, (d) correspond à l’éthylhexyl triazone. In particular, (d) corresponds to ethylhexyl triazone.
Dans ce mode de réalisation particulier, la phénylène bis-diphényltriazine représente entre 1 % et 5 %, notamment entre 2 % et 5 %, en particulier entre 2 % et 4 %, typiquement entre 3 % et 4 % en poids par rapport au poids total de la composition, le DHHB représente entre 1 % et 10 %, par exemple entre 3 % et 10 %, en particulier entre 4 % et 9 %, typiquement entre 5 % et 8 %, par exemple entre 5 % et 7 %, notamment entre 6 % et 7 % ou avantageusement entre 5 % et 6 % en poids, par rapport au poids total de la composition, la BEMT représente entre 1 % et 4 %, notamment entre 2 % et 4 %, en particulier entre 2 % et 3 % en poids de la composition par rapport au poids total de la composition, et l’EHT représente entre 1 % et 6 %, typiquement entre 2 % et 5 %, notamment entre 3 % et 5 %, en particulier entre 3,5 % et 4,5 % en poids par rapport au poids total de la composition. In this particular embodiment, the phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the weight. total composition, DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, for example between 5% and 7%, in particular between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition, the BEMT represents between 1% and 4%, in particular between 2% and 4%, in particular between 2% and 3% by weight of the composition relative to the total weight of the composition, and the EHT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3, 5% and 4.5% by weight relative to the total weight of the composition.
Dans la présente invention, on entend désigner par « cosmétiquement et/ou pharmaceutiquement acceptable » ce qui est utile dans la préparation d'une composition pouvant avoir une application cosmétique et/ou pharmaceutique, et qui est généralement sûr, non toxique et ni biologiquement ni autrement non souhaitable et qui est acceptable pour une utilisation cosmétique ou pharmaceutique humaine. Par « excipient pharmaceutiquement et/ou cosmétiquement acceptable », on entend tout adjuvant cosmétiquement et/ou pharmaceutiquement acceptable permettant la fabrication, la conservation ou l'administration de la composition. In the present invention, the term "cosmetically and/or pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a composition which can have a cosmetic and/or pharmaceutical application, and which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for human cosmetic or pharmaceutical use. By “pharmaceutically and/or cosmetically acceptable excipient” is meant any cosmetically and/or pharmaceutically acceptable adjuvant allowing the manufacture, conservation or administration of the composition.
Les compositions pour une utilisation selon l’invention peuvent ainsi comprendre des adjuvants pharmaceutiques ou dermatologiques classiques notamment choisis parmi les composés lipophiles liquides, les émulsifiants, les agents de consistance, les agents de rémanence à l’eau, les agents de texture, les opacifiants, les pigments colorants, les agents anti-mousse, les parfums, les conservateurs, les polymères, les charges, les séquestrants, les bactéricides, les absorbeurs d’odeur, les agents alcalinisants ou acidifiants, les tensio-actifs, les antiradicaux libres, les vitamines, les alpha- hydroxyacides, des agents actifs (en particulier des adoucissants, des agents hydratants, des antioxydants) ou tout autre ingrédient habituellement utilisé pour la fabrication de compositions anti- solaires. The compositions for use according to the invention may thus comprise conventional pharmaceutical or dermatological adjuvants chosen in particular from liquid lipophilic compounds, emulsifiers, consistency agents, water retention agents, texture agents, opacifiers. , coloring pigments, anti-foaming agents, perfumes, preservatives, polymers, fillers, sequestrants, bactericides, odor absorbers, alkalizing or acidifying agents, surfactants, free radical scavengers, vitamins, alpha-hydroxy acids, active agents (in particular softeners, moisturizing agents, antioxidants) or any other ingredient usually used for the manufacture of anti- solar.
La composition peut ainsi comprendre un composé lipophile liquide ou une combinaison de plusieurs composés lipophiles liquides, typiquement un émollient lipophile liquide ou une combinaison d’émollients lipophiles liquides, notamment un corps gras liquide ou une combinaison de corps gras liquides. The composition may thus comprise a liquid lipophilic compound or a combination of several liquid lipophilic compounds, typically a liquid lipophilic emollient or a combination of liquid lipophilic emollients, in particular a liquid fatty substance or a combination of liquid fatty substances.
Par « composé lipophile liquide », on entend désigner un composé qui présente une affinité pour les substances apolaires tels que les lipides, et se présente sous forme liquide notamment pour une température comprise entre 5°C et la température ambiante (entre 20°C et 25°C). Il comporte typiquement une ou plusieurs fonction(s) chimique(s) polaire(s) choisis parmi les fonctions ester (-CO2- ), alcool (-OH), éther (-O-), carbonate (-OCO2-) et acide carboxylique (-CO2H), et un ou plusieurs groupement(s) lipophile(s), c’est-à-dire un ou plusieurs groupement(s) hydrocarboné(s) aliphatiques et/ou aromatique (s), en particulier une ou plusieurs chaîne(s) hydrocarbonée(s) saturée(s) ou insaturée(s), linéaire(s) ou ramifiée(s), comportant entre 6 et 20 atomes de carbone, par exemple entre 7 et 18 atomes de carbone, notamment entre 8 et 16 atomes de carbone, un II peut être choisi en particulier parmi le C12-C15 alkyl benzoate, les triglycérides caprylique/caprique, le dicaprylyl carbonate, le coco- caprylate, le diisopropyl sébacate, le diéthylhexyl succinate, l’isopropyl palmitate, l’isopropyl myristate, le propylheptyl caprylate, le phénéthyl benzoate, le dibutyl adipate, le diisopropyl adipate, le glycéryl tri-2-éthylhexanoate, le pentaerythrityl tetra-2-éthylhexanoate, le cétyl 2-éthylhexanoate, l’isononyl isonanoate, le butylène glycol dicaprylate/dicaprate, l’octyldodécanol, le propylène glycol dicaprylate/dicaprate et le dicaprylyl éther, en particulier parmi les triglycérides caprylique/caprique, le dicaprylyl carbonate, l’isopropyl palmitate, le propylheptyl caprylate, le phénéthyl benzoate, le diisopropyl adipate, le glycéryl tri-2-éthylhexanoate, le pentaerythrityl tetra-2-éthylhexanoate, le cétyl 2-éthylhexanoate, l’isononyl isononoate, le butylène glycol dicaprylate/dicaprate, l’octyldodécanol, le propylène glycol dicaprylate/dicaprate, le dicaprylyl éther et leurs combinaisons. By “liquid lipophilic compound”, we mean a compound which has an affinity for non-polar substances such as lipids, and is in liquid form in particular for a temperature between 5°C and room temperature (between 20°C and 25°C). It typically comprises one or more polar chemical function(s) chosen from the ester (-CO2-), alcohol (-OH), ether (-O-), carbonate (-OCO2-) and acid functions. carboxylic acid (-CO2H), and one or more lipophilic group(s), that is to say one or more aliphatic and/or aromatic hydrocarbon group(s), in particular one or more several saturated or unsaturated hydrocarbon chain(s), linear or branched, comprising between 6 and 20 carbon atoms, for example between 7 and 18 carbon atoms, in particular between 8 and 16 carbon atoms, a II can be chosen in particular from C12-C15 alkyl benzoate, caprylic/capric triglycerides, dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2-ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isonanoate, butylene glycol dicaprylate/dicaprate, octyldodecanol, propylene glycol dicaprylate/dicaprate and dicaprylyl ether, in particular among caprylic/capric triglycerides, dicaprylyl carbonate, isopropyl palmitate, propylheptyl caprylate, phenethyl benzoate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2-ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isononoate, butylene glycol dicaprylate/dicaprate, octyldodecanol, propylene glycol dicaprylate/dicaprate, dicaprylyl ether and their combinations.
Le ou les émollients lipophiles liquides sont choisis en particulier parmi le C12-C15 alkyl benzoate, les triglycérides caprylique/caprique et le dicaprylyl carbonate. The liquid lipophilic emollient(s) are chosen in particular from C12-C15 alkyl benzoate, caprylic/capric triglycerides and dicaprylyl carbonate.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend pas de diisopropyl sébacate, diéthylhexyl succinate, isopropyl myristate et/ou dibutyl adipate. Typiquement, elle ne comprend pas de dicaprylyl carbonate, coco-caprylate, diisopropyl sébacate, diéthylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phénéthyl benzoate, dibutyl adipate, diisopropyl adipate, glycéryl tri-2-éthylhexanoate, pentaerythrityl tetra-2- éthylhexanoate, cétyl 2-éthylhexanoate, isononyl isononoate, butylène glycol, dicaprylate/dicaprate, octyldodécanol, propylène glycol dicaprylate/dicaprate et/ou dicaprylyl éther. La composition peut comprendre en outre un polyol miscible à l’eau à la température ambiante (environ 25 °C), notamment choisi parmi les polyols ayant notamment de 2 à 20 atomes de carbones, de préférence ayant de 2 à 10 atomes de carbone, et préférentiellement ayant de 2 à 6 atomes de carbones, tels que la glycérine ; les dérivés de glycol tel que le propylène glycol, le butylène glycol, le pentylène glycol, l’hexylène glycol, le dipropylène glycol, le diéthylène glycol ; les éthers de glycol tels que les éthers d’alkyle en C1-C4 de mono-, di- ou tri -propylène glycol, les éthers d’alkyle en C1-C4 de mono-, di- ou tri -éthylène glycol et leurs mélanges. In a particular embodiment, the composition for use according to the invention does not comprise diisopropyl sebacate, diethylhexyl succinate, isopropyl myristate and/or dibutyl adipate. Typically, it does not include dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2- ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isononoate, butylene glycol, dicaprylate/dicaprate, octyldodecanol, propylene glycol dicaprylate/dicaprate and/or dicaprylyl ether. The composition may further comprise a polyol miscible with water at room temperature (approximately 25°C), in particular chosen from polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having 2 to 6 carbon atoms, such as glycerin; glycol derivatives such as propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol; glycol ethers such as C1-C4 alkyl ethers of mono-, di- or tri-propylene glycol, C1-C4 alkyl ethers of mono-, di- or tri-ethylene glycol and mixtures thereof .
La composition peut également comprendre ou un plusieurs émulsifiants anioniques, cationiques et non ioniques choisis parmi les dérivés du glucose tels que le cétéaryl glucoside, l'arachidyl glucoside, le lauryl glucoside, le polyglycéryl-3 méthylglucose distéarate et le méthyl glucose sesquistearate ; les dérivés du saccharose tels que le polystéarate de saccharose et le palmitate de saccharose ; les glycérides d'acides gras tels que le stéarate de glycéryle, l'oléate de glycéryle et le glycéryl stéarate citrate ; les dérivés de l'acide glutamique tel que le stéaroyl glutamate de sodium ; les dérivés de l'acide sulfosuccinique tel que le cétéaryl-sulfosuccinate disodique et le sulfosuccinate de dioctyle de sodium ; les dérivés de l'acide phosphorique tel que le cétyl phosphate de potassium ; les esters d'acides gras de polyglycéryle tels que le polyglycéryl-3 -diisostéarate et le polyglycéryl-2-dipolyhydroxystéarate ; les dérivés du sorbitol tels que le polysorbate-n, PEG- 10 sorbitan laurate et les esters de sorbitane ; les polyglycoléthers d'alcool gras et d'acide gras tels que le cétéareth-20, le beheneth-25, le stéareth-2, le tridéceth-9, le PEG-5 éthylhexanoate et le PEG- 100 stéarate ; le sulfate de lauryle de sodium, le stéarate de sodium, et les copolymères et dérivés de silicone / polysiloxane / polyalkyle / polyéther oxyalcénylés organomodifiés. The composition may also comprise one or more anionic, cationic and nonionic emulsifiers chosen from glucose derivatives such as cetearyl glucoside, arachidyl glucoside, lauryl glucoside, polyglyceryl-3 methylglucose distearate and methyl glucose sesquistearate; sucrose derivatives such as sucrose polystearate and sucrose palmitate; glycerides of fatty acids such as glyceryl stearate, glyceryl oleate and glyceryl stearate citrate; glutamic acid derivatives such as sodium stearoyl glutamate; sulfosuccinic acid derivatives such as disodium cetearyl sulfosuccinate and sodium dioctyl sulfosuccinate; phosphoric acid derivatives such as potassium cetyl phosphate; polyglyceryl fatty acid esters such as polyglyceryl-3-diisostearate and polyglyceryl-2-dipolyhydroxystearate; sorbitol derivatives such as polysorbate-n, PEG-10 sorbitan laurate and sorbitan esters; fatty alcohol and fatty acid polyglycol ethers such as ceteareth-20, beheneth-25, steareth-2, trideceth-9, PEG-5 ethylhexanoate and PEG-100 stearate; sodium lauryl sulfate, sodium stearate, and organomodified oxyalkenyl silicone/polysiloxane/polyalkyl/polyether copolymers and derivatives.
Le ou les émulsifiants sont choisis en particulier parmi le cétyl phosphate de potassium, le lauryl glucoside et le glycéryl stéarate citrate. The emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend pas d’émulsifiant éthoxylé et/ou comprenant de chaîne PEG. In a particular embodiment, the composition for use according to the invention does not comprise an ethoxylated emulsifier and/or comprising a PEG chain.
En particulier, la composition ne comprend pas de dérivés du sorbitol tels que le polysorbate-n et le PEG- 10 sorbitan laurate ; de polyglycoléthers d'alcool gras et d'acide gras tels que le cétéareth-20, le beheneth-25, le stéareth-2 et le PEG- 100 stéarate ; et de copolymères et dérivés de silicone / polysiloxane / polyalkyle / polyéther oxyalcénylés organomodifiés. In particular, the composition does not include sorbitol derivatives such as polysorbate-n and PEG-10 sorbitan laurate; fatty alcohol and fatty acid polyglycol ethers such as ceteareth-20, beheneth-25, steareth-2 and PEG-100 stearate; and organomodified oxyalkenylated silicone/polysiloxane/polyalkyl/polyether copolymers and derivatives.
La composition peut également comprendre ou un plusieurs agents de consistance sous forme solide choisis parmi les alcools gras tels que l'alcool cétylique, l'alcool cétéarylique et l'alcool stéarylique ; les acides gras tel que l'acide stéarique ; les esters d'acides gras tel que le stéarate de myristyle ; les polysaccharides ou dérivés tels que la gomme xanthane, la gomme guar, la gomme agar, les alginates, la gomme gellane et le carraghénane ; les dérivés de la cellulose tel que l'hydroxypropylcellulose ; les cires telles que la cire d'abeille, la cire de carnauba, la cire microcristalline, la cérésine, et l'ozocérite ; les polyacrylates ou homopolymères d'acides acryliques ou de polyacrylamides réticulés tels que les carbomères, les copolymères d'acrylate, les copolymères réticulés acrylate/(Cio-C3o)alkylacrylate, les copolymères acrylate/méthacrylate de béhénéthyle-25 ; et les dérivés de silicates tels que les silicates de magnésium. The composition may also comprise one or more consistency agents in solid form chosen from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyl stearate; THE polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; cellulose derivatives such as hydroxypropylcellulose; waxes such as beeswax, carnauba wax, microcrystalline wax, ceresin, and ozocerite; polyacrylates or homopolymers of crosslinked acrylic acids or polyacrylamides such as carbomers, acrylate copolymers, crosslinked acrylate/(Cio-C3o)alkylacrylate copolymers, acrylate/behenethyl-25 methacrylate copolymers; and silicate derivatives such as magnesium silicates.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention comprend un ou plusieurs agents de consistance choisis parmi les alcools gras tels que l'alcool cétylique, l'alcool cétéarylique et l'alcool stéarylique ; les acides gras tel que l'acide stéarique ; les esters d'acides gras tel que le stéarate de myristyle ; les polysaccharides ou dérivés tels que la gomme xanthane, la gomme guar, la gomme agar, les alginates, la gomme gellane et le carraghénane ; et les dérivés de la cellulose tel que l'hydroxypropylcellulose. In a particular embodiment, the composition for use according to the invention comprises one or more consistency agents chosen from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyl stearate; polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; and cellulose derivatives such as hydroxypropylcellulose.
Dans un mode de réalisation particulier, la composition ne comprend pas d’agent de consistance choisi parmi les acrylates et leurs dérivés. In a particular embodiment, the composition does not include a consistency agent chosen from acrylates and their derivatives.
La composition peut également comprendre ou un plusieurs agents de rémanence à l’eau choisis parmi un copolymère de N-vinylpyrrolidone (VP) et d’eicosène (INCI : VP/eicosen copolymer), un polymère réticulé de triméthylpentanediol, d’acide adipique et de glycérol (INCI : trimethylpentanediol/adipic acid/glycerin crosspolymer), le polyamide 3 (INCI), un copolymère d’acrylate et d’ octylacrylamide (INCI : acrylates/octylacrylamide copolymer), et le triacontanyl PVP (INCI). The composition may also comprise one or more water retention agents chosen from a copolymer of N-vinylpyrrolidone (VP) and eicosene (INCI: VP/eicosen copolymer), a crosslinked polymer of trimethylpentanediol, adipic acid and glycerol (INCI: trimethylpentanediol/adipic acid/glycerin crosspolymer), polyamide 3 (INCI), a copolymer of acrylate and octylacrylamide (INCI: acrylates/octylacrylamide copolymer), and triacontanyl PVP (INCI).
De préférence, la composition pour une utilisation selon l’invention comprend du VP / eicosène copolymère en tant qu’agent de rémanence à l’eau. Preferably, the composition for use according to the invention comprises VP/eicosene copolymer as a water retention agent.
La composition peut également comprendre ou un plusieurs agents de texture sous forme de poudres, en particulier choisis parmi les ingrédients de la famille des amidons, tels que les amidons de riz, de maïs, et du tapioca ; des talcs et des dérivés de celluloses tel que la cellulose microcristalline. The composition may also comprise one or more texturing agents in the form of powders, in particular chosen from ingredients of the starch family, such as rice, corn and tapioca starches; talcs and cellulose derivatives such as microcrystalline cellulose.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention ne comprend pas d’agent de texture choisi parmi les dérivés du nylon et le polyméthacrylate de méthyle (PMMA). In a particular embodiment, the composition for use according to the invention does not comprise a texturing agent chosen from nylon derivatives and polymethyl methacrylate (PMMA).
La composition peut également comprendre des pigments colorants, en particulier choisis parmi le CI77891, le CI77491, le CI77492 et le CI77499 (désignations INCI). Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention comprend une quantité d’alcools en C1-C4, tels que l’éthanol et l’isopropanol, inférieure ou égale à 4 % en poids, de préférence inférieure ou égale à 2 % en poids, notamment inférieure ou égale à 1 % en poids, en particulier inférieure ou égale à 0,5 % en poids, par rapport au poids total de la composition. The composition may also comprise coloring pigments, in particular chosen from CI77891, CI77491, CI77492 and CI77499 (INCI designations). In a particular embodiment, the composition for use according to the invention comprises a quantity of C1-C4 alcohols, such as ethanol and isopropanol, less than or equal to 4% by weight, preferably less than or equal to 2% by weight, in particular less than or equal to 1% by weight, in particular less than or equal to 0.5% by weight, relative to the total weight of the composition.
Dans un autre mode de réalisation particulier, la composition est dépourvue d’éthanol et d’isopropanol. In another particular embodiment, the composition is free of ethanol and isopropanol.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention comprend une quantité d’ingrédients volatils inférieure ou égale à 5 % en poids, de préférence inférieure ou égale à 2 % en poids, notamment inférieure ou égale à 1 % en poids, en particulier inférieure ou égale à 0,5 % en poids, par rapport au poids total de la composition. Par « ingrédients volatils », on entend, au sens de la présente invention, les composés organiques ou inorganiques volatils non alcooliques tels que des esters, des silicones ou des alcanes volatils, caractérisés par un point éclair inférieur à 60°C. Par « point éclair » (noté PE), on entend, au sens de la présente invention, la température minimale à laquelle une substance combustible émet des vapeurs en concentration suffisante pour former avec l’air ambiant un mélange gazeux qui s’enflamme au contact d’une flamme ou d’un point chaud, mais insuffisante pour que la combustion se propage d’elle-même en l’absence de la flamme dite pilote. Selon le règlement (CE) N° 1272/2008 relatif à la classification, à l’étiquetage et à l’emballage des substances et des mélanges, une substance ayant un PE tel que 23°C < PE < 60°C appartient à la catégorie 3 « faiblement inflammable ». In a particular embodiment, the composition for use according to the invention comprises a quantity of volatile ingredients less than or equal to 5% by weight, preferably less than or equal to 2% by weight, in particular less than or equal to 1% by weight, in particular less than or equal to 0.5% by weight, relative to the total weight of the composition. By “volatile ingredients” is meant, within the meaning of the present invention, non-alcoholic volatile organic or inorganic compounds such as esters, silicones or volatile alkanes, characterized by a flash point below 60°C. By “flash point” (denoted PE), we mean, within the meaning of the present invention, the minimum temperature at which a combustible substance emits vapors in sufficient concentration to form a gaseous mixture with the ambient air which ignites on contact. of a flame or a hot spot, but insufficient for combustion to propagate itself in the absence of the so-called pilot flame. According to Regulation (EC) No. 1272/2008 relating to the classification, labeling and packaging of substances and mixtures, a substance with a PE such as 23°C < PE < 60°C belongs to the category 3 “lowly flammable”.
Parmi les esters volatils, on peut notamment citer l’isohexyl neopentanoate. Parmi les silicones volatils, on peut notamment citer le cyclopentasiloxane. Parmi les alcanes volatils, on peut notamment citer l’isohexadecane. Among the volatile esters, we can notably cite isohexyl neopentanoate. Among the volatile silicones, we can notably cite cyclopentasiloxane. Among the volatile alkanes, we can notably cite isohexadecane.
Dans un autre mode de réalisation particulier, la composition pour une utilisation selon l’invention est dépourvue d’ingrédients volatils au sens de la présente invention. In another particular embodiment, the composition for use according to the invention is devoid of volatile ingredients within the meaning of the present invention.
La composition peut également comprendre des agents alcalinisants ou acidifiants, et plus particulièrement des acides et des bases permettant d’ajuster la zone de pH de ladite composition. Les bases peuvent être minérales (soude, potasse, ammoniaque, etc.) ou organiques, telles que la mono-, dion triéthanolamine, un aminométhylpropanediol, la N-méthyl-glucamine, les acides aminés basiques comme l’arginine et la lysine, et leurs mélanges. Les acides peuvent être minéraux (acide chlorhydrique, etc.) ou organiques, tels que l’acide lactique et l’acide citrique. The composition may also comprise alkalizing or acidifying agents, and more particularly acids and bases making it possible to adjust the pH zone of said composition. The bases can be mineral (soda, potash, ammonia, etc.) or organic, such as mono-, dion triethanolamine, aminomethylpropanediol, N-methyl-glucamine, basic amino acids such as arginine and lysine, and their mixtures. Acids can be mineral (hydrochloric acid, etc.) or organic, such as lactic acid and citric acid.
La composition pour une utilisation selon l’invention peut comprendre en outre des agents actifs additionnels choisis notamment parmi les agents hydratants, les agents desquamants, les agents améliorant la fonction barrière, les agents dépigmentants, les agents anti-oxydants, les agents dermocontractants, les agents anti-glycation, les agents stimulant la synthèse de macromolécules dermiques et/ou épidermiques et/ou empêchant leur dégradation, les agents stimulant la prolifération des fibroblastes ou des kératinocytes et/ou la différenciation des kératinocytes, les inhibiteurs de NO synthase, les agents augmentant l’activité de la glande sébacée, les agents tenseurs, les agents liporestructurants, les agents amincissants, les agents favorisant la microcirculation cutanée, les agents apaisants et/ou irritants, les sébo-régulateurs ou anti-séborrhéiques, les agents astringents, les agents cicatrisants, les agents antiinflammatoires, les agents anti-acné, et leurs mélanges. The composition for use according to the invention may further comprise additional active agents chosen in particular from moisturizing agents, desquamating agents, improving the barrier function, depigmenting agents, anti-oxidant agents, dermocontracting agents, anti-glycation agents, agents stimulating the synthesis of dermal and/or epidermal macromolecules and/or preventing their degradation, agents stimulating the proliferation of fibroblasts or keratinocytes and/or the differentiation of keratinocytes, NO synthase inhibitors, agents increasing the activity of the sebaceous gland, tensing agents, liporestructuring agents, slimming agents, agents promoting skin microcirculation, agents soothing and/or irritant agents, sebo-regulators or anti-seborrheic agents, astringent agents, healing agents, anti-inflammatory agents, anti-acne agents, and mixtures thereof.
Dans un mode de réalisation particulier, la composition pour une utilisation selon l’invention est dépourvue de silicone. In a particular embodiment, the composition for use according to the invention is silicone-free.
Dans un mode de réalisation préféré, la composition pour une utilisation selon l’invention comprend un ou plusieurs antioxydants, typiquement choisis parmi la vitamine E et ses dérivés. Avantageusement, la composition pour une utilisation selon l’invention comprend un ou plusieurs composés choisis parmi les tocophérols, les tocotriénols et leurs dérivés. Par « tocophérols » ou « tocotriénols », on entend désigner les composés a-, P-, y- et ô- tocophérol ou tocotriénol. Le terme « tocophérol » désigne de manière usuelle l’a-tocophérol. Parmi les dérivés de tocophérol(s), on peut notamment citer les dérivés esters, tel que l’acétate de tocophérol, et les dérivés glycosylés, tel que le glucoside de tocophéryle (INCI : tocopheryl glucoside). In a preferred embodiment, the composition for use according to the invention comprises one or more antioxidants, typically chosen from vitamin E and its derivatives. Advantageously, the composition for use according to the invention comprises one or more compounds chosen from tocopherols, tocotrienols and their derivatives. By “tocopherols” or “tocotrienols” is meant the compounds a-, P-, y- and ô-tocopherol or tocotrienol. The term “tocopherol” usually refers to a-tocopherol. Among the tocopherol derivatives, we can in particular cite ester derivatives, such as tocopheryl acetate, and glycosylated derivatives, such as tocopheryl glucoside (INCI: tocopheryl glucoside).
Dans un mode de réalisation préféré, la composition pour une utilisation selon l’invention comprend un ou plusieurs antioxydants choisis parmi le tocophérol et ses dérivés, en particulier parmi le tocophérol, le glycoside de tocophérol et leurs mélanges, en une quantité typiquement comprise entre 0,01 % et 1 % en poids par rapport au poids total de la composition. In a preferred embodiment, the composition for use according to the invention comprises one or more antioxidants chosen from tocopherol and its derivatives, in particular from tocopherol, tocopherol glycoside and mixtures thereof, in an amount typically between 0 .01% and 1% by weight relative to the total weight of the composition.
EXEMPLES EXAMPLES
Modèle RHE + microbiote + sébum RHE + microbiota + sebum model
Les inventeurs ont développé un modèle d’épiderme humain reconstruit (RHE) colonisé par le microbiote cutané et le sébum de donneurs afin de reproduire la complexité de l’écosystème cutané. Ce modèle se rapproche de la réalité de la physiologie cutanée et permet d'étudier les interactions entre la peau et le microbiote. The inventors have developed a model of reconstructed human epidermis (RHE) colonized by skin microbiota and sebum from donors in order to reproduce the complexity of the skin ecosystem. This model comes closer to the reality of skin physiology and makes it possible to study the interactions between the skin and the microbiota.
L’épiderme a été reconstruit à partir d’exérèses cutanées provenant de chirurgie esthétique selon la méthode décrite par Frankart et al. (Frankart et al., Exp. Dermatol. 2012, 21(11), 871-875). Brièvement, les cellules (kératinocytes) ont été isolées des exérèses cutanées, puis mises en culture avant d’être ensemencées sur des inserts de culture en immersion dans du milieu de culture puis les inserts de cultures sont mis à l’interface air/liquide dans un incubateur à 37°C dans une atmosphère humidifiée avec 5% de CO2, pour former le stratum corneum. The epidermis was reconstructed from skin excisions from cosmetic surgery according to the method described by Frankart et al. (Frankart et al., Exp. Dermatol. 2012, 21(11), 871-875). Briefly, the cells (keratinocytes) were isolated from skin excisions, then cultured before being seeded on culture inserts immersed in culture medium then the culture inserts are placed at the air/liquid interface in an incubator at 37°C in a humidified atmosphere with 5% CO2, to form the stratum corneum.
Au bout de 14 jours, un épiderme reconstruit d’une surface de 0,6 cm2 est formé. Le milieu de culture est renouvelé toutes les 24 heures. After 14 days, a reconstructed epidermis with a surface area of 0.6 cm 2 is formed. The culture medium is renewed every 24 hours.
Au terme de la reconstruction, le microbiote et le sébum provenant de volontaires sains sont inoculés. At the end of the reconstruction, the microbiota and sebum from healthy volunteers are inoculated.
- Préparation du sébum - Preparation of sebum
Le sébum est prélevé sur le front de 10 volontaires sans pathologie cutanée apparente avec un kit de prélèvement standard. Chaque tube de prélèvement est ensuite lavé 3 fois avec de l’hexane pour extraire le sébum. Les extraits sont ensuite combinés puis le solvant est évaporé sous vide. La masse du sébum récolté est contrôlée (par ex. 1 100 mg pour une préparation) puis le sébum est repris dans 20 ml d’hexane. 100 fioles de sébum sont réalisées avec 9 mg de substance par fiole et conditionnées sous argon. Pour le dépôt du sébum sur l’épiderme reconstruit, les fioles sont ensuite reprises avec 250 pL d’éthanol absolu (Fischer Scientific, Illkirch, France) puis diluées au l/20eme dans du sérum physiologique. Sebum is collected from the foreheads of 10 volunteers without apparent skin pathology using a standard collection kit. Each collection tube is then washed 3 times with hexane to extract the sebum. The extracts are then combined and the solvent is evaporated under vacuum. The mass of the sebum collected is controlled (e.g. 1,100 mg for a preparation) then the sebum is taken up in 20 ml of hexane. 100 vials of sebum are made with 9 mg of substance per vial and packaged under argon. For the deposition of sebum on the reconstructed epidermis, the vials are then taken up with 250 μL of absolute ethanol (Fischer Scientific, Illkirch, France) then diluted 1/20 in physiological serum.
- Préparation du microbiote - Preparation of the microbiota
Le microbiote est prélevé sur 18 volontaires sans pathologie cutanée apparente à l’aide d’un écouvillon imbibé de sérum physiologique (Fischer Scientific, Illkirch, France) contenant 0,1 % en volume de Triton X-100 (Fischer Scientific, Illkirch, France). L’écouvillon est frotté énergétiquement sur le front du donneur durant 40 secondes. Chaque écouvillon est ensuite placé dans un tube pour être centrifugé. Après centrifugation, un liquide incolore est récupéré (environ 60 pL) et son volume est ajusté jusqu’à 120 pL avec du sérum physiologique. Chaque microbiote est ensuite mélangé avec le sébum afin de pouvoir réaliser le dépôt. The microbiota is collected from 18 volunteers without apparent skin pathology using a swab soaked in physiological serum (Fischer Scientific, Illkirch, France) containing 0.1% by volume of Triton X-100 (Fischer Scientific, Illkirch, France). ). The swab is rubbed energetically on the donor's forehead for 40 seconds. Each swab is then placed in a tube to be centrifuged. After centrifugation, a colorless liquid is recovered (approximately 60 pL) and its volume is adjusted to 120 pL with physiological saline. Each microbiota is then mixed with the sebum in order to be able to produce the deposit.
Le mélange sébum/microbiote (22 pL) est déposé à la surface de l’épiderme reconstruit humain et étalé à l’aide d’un doigtier. The sebum/microbiota mixture (22 pL) is deposited on the surface of the reconstructed human epidermis and spread using a finger cot.
Les épidermes reconstruits humains ainsi obtenus sont incubés à 32°C, 5 % CO2, 60 % d’humidité durant 24 h. The reconstructed human epidermis thus obtained are incubated at 32°C, 5% CO2, 60% humidity for 24 hours.
Formulations Formulations
Les formulations suivantes ont été évaluées dans les expériences décrites ci -après. Formulation AThe following formulations were evaluated in the experiments described below. Wording A
Tableau 1
Figure imgf000018_0001
Formulation BTable 1
Figure imgf000018_0001
Formulation B
Tableau 2
Figure imgf000018_0002
Figure imgf000019_0001
Table 2
Figure imgf000018_0002
Figure imgf000019_0001
Effet de la phénylène bis-diphényltriazine contre les effets délétères des rayonnements UV sur les défenses immunitaires de la peau : approche métabolomique Effect of phenylene bis-diphenyltriazine against the deleterious effects of UV radiation on the skin's immune defenses: metabolomic approach
Méthodes Methods
Six groupes de dix-huit épidermes reconstruits avec du microbiote et du sébum provenant de 18 donneurs distincts sont étudiés (non traité / non irradié ; formulation A / non irradié ; formulation A / irradié ; formulation B / non irradié ; formulation B / irradié). Six groups of eighteen epidermis reconstructed with microbiota and sebum from 18 distinct donors are studied (untreated / non-irradiated; formulation A / non-irradiated; formulation A / irradiated; formulation B / non-irradiated; formulation B / irradiated) .
Les épidermes reconstruits sont irradiés par des rayonnements solaires simulés en utilisant une chambre Suntest CPS+ (ATLAS Material Testing Technology BV, Moussy le Neuf, France) équipée d'une lampe à xénon NXE 1500, et munie d'un filtre UV pour éliminer les longueurs d'onde inférieures à 290 nm. L’irradiance dans les spectres UV est d'environ 70 W/m2 de 290 à 400 nm. Les modèles de peau sont exposés à une dose unique aiguë d'UV de 16,5 J/cm2 (environ 45 min) et la chambre d'irradiation est maintenue à 37°C à l'aide d'eau glacée et d'un flux d'air. The reconstructed epidermis are irradiated by simulated solar radiation using a Suntest CPS+ chamber (ATLAS Material Testing Technology BV, Moussy le Neuf, France) equipped with an NXE 1500 xenon lamp, and equipped with a UV filter to eliminate the lengths waves less than 290 nm. The irradiance in the UV spectra is approximately 70 W/m 2 from 290 to 400 nm. The skin models are exposed to a single acute UV dose of 16.5 J/cm 2 (approximately 45 min) and the irradiation chamber is maintained at 37°C using ice-cold water and a flow of air.
La formulation A ou B est appliquée à la dose de 2 mg/cm2 sur la surface des épidermes reconstruits. Après irradiation avec le spectre solaire total (jusqu’à 790 nm), le modèle est maintenu en culture 24 heures à 32°C et 60 % d’humidité. Formulation A or B is applied at a dose of 2 mg/cm 2 to the surface of the reconstructed epidermis. After irradiation with the total solar spectrum (up to 790 nm), the model is maintained in culture for 24 hours at 32°C and 60% humidity.
A la fin de l'expérience, la surface des épidermes reconstruits est lavée deux fois avec 100 pL de sérum physiologique, et ensuite séchée avec un coton-tige. Cette étape a pour but de récupérer le microbiote cutané ainsi que le film hydrolipidique. Les épidermes reconstruits sont séparés de l’insert et sont pesés afin de standardiser les résultats obtenus avec l’approche métabolomique. Les épidermes reconstruits sont broyés et 108 échantillons sont extraits. Brièvement, les échantillons sont broyés dans 2 x ImL d'acétonitrile/eau 1/9 (v:v) avec un fastprep utilisant des tubes Lysing Matrix M, 6 cycles de 20 secondes à force 4, avec 2 min sur glace entre chaque cycle. Un volume de 800 pL de chaque échantillon a été évaporé à sec avec un SpeedVac puis normalisé dans 220 pL de D2O. Les échantillons ont été analysés en RMN puis spectrométrie de masse. At the end of the experiment, the surface of the reconstructed epidermis is washed twice with 100 μL of physiological serum, and then dried with a cotton swab. This step aims to recover the skin microbiota as well as the hydrolipidic film. The reconstructed epidermis are separated from the insert and are weighed in order to standardize the results obtained with the metabolomic approach. The reconstructed epidermis is crushed and 108 samples are extracted. Briefly, samples are ground in 2 x ImL of acetonitrile/water 1/9 (v:v) with fastprep using Lysing Matrix M tubes, 6 cycles of 20 seconds at force 4, with 2 min on ice between each cycle . A volume of 800 pL of each sample was evaporated to dryness with a SpeedVac then normalized in 220 pL of D2O. The samples were analyzed by NMR then mass spectrometry.
Les spectres RMN 1H sont obtenus à 300 K sur un spectromètre RMN Bruker Avance III HD 600 MHz (Bruker Biospin, Rheinstetten, Allemagne), fonctionnant à 600,13 MHz pour la fréquence de résonance 1H, en utilisant une cryosonde 1H-13C-15N-31P de 5 mm à détection inverse attachée à une Cryoplatforme (l'unité de préamplification). Les spectres de RMN 1H sont acquis en utilisant l'expérience NOESY 1D avec pré-saturation pour la suppression de l'eau (noesyprld), avec un temps de mélange de 100 ms. 1H NMR spectra are obtained at 300 K on a Bruker Avance III HD 600 MHz NMR spectrometer (Bruker Biospin, Rheinstetten, Germany), operating at 600.13 MHz for the resonance frequency 1H, using a 5 mm reverse sensing 1H-13C-15N-31P cryoprobe attached to a Cryoplatform (the preamplification unit). 1H NMR spectra are acquired using the NOESY 1D experiment with pre-saturation for water removal (noesyprld), with a mixing time of 100 ms.
Après les analyses par RMN, les échantillons sont transférés des tubes RMN aux flacons UHPLC. Les échantillons sont centrifugés à 9000 g pendant 5 min. Un volume de 10 pL est ensuite injecté dans le système UHPLC ACQUITY de Waters (Manchester, UK), en utilisant de l'eau/méthanol/acide acétique 95/5/0,1 (v:v:v) comme phase mobile A et du méthanol/acide acétique 100/0,1 (v:v) comme phase mobile B, à un débit de 0,3 mL/min. Le gradient suivant est utilisé : 0-30 min : 0 % à 100 % de B, 30- 34 min : 100 % de B. La séparation est réalisée à 30°C avec une colonne Hypersil Gold C18 (100 x 2,1 mm, 1,9 pm) de Thermo Scientific (Les Ulis, France). Les paramètres d'électrospray suivants sont appliqués : tension capillaire de 0,5 kV, tension du cône d'échantillonnage de 30 V, température de la source de 120 °C, température de désolvatation de 350 °C, débit du gaz du cône de 50 L/h et débit du gaz de désolvatation de 600 L/h en mode positif ; tension capillaire de 0,5 kV, tension du cône d'échantillonnage de 30 V, température de la source de 120 °C, température de désolvatation de 550 °C, débit du gaz du cône de 30 L/h et débit du gaz de désolvatation de 600 L/h en mode négatif. Les spectres de masse à haute résolution sont acquis avec un spectromètre de masse Synapt G2-Si de Waters (Manchester, UK), entre m/z 50 et 800 dans les modes sensibilité et centroïde. Les échantillons sont analysés de manière aléatoire, et un échantillon QC correspondant à un pool de tous les échantillons, est analysé 11 fois le long de la séquence. After NMR analyses, samples are transferred from NMR tubes to UHPLC vials. The samples are centrifuged at 9000 g for 5 min. A volume of 10 pL is then injected into the ACQUITY UHPLC system from Waters (Manchester, UK), using water/methanol/acetic acid 95/5/0.1 (v:v:v) as mobile phase A and methanol/acetic acid 100/0.1 (v:v) as mobile phase B, at a flow rate of 0.3 mL/min. The following gradient is used: 0-30 min: 0% to 100% B, 30-34 min: 100% B. The separation is carried out at 30°C with a Hypersil Gold C18 column (100 x 2.1 mm , 1.9 pm) from Thermo Scientific (Les Ulis, France). The following electrospray parameters are applied: capillary voltage of 0.5 kV, sampling cone voltage of 30 V, source temperature of 120 °C, desolvation temperature of 350 °C, cone gas flow rate of 50 L/h and desolvation gas flow rate of 600 L/h in positive mode; capillary voltage of 0.5 kV, sampling cone voltage of 30 V, source temperature of 120 °C, desolvation temperature of 550 °C, cone gas flow rate of 30 L/h and gas flow rate of desolvation of 600 L/h in negative mode. High-resolution mass spectra are acquired with a Synapt G2-Si mass spectrometer from Waters (Manchester, UK), between m/z 50 and 800 in sensitivity and centroid modes. Samples are analyzed randomly, and a QC sample, corresponding to a pool of all samples, is analyzed 11 times along the sequence.
Les identifications structurelles des métabolites discriminants sont réalisées sur un spectromètre de masse LTQ Orbitrap XL (Thermo Scientific, Les Ulis, France) couplé à un système de chromatographie liquide U3000 (Thermo Scientific, Les Ulis, France). The structural identifications of the discriminating metabolites are carried out on an LTQ Orbitrap XL mass spectrometer (Thermo Scientific, Les Ulis, France) coupled to a U3000 liquid chromatography system (Thermo Scientific, Les Ulis, France).
Analyse des données : Data analysis :
L'analyse statistique et la cartographie du réseau sont réalisées par la plateforme MetaboHUB- MetaToul-AXIOM. Statistical analysis and network mapping are carried out by the MetaboHUB-MetaToul-AXIOM platform.
Les données sont normalisées pour permettre la quantification des signaux détectés dans plusieurs échantillons. Data are normalized to allow quantification of signals detected in multiple samples.
L'analyse des composantes principales est d'abord appliquée pour vérifier la validité de l'acquisition, pour détecter les valeurs aberrantes potentielles et les clusters internes. Principal component analysis is first applied to check the validity of the acquisition, to detect potential outliers and internal clusters.
Dans un contexte biologique, des facteurs de confusion sont généralement rencontrés : ces facteurs ajoutent du bruit dans les données correspondant à une variabilité non désirée. Plusieurs sources de bruit sont possibles : expérimentales, instrumentales... Lorsque la variabilité due à ces facteurs est supérieure à la variabilité due au facteur d'intérêt, aucune discrimination entre les groupes de traitement ne peut être trouvée. L'analyse discriminante par la méthode des moindres carrés partiels orthogonaux (O-PLS- DA) vise à éliminer cette variation indésirable. Un test de permutation est effectué pour évaluer la robustesse des modèles PLS-DA. La valeur de la Variable Importance in Projection (VIP) (seuil=l) a été utilisée pour trouver des caractéristiques discriminantes. In a biological context, confounding factors are generally encountered: these factors add noise to the data corresponding to unwanted variability. Several sources of noise are possible: experimental, instrumental, etc. When the variability due to these factors is greater than the variability due to the factor of interest, no discrimination between the treatment groups can be found. Discriminant analysis using the orthogonal partial least squares (O-PLS-DA) method aims to eliminate this undesirable variation. A permutation test is performed to evaluate the robustness of the PLS-DA models. The value of the Variable Importance in Projection (VIP) (threshold=l) was used to find discriminating characteristics.
Pour chaque caractéristique discriminante, un test de Wilcoxon univarié et une correction du taux de fausse découverte (FDR) sont effectués pour prendre en compte les tests multiples (seuil de la valeur de p corrigée par le FDR = 0,05). For each discriminating feature, a univariate Wilcoxon test and false discovery rate (FDR) correction are performed to account for multiple testing (FDR-corrected p-value threshold = 0.05).
Les analyses multivariées sont effectuées à l'aide du logiciel SIMCA vl5 (Umetrics, Umeâ, Suède). Le paquet mixOmics (Rohart et al., 2017) est utilisé pour effectuer des analyses multiniveaux. Multivariate analyzes are carried out using SIMCA vl5 software (Umetrics, Umeâ, Sweden). The mixOmics package (Rohart et al., 2017) is used to perform multilevel analyses.
Pour créer le réseau métabolique, un logiciel librement accessible est développé et utilisé par l'INRAE, Toxalim : MetExplore. Il s’agit un serveur web qui offre la possibilité de relier les métabolites identifiés dans des expériences métabolomiques non ciblées dans le contexte de réseaux métaboliques reconstruits à l'échelle du génome. Le pipeline d'analyse comprend le mappage des données métabolomiques sur le réseau métabolique spécifique d'un organisme, puis l'application de méthodes basées sur les graphes et d'outils de visualisation avancés pour améliorer l'analyse des données. To create the metabolic network, freely accessible software is developed and used by INRAE, Toxalim: MetExplore. This is a web server that offers the possibility of linking metabolites identified in untargeted metabolomics experiments in the context of reconstructed genome-scale metabolic networks. The analysis pipeline includes mapping metabolomics data to an organism's specific metabolic network, then applying graph-based methods and advanced visualization tools to improve data analysis.
Tous les échantillons sont discriminés à partir des données RMN selon les facteurs de traitement et d’irradiation. A partir de cette discrimination significative, 52 caractéristiques sont discriminantes (VIP >1) significatives (valeur p corrigée par le FDR du test de Mann Whitney <0 ,05). a) Métabolisme des acides aminés All samples are discriminated from NMR data according to processing and irradiation factors. From this significant discrimination, 52 characteristics are discriminative (VIP >1) significant (p-value corrected by the FDR of the Mann Whitney test <0.05). a) Amino acid metabolism
Les tableaux qui suivent rapportent les variations observées (Log 2 de variations) sous l’effet de l’irradiation UV pour différents acides aminés discriminants du système immunitaire, dans l’épiderme du modèle. The following tables report the variations observed (Log 2 of variations) under the effect of UV irradiation for different discriminating amino acids of the immune system, in the epidermis of the model.
- Acides aminés ramifiés (BCAA, « branched-chain amino acid ») - Branched-chain amino acids (BCAA)
Tableau 3
Figure imgf000021_0001
: Non irradié ; IR : Irradié ; CTRL : Contrôle ; FA : Formulation A ; FB : Formulation B ; ns : non significatif Table 3
Figure imgf000021_0001
: Not irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: no significant
- Acides aminés aromatiques - Aromatic amino acids
Tableau 4
Figure imgf000022_0001
Table 4
Figure imgf000022_0001
Les BCAA, les acides aminés aromatiques et leurs métabolites jouent un rôle important dans la réponse immunitaire. BCAAs, aromatic amino acids and their metabolites play an important role in the immune response.
Les résultats ci-dessus démontrent que l’application topique d’une formulation comprenant la phénylène bis-diphényltriazine associée (B) ou non (A) à d’autres filtres solaires permet d’amortir très significativement les déséquilibres induits par le rayonnement UV, et ainsi de prévenir et/ou diminuer l’altération du système immunitaire cutané. b) Métabolisme lipidique The above results demonstrate that the topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to very significantly cushion the imbalances induced by UV radiation, and thus prevent and/or reduce the alteration of the skin immune system. b) Lipid metabolism
- Acide arachidonique - Arachidonic acid
L’acide arachidonique et ses métabolites sont bien connus comme modulateurs des réponses immunitaires. Le tableau qui suit montre les concentrations en acide arachidonique dans l’épiderme reconstruit, déterminées par chromatographie en phase liquide - spectrométrie de masse (LC/MS).Arachidonic acid and its metabolites are well known as modulators of immune responses. The following table shows the concentrations of arachidonic acid in the reconstructed epidermis, determined by liquid chromatography - mass spectrometry (LC/MS).
Paramètres LC : LC parameters:
- Colonne : Waters XTERRA RP 18 3.5pm 4.6 x 250 mm - Column: Waters XTERRA RP 18 3.5pm 4.6 x 250 mm
- Phase mobile : méthanol / heptane / chloroforme / acide acétique (90/10/1/0,1) - Mobile phase: methanol / heptane / chloroform / acetic acid (90/10/1/0.1)
- Température passeur : 10 °C - Passer temperature: 10°C
- Température colonne : 25 °C - Column temperature: 25°C
- Débit : 0,5 mL/min - Flow rate: 0.5 mL/min
- Volume d’injection : 10 pL - Injection volume: 10 pL
- Pression : 77 bars - Pressure: 77 bars
- Durée d’élution : 12 min - Elution time: 12 min
Paramètres MS (ESI) : MS Parameters (ESI):
- Appareillage : Agilent - Durée de balayage : 50 scan/min - Equipment: Agilent - Scanning time: 50 scan/min
- Fragmentation : 380 V - Fragmentation: 380 V
- Cell Acc. : 5 V - Cell Acc. : 5V
- Polarité : négative - Polarity: negative
- Nébuliseur : 20 psi - Nebulizer: 20 psi
- Température gaz : 200°C - Gas temperature: 200°C
- Température et débit du gaz rideau : 250 °C, 11 L/min - Temperature and flow rate of curtain gas: 250 °C, 11 L/min
- Capillaire : 3000 V - Capillary: 3000 V
- Tension de charge : 1500 V - Charging voltage: 1500 V
Résultats : Results :
Tableau 5
Figure imgf000023_0001
Table 5
Figure imgf000023_0001
*P<0,05 versus groupe Irradié *P<0.05 versus Irradiated group
Le rayonnement UV induit une diminution significative de la concentration de l’acide arachidonique dans les épidermes reconstruits. L’application topique d’une formulation comprenant la phénylène bis- diphényltriazine associée (B) ou non (A) à d’autres filtres solaires permet de maintenir un niveau en acide arachidonique équivalent à un groupe contrôle, malgré une exposition au rayonnement UV. UV radiation induces a significant decrease in the concentration of arachidonic acid in the reconstructed epidermis. Topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to maintain a level of arachidonic acid equivalent to a control group, despite exposure to UV radiation.
- Autres marqueurs lipidiques - Other lipid markers
Le tableau qui suit rapporte les variations observées (Log 2 de variations) sous l’effet de l’irradiation UV pour différents marqueurs lipidiques discriminants du système immunitaire, dans l’épiderme du modèle. The following table reports the variations observed (Log 2 of variations) under the effect of UV irradiation for different discriminating lipid markers of the immune system, in the epidermis of the model.
Tableau 6
Figure imgf000023_0002
NI : Non irradié ; IR : Irradié ; CTRL : Contrôle ; FA : Formulation A ; FB : Formulation B ; ns : non significatif Table 6
Figure imgf000023_0002
NI: Not irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: not significant
Ces résultats démontrent que l’application topique d’une formulation comprenant la phénylène bis- diphényltriazine associée (B) ou non (A) à d’autres filtres solaires permet d’amortir très significativement les déséquilibres induits par le rayonnement UV, et ainsi de prévenir et/ou diminuer l’altération du système immunitaire cutané. These results demonstrate that the topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to very significantly cushion the imbalances induced by UV radiation, and thus to prevent and/or reduce the alteration of the skin immune system.
L’ensemble des résultats ci-dessus permet de conclure que la phénylène bis-diphényltriazine permet de lutter efficacement contre les désordres du système immunitaire cutané engendrés par le rayonnement UV, et ainsi de préserver les défenses immunitaires de la peau, notamment l’immunité innée. All of the above results allow us to conclude that phenylene bis-diphenyltriazine can effectively fight against disorders of the skin's immune system caused by UV radiation, and thus preserve the skin's immune defenses, particularly innate immunity. .

Claims

REVENDICATIONS
1. 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine pour son utilisation dans la préservation des défenses immunitaires de la peau. 1. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use in preserving the skin's immune defenses.
2. 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine pour son utilisation selon la revendication 1, pour la préservation de l’immunité innée. 2. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for its use according to claim 1, for the preservation of innate immunity.
3. Composition comprenant de la 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine et au moins un excipient cosmétiquement et/ou pharmaceutiquement acceptable, dans la préservation des défenses immunitaires de la peau. 3. Composition comprising 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine and at least one cosmetically and/or pharmaceutically excipient acceptable, in the preservation of the skin's immune defenses.
4. Composition pour son utilisation selon la revendication 3, pour la préservation de l’immunité innée. 4. Composition for its use according to claim 3, for the preservation of innate immunity.
5. Composition pour son utilisation selon la revendication 3 ou 4, caractérisée en ce qu’elle comprend un système photoprotecteur constitué de : 5. Composition for its use according to claim 3 or 4, characterized in that it comprises a photoprotective system consisting of:
(a) 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine, (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine,
(b) 2,4-bis[4-(2-éthylhexyloxy)-2-hydroxyphényl]-6-(4-méthoxyphényl)-l,3,5-triazine, (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine,
(c) hexyl 2-[4-(diéthylamino)-2-hydroxybenzoyl]benzoate, et (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and
(d) éthylhexyl triazone ou diéthylhexyl butamido triazone, le système photoprotecteur représentant entre 4 % et 25 % en poids par rapport au poids total de la composition, ladite composition ne comprenant aucun fdtre solaire autre que ceux constitutifs dudit système photoprotecteur. (d) ethylhexyl triazone or diethylhexyl butamido triazone, the photoprotective system representing between 4% and 25% by weight relative to the total weight of the composition, said composition not comprising any solar filter other than those constituting said photoprotective system.
6. Composition pour son utilisation selon Tune quelconque des revendications 3 à 5, caractérisée en ce que la 5,6,5’,6’-tétraphényl-3,3’-(l,4-phénylène)-bis[l,2,4]triazine représente entre 1 % et 5 % en poids par rapport au poids total de la composition. 6. Composition for its use according to any one of claims 3 to 5, characterized in that 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2 ,4]triazine represents between 1% and 5% by weight relative to the total weight of the composition.
7. Composition pour son utilisation selon Tune quelconque des revendications 3 à 6, caractérisée en ce que la 2,4-bis[4-(2-éthylhexyloxy)-2-hydroxyphényl]-6-(4-méthoxyphényl)-l,3,5-triazine représente entre 1 % et 4 % en poids par rapport au poids total de la composition. 7. Composition for its use according to any one of claims 3 to 6, characterized in that 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3 ,5-triazine represents between 1% and 4% by weight relative to the total weight of the composition.
8. Composition pour son utilisation selon Tune quelconque des revendications 3 à 7, caractérisée en ce que l’hexyl 2-[4-(diéthylamino)-2-hydroxybenzoyl]benzoate représente entre 1 % et 10 % en poids par rapport au poids total de la composition. 8. Composition for its use according to any one of claims 3 to 7, characterized in that hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate represents between 1% and 10% by weight relative to the total weight of the composition.
9. Composition pour son utilisation selon l’une quelconque des revendications 3 à 8, caractérisée en ce que le filtre solaire (d) représente entre 1 % et 6 % en poids par rapport au poids total de la composition. 9. Composition for its use according to any one of claims 3 to 8, characterized in that the solar filter (d) represents between 1% and 6% by weight relative to the total weight of the composition.
10. Composition pour son utilisation selon l’une quelconque des revendications 3 à 9, caractérisée en ce que le filtre solaire (d) est l’éthylhexyl triazone. 10. Composition for its use according to any one of claims 3 to 9, characterized in that the sun filter (d) is ethylhexyl triazone.
PCT/EP2023/062038 2022-05-05 2023-05-05 Use of phenylene bis-diphenyltriazine for preserving immune defenses of the skin WO2023214065A1 (en)

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