USE OF PHENYLENE BIS-DIPHENYLTRIAZINE FOR THE PRESERVATION OF THE SKIN'S IMMUNE DEFENSES

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 it, for its use in preserving the immune defenses of the skin, in particular preserving innate immunity.

Description

Title of the invention: USE OF PHENYLENE BIS-DIPHENYLTRIAZINE FOR THE PRESERVATION OF SKIN'S IMMUNE DEFENSES Scope of the invention

[0001] The invention relates to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine (phenylene bis-diphenyltriazine), and a composition comprising it, for its use in preserving the immune defenses of the skin, in particular preserving innate immunity. Technical context

[0002] The skin is much more than an external covering; it is, in fact, a true organ necessary for life. It is a site of exchange between the body and the external environment, and is therefore exposed to numerous physical, chemical, or microbiological aggressions, against which it constitutes the first line of anatomical defense. The skin thus performs, among other things, a true barrier function.

[0003] The skin is composed of several types of cells organized into three layers: (i) the hypodermis, the deepest layer, consists of adipose tissue; the dermis, the middle and thickest layer, corresponds to supporting connective tissue; and (iii) the epidermis, the superficial layer, which is mainly composed of keratinocytes. The epidermis is separated from the external environment by the stratum corneum, a protective barrier rich in corneocytes. However, the skin is not simply a physical barrier: it also constitutes an immunological barrier, capable of developing innate and adaptive immune responses, which allow it to defend the host against various types of aggression.

[0004] The cutaneous immune system is based on different resident cells with specific and varied functions depending on their location, specialized recruited cellular actors (leukocytes) and soluble mediators (cytokines and chemokines).

[0005] The dermis notably contains fibroblasts, mast cells, macrophages and dendritic cells, which participate directly or indirectly in the immunology of the skin.

[0006] Within the epidermis, two types of cells play a major role in cutaneous immunity, whether innate or adaptive.

[0007] - Keratinocytes, which represent 90% of the epidermal cell population, are important in the development of the immune response due to their number and their ability to secrete cytokines and antimicrobial peptides.

[0008] - Langerhans cells are dendritic cells that act as These are vital sentinels of the cutaneous immune system. They have the ability to detect antigens that cross the stratum corneum and migrate to the lymph nodes to present them to T lymphocytes.

[0009] The cutaneous immune system can be disrupted by various intrinsic or extrinsic factors, such as aging or UV radiation.

[0010] The field of photoprotection remains a major public health issue for preventing skin damage from overexposure to the sun. Skin damage is mainly induced by ultraviolet radiation (UVA and / or UVB), but also by visible light, particularly high-energy blue visible light, and infrared radiation via damage to macromolecules leading to DNA lesions, oxidative stress, lipid peroxidation, and degradation of the dermal matrix.

[0011] To assess the impact of sun exposure, the cutaneous ecosystem, consisting of the skin, sebum (hydrolipidic film), and microbiota (skin flora), must be studied as a whole to understand how its components interact with each other and contribute to responding to external stress. The inventors have thus developed a model that reproduces the complexity of cutaneous physiology and have demonstrated, quite unexpectedly, that the phenylene bis-diphenyltriazine sunscreen has the ability to prevent and / or reduce the impairment of the cutaneous immune system. Description of the invention

[0012] The present invention therefore relates to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use in preserving the immune defenses of the skin.

[0013] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine (CAS No. 55514-22-2), also known as phenylene bis-diphenyltriazine, is a sunscreen; more specifically, an ultra-broad-spectrum sunscreen capable of filtering the harmful part of the solar spectrum, which includes UV radiation (UVB and UVA), as well as high-energy visible blue light. In the following description, the names 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and phenylene bis-diphenyltriazine are used interchangeably.

[0014] The term “sunscreen” refers to a substance capable of filtering solar radiation to protect a surface, typically the skin or hair, against the harmful effects of this radiation.

[0015] 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.

[0016] By "UVA radiation" or simply "UVA", we mean ultraviolet rays having an X wavelength between 320 and 400 nm.

[0017] By "UVB radiation" or simply "UVB", we mean ultraviolet rays having an X wavelength between 290 and 320 nm.

[0018] A sunscreen is described as a "UVA filter" or "UVB filter" depending on whether it filters mostly UVA or UVB.

[0019] A sunscreen called “broadband” or “broad spectrum” filters both UVA and UVB rays.

[0020] Depending on the radiation filtration mechanism, that is, depending on whether the radiation is absorbed and / or reflected, or even diffused by the solar filter, we can strictly distinguish:

[0021] - the filters stricto sensu, which mostly absorb radiation, and

[0022] - screens, which absorb and reflect radiation.

[0023] However, in the remainder of the description, the term "filter" will be used interchangeably. solar”, sometimes abbreviated “filter”, whether it is a filter or a screen.

[0024] A sunscreen filter can be "lipid-soluble" or "water-soluble," depending on whether it dissolves more readily in lipids or in water, or even "insoluble." An insoluble sunscreen filter is typically in particulate form and can nevertheless be incorporated into a sun protection composition, particularly in a dispersed form, especially a water-dispersed form when dispersed in an aqueous phase.

[0025] Phenylene bis-diphenyltriazine is a non-soluble type filter. In particular, it is a water-dispersible filter, which typically takes 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 total weight of the dispersion.

[0026] Advantageously, the process for preparing the aqueous dispersion consists of grinding the insoluble organic filter into particles using a grinding apparatus and in the presence of a grinding aid. Conventionally, wet grinding processes are used (wet grinding, wet mixing), and the grinding aid improves particle dispersion. These techniques are well known to those skilled in the art. The grinding apparatus can be, for example, a micro-bead mill, a vibrating mill, or a ball mill. Depending on the grinding process, the grinding aid is selected from the group consisting of anionic, nonionic, or amphoteric surfactants, emulsifiers, and dispersants such as PPG-1-PEG-9 Lauryl Glycol Ether (Eumulgin® L, marketed by BASF).

[0027] In a particular embodiment, the D50 size of the bis-diphenyltriazine phenylene particles is between 100 and 1000 nm, more particularly between 100 and 500 nm, even more particularly between 120 and 400 nm, especially between 120 and 250 nm, particularly between 120 and 200 nm, typically between 150 and 200 nm.

[0028] 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 relation:

[0029] [Math.l] Di Ff f (D^dD o

[0030] in which:

[0031] f(D) is the number size distribution of the particles, and

[0032] Di is a size class.

[0033] The value of D50 can be determined using a Mastersizer 3000 liquid-mode laser diffraction particle size analyzer.

[0034] Topical application of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine prevents and / or reduces alteration of the cutaneous immune system.

[0035] Phenylene bis-diphenyltriazine therefore helps 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.

[0036] It thus helps to protect and preserve skin immunity, in particular innate immunity, especially against external stress, such as exposure to UV radiation.

[0037] The present invention also relates to a method for preventing and / or reducing the alteration of the cutaneous immune system, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine.

[0038] It further relates to a method for preserving the immune defenses of the skin, in particular its natural immune defenses, and therefore a method for preserving cutaneous immunity, in particular innate immunity, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine.

[0039] According to another aspect, the present invention relates to a composition comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and at least one cosmetically and / or pharmaceutically acceptable excipient, for the same uses as those presented above.

[0040] In a particular embodiment, the composition for use according to the invention is in the form of an emulsion.

[0041] For the purposes of this invention, "emulsion" means any type of emulsion obtained by dispersing a discontinuous internal phase in a continuous external phase, one of these phases being an aqueous phase and the other being a phase oily. This is, for example, an oil-in-water or water-in-oil emulsion or multiple emulsions, preferably an oil-in-water emulsion.

[0042] These emulsions can be more or less fluid and may be presented 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, a foam or a spray, and may also be water-resistant.

[0043] The composition for use according to the invention is intended for topical application to the skin.

[0044] 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 total weight of the composition.

[0045] It is understood that these mass percentages, as well as all those indicated in the description, are expressed as a percentage by mass of active material relative to the total mass of the composition.

[0046] In the composition for use according to the present invention, phenylene bis-diphenyltriazine can be associated with one or more other sunscreens, to constitute a photoprotective system which, after application to a surface (skin, hair, etc.), by mechanisms of absorption and / or reflection and / or diffusion of UVA and / or UVB radiation, prevents, or at least limits, the contact of said radiation with said surface.

[0047] The photoprotective system constituting a composition for use according to the invention preferably comprises one or more liposoluble UV filters selected from the following filters (i) to (v):

[0048] (i) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (CAS number: 302776-68-7), also known as diethylamino hydroxybenzoyl hexyl benzoate or DHHB, marketed by BASF under the name Uvinul A Plus®.

[0049] This is a liposoluble UVA filter, having a maximum absorption wavelength Xmax equal to 354 nm.

[0050] In a particular embodiment, 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%, notably between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition.

[0051] (ii) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazin e (CAS No. 187393-00-6), also known as bis-ethylhexyloxyphenol methoxyphenyl triazine or BEMT, marketed by BASF under the name Tinosorb S®.

[0052] This is a liposoluble broadband filter, having two absorption peaks at 310 nm and 340 nm.

[0053] In a particular embodiment, the BEMT represents between 1% and 4%, in particular between 2% and 4%, especially between 2% and 3% by weight relative to the total weight of the composition.

[0054] (iii) 4-tert-butyl-4-methoxydibenzoylmethane or butyl methoxydibenzoylmethane (chemical name: l,4-(l,l-dimethylethyl)phenyl-3-(4-methoxyphenyl)-l,3-propanedione; CAS No.: 70356-09-1), also known as avobenzone or BMDBM, marketed notably by DSM under the name Parsol 1789®.

[0055] This is a liposoluble UVA filter, having a maximum absorption wavelength Xmax equal to 357 nm.

[0056] In a particular embodiment, the BMDBM represents between 1% and 10%, for example between 1% and 8%, in particular between 1% and 5%, typically between 2% and 4% by weight, relative to the total weight of the composition.

[0057] (iv) ethylhexyl triazone or EHT (chemical name: acid 4- [ [4,6-bis [[4-(2-ethylhexoxy-oxomethyl)phenyl] amino] -1,3,5-triazin-2-yl] amino]benzoic 2-ethylhexyl ester; CAS No.: 88122-99-00), marketed by BASF under the name Uvinul T 150®.

[0058] This is a liposoluble UVB filter, having a maximum absorption wavelength Xmax equal to 314 nm.

[0059] In a particular embodiment, 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.

[0060] (v) diethylhexyl butamido triazone or DBT (chemical name: 4,4'-[[6-[[4-[[(l,l-dimethylethyl)amino]carbonyl]phenyl]amino]-l,3,5-triazine-2,4-diyl ]diimino]bis-, bis(2-ethylhexyl)benzoate; CAS No.: 154702-15-5), marketed by 3V Sigma under the name Uvasorb HEB®.

[0061] This is a liposoluble UVB filter, having a maximum absorption wavelength Xmax equal to 310 nm.

[0062] 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.

[0063] The photoprotective system constituting a composition for use according to the invention may include one or more additional particulate organic UV filters, in addition to phenylene bis-diphenyltriazine, selected from the following filters (vi) and (vii):

[0064] (vi) methylene bis-benzotriazolyl tetramethylbutylphenol (chemical name: 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol; CAS No.: 103597-45-1) also known as MBBT, marketed by BASF under the name Tinosorb M®.

[0065] This is a broadband filter, having two absorption peaks at 306 nm and 348 nm, of the non-soluble type.

[0066] MBBT is typically presented 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.

[0067] In a particular embodiment, 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.

[0068] In a particular embodiment, the D50 size of the MBBT particles is between 50 nm and 250 nm, in particular between 60 nm and 150 nm.

[0069] (vii) 2,4,6-tris(biphenyl-4-yl)-l,3,5-triazine (CAS No. 31274-51-8) also tris-biphenyl triazine or TBPT, marketed by BASF under the name Tinosorb A2B®.

[0070] This is an essentially UVB filter, having a maximum absorption wavelength Xmax equal to 310 nm, of the non-soluble type.

[0071] TBPT is typically presented 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.

[0072] In a particular embodiment, the TBPT represents between 1% and 7%, in particular between 2% and 7%, notably between 2% and 6% by weight relative to the total weight of the composition.

[0073] In a particular embodiment, the D50 size of the TBPT particles is between 50 nm and 250 nm, in particular between 80 nm and 150 nm.

[0074] 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.

[0075] In a particular embodiment, the composition for use according to the invention does not include any water-soluble filter.

[0076] The absence of water-soluble filters is particularly advantageous, since water-soluble filters are generally more readily assimilated by marine organisms than fat-soluble or insoluble filters. Therefore, the Applicant's choice to use only fat-soluble or particulate filters, particularly water-dispersed ones, minimizes the impact of the composition according to the invention on the marine environment.

[0077] In a particular embodiment, the composition for use according to the invention comprises one or more particulate inorganic filters, such as titanium dioxide (TiO2) or zinc oxide (ZnO).

[0078] The inorganic particulate filter(s) possibly present in the composition according to the invention typically have a particle size D50 between 15 nm and 150 nm.

[0079] In another particular embodiment, the composition for use according to the invention does not include any particulate inorganic filter.

[0080] 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 the UV filters present in the composition represent between 4% and 25% by weight, in particular between 6% and 20% by weight, notably between 7% and 18% by weight, typically between 8% and 17% by weight, relative to the total weight of the composition.

[0081] In an advantageous embodiment, the photoprotective system consists of:

[0082] (a) 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine,

[0083] (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine,

[0084] (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and

[0085] (d) ethylhexyl triazone or diethylhexyl butamido triazone.

[0086] In particular, (d) corresponds to ethylhexyl triazone.

[0087] In this 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 total weight of the 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; 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 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.

[0088] In the present invention, "cosmetically and / or pharmaceutically acceptable" means anything useful in the preparation of a composition that may have a cosmetic and / or pharmaceutical application, and that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that is acceptable for human cosmetic or pharmaceutical use. "Pharmaceutically and / or cosmetically acceptable excipient" means any cosmetically and / or pharmaceutically acceptable adjuvant that enables the manufacture, preservation, or administration of the composition.

[0089] Compositions for use according to the invention may thus include conventional pharmaceutical or dermatological adjuvants, in particular selected from liquid lipophilic compounds, emulsifiers, consistency agents, water-retaining agents, texturizing agents, opacifiers, colour pigments, antifoaming 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 emollients, moisturizing agents, antioxidants) or any other ingredient usually used for the manufacture of sunscreen compositions.

[0090] The composition may thus include 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 fat or a combination of liquid fats.

[0091] By "liquid lipophilic compound" is meant a compound which has an affinity for nonpolar substances such as lipids, and is in liquid form in particular at a temperature between 5°C and room temperature (between 20°C and 25°C). It typically comprises one or more polar chemical functions chosen from among the ester (-CO2-), alcohol (-OH), ether (-O-), carbonate (-OCO2-) and carboxylic acid (-CO2H) functions, and one or more lipophilic group(s), i.e. one or more aliphatic and / or aromatic hydrocarbon group(s), in particular one or more saturated or unsaturated, linear or branched hydrocarbon chains, comprising between 6 and 20 carbon atoms, for example between 7 and 18 carbon atoms, notably between 8 and 16 carbon atoms. A second group may be chosen in particular from Ci2-Ci5 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.

[0092] The liquid lipophilic emollient(s) are chosen in particular from the Ci2-Ci5 alkyl benzoate, caprylic / capric triglycerides and dicaprylyl carbonate.

[0093] 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 comprise 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.

[0094] The composition may further comprise a polyol miscible with water at room temperature (approximately 25°C), in particular selected from polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having from 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 Ci-C4 alkyl ethers of mono-, di- or tri-propylene glycol, Ci-C4 alkyl ethers of mono-, di- or tri-ethylene glycol and mixtures thereof.

[0095] The composition may also include one or more anionic, cationic and non-ionic emulsifiers selected 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; fatty acid glycerides 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 silicone / polysiloxane / polyalkyl / polyether oxyalkenyl copolymers and derivatives.

[0096] The emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.

[0097] In a particular embodiment, the composition for use according to the invention does not include an ethoxylated emulsifier and / or one comprising a PEG chain.

[0098] 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 silicone / polysiloxane / polyalkyl / polyether oxyalkenyl copolymers and derivatives.

[0099] The composition may also include one or more solid consistency agents selected from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyle stearate; 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 acrylic acids or crosslinked poly-acrylamides such as carbomers, acrylate copolymers, acrylate / (Cio-C3O)alkylacrylate crosslinked copolymers, acrylate / behenethyl-25 methacrylate copolymers; and silicate derivatives such as magnesium silicates.

[0100] In a particular embodiment, the composition for use according to the invention comprises one or more consistency agents selected from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyle stearate; polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; and cellulose derivatives such as hydroxypropylcellulose.

[0101] In a particular embodiment, the composition does not include a consistency agent selected from acrylates and their derivatives.

[0102] The composition may also include one or more water-resistant remanent agents selected from an N-vinylpyrrolidone (VP) and eicosene copolymer (INCI: VP / eicosen copolymer), a trimethylpentanediol, adipic acid and glycerin crosspolymer (INCI: trimethylpentanediol / adipic acid / glycerin crosspolymer), polyamide 3 (INCI), an acrylate and octylacrylamide copolymer (INCI: acrylates / octylacrylamide copolymer), and triacontanyl PVP (INCI).

[0103] Preferably, the composition for use according to the invention comprises VP / eicosene copolymer as a water-resistant agent.

[0104] The composition may also include one or more texturizing agents in powder form, in particular selected from ingredients in the starch family, such as rice, corn, and tapioca starches; talcs and cellulose derivatives such as microcrystalline cellulose.

[0105] In a particular embodiment, the composition for use according to the invention does not include a texturizing agent selected from nylon derivatives and polymethyl methacrylate (PMMA).

[0106] The composition may also include colour pigments, in particular selected from CI77891, CI77491, CI77492 and CI77499 (INCI designations).

[0107] In a particular embodiment, the composition for use according to the invention comprises an amount of C, 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.

[0108] In another particular embodiment, the composition is devoid of ethanol and isopropanol.

[0109] In a particular embodiment, the composition for use according to the invention comprises an amount 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. For the purposes of this invention, "volatile ingredients" means non-alcoholic volatile organic or inorganic compounds such as volatile esters, silicones, or alkanes, characterized by a flash point below 60°C.For the purposes of this invention, "flash point" (FP) means the minimum temperature at which a combustible substance emits vapors in a concentration sufficient to form a gaseous mixture with the surrounding air that ignites upon contact with a flame or a hot spot, but insufficient for combustion to propagate spontaneously in the absence of a pilot flame. According to Regulation (EC) No 1272 / 2008 on the classification, labelling and packaging of substances and mixtures, a substance with an FP such that 23°C < FP < 60°C belongs to category 3 "low flammability".

[0110] Among volatile esters, isohexyl neopentanoate is a notable example. Among volatile silicones, cyclopentasiloxane is a notable example. Among volatile alkanes, isohexadecane is a notable example.

[0111] In another particular embodiment, the composition for use according to the invention is devoid of volatile ingredients within the meaning of the present invention.

[0112] The composition may also include alkalizing or acidifying agents, and more particularly acids and bases for adjusting the pH range of said composition. The bases may be mineral (sodium hydroxide, potassium hydroxide, ammonia, etc.) or organic, such as mono-, di-, or triethanolamine, an aminomethylpropanediol, N-methylglucamine, basic amino acids such as arginine and lysine, and mixtures thereof. The acids may be mineral (hydrochloric acid, etc.). or organic, such as lactic acid and citric acid.

[0113] The composition for use according to the invention may further include additional active agents selected in particular from moisturizing agents, desquamating agents, barrier function improving agents, depigmenting agents, antioxidant 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, tightening agents, liporestructuring agents, slimming agents, agents promoting cutaneous microcirculation, soothing and / or irritating agents, sebo-regulators or antiseborrheic agents, astringent agents, healing agents, anti-inflammatory agents, anti-acne agents, and mixtures thereof.

[0114] In a particular embodiment, the composition for use according to the invention is devoid of silicone.

[0115] In a preferred embodiment, the composition for use according to the invention comprises one or more antioxidants, typically selected from vitamin E and its derivatives. Advantageously, the composition for use according to the invention comprises one or more compounds selected from tocopherols, tocotrienols, and their derivatives. "Tocopherols" or "tocotrienols" are understood to mean the compounds α-, γ-, γ-, and β-tocopherol or tocotrienol. The term "tocopherol" commonly refers to α-tocopherol. Among the tocopherol derivatives, examples include ester derivatives, such as tocopheryl acetate, and glycosylated derivatives, such as tocopheryl glucoside (INCI: tocopheryl glucoside).

[0116] In a preferred embodiment, the composition for use according to the invention comprises one or more antioxidants selected 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. EXAMPLES RHE model + microbiota + sebum

[0117] The inventors have developed a reconstructed human epidermis (RHE) model colonized by skin microbiota and donor sebum in order to reproduce the complexity of the skin ecosystem. This model closely resembles real skin physiology and allows the study of interactions between the skin and the microbiota.

[0118] The epidermis was reconstructed from skin excisions obtained from cosmetic surgery according to the method described by Frankart et al. (Frankart et al., Exp. Dermatol. 2012,21(11), 871-875).

[0119] Briefly, the cells (keratinocytes) were isolated from the skin excisions, then cultured before being seeded onto 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 comeum.

[0120] After 14 days, a reconstructed epidermis with a surface area of ​​0.6 cm2 is formed. The culture medium is renewed every 24 hours.

[0121] At the end of the reconstruction, microbiota and sebum from healthy volunteers are inoculated.

[0122] - Sebum preparation

[0123] Sebum is collected from the foreheads of 10 volunteers with no apparent skin pathology using a standard collection kit. Each collection tube is then washed three times with hexane to extract the sebum. The extracts are then combined, and the solvent is evaporated under vacuum. The mass of the collected sebum is checked (e.g., 1100 mg for one preparation), and then the sebum is resuspended in 20 mL of hexane. One hundred vials of sebum are prepared, with 9 mg of substance per vial, and packaged under argon. For deposition of the sebum onto the reconstructed epidermis, the vials are then resuspended with 250 µL of absolute ethanol (Fischer Scientific, Illkirch, France) and then diluted 1 / 20th in physiological saline.

[0124] - Microbiota preparation

[0125] The microbiota was collected from 18 volunteers without apparent skin pathology using a swab soaked in physiological saline (Fischer Scientific, Illkirch, France) containing 0.1% by volume of Triton X-100 (Fischer Scientific, Illkirch, France). The swab was vigorously rubbed on the donor's forehead for 40 seconds. Each swab was then placed in a tube for centrifugation. After centrifugation, a colorless liquid (approximately 60 pL) was collected, and its volume was adjusted to 120 pL with physiological saline. Each microbiota sample was then mixed with sebum to facilitate deposition.

[0126] The sebum / microbiota mixture (22 pL) is deposited on the surface of the reconstructed human epidermis and spread using a finger cot.

[0127] The reconstructed human epidermis thus obtained are incubated at 32°C, 5% CO2, 60% humidity for 24 h. Formulations

[0128] The following formulations were evaluated in the experiments described below. Formulation A

[0129] [Tables 1] Ingredients % (w / w) 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine 3-3.5 Glycerin 5.0 Demineralized water qs 100 Xanthan gum 0.2 C12-C15 alkyl benzoate 12.0 Dicaprylyl carbonate 9.0 Caprylic / capric triglycerides 9.0 Preservatives qs Stearyl alcohol 1.0 Glyceryl monostearate 0.5 Glyceryl behenate 0.4 PEG-100 stearate 0.5 VP / eicosene copolymer 1.0 Polyacrylate 0.2 Potassium cetyl phosphate 2.0 Formulation B

[0130] [Tables2] Ingredients % (w / w) 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine 3-3,5 Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine 2,5-3 Diethylamino hydroxybenzoyl hexyl benzoate 5-6 Ethyl hexyl Triazone 3,5-4 Glycerin 5.0 Demineralized water qs 100 Xanthan gum 0.2 C12-C15 alkyl benzoate 12.0 Dicaprylyl carbonate 9.0 Caprylic / capric triglycerides 9.0 Preservatives qs Stearyl alcohol 1.0 Glyceryl monostearate 0.5 Glyceryl behenate 0.4 PEG-100 stearate 0.5 VP / eicosene copolymer 1.0 Polyacrylate 0.2 Potassium cetyl phosphate 2.0

[0131] Effect of phenvlene bis-diphenvltriazine against the deleterious effects of UV radiation on the skin's immune defenses: a meta-bolomiaue approach Methods

[0132] Six groups of eighteen reconstructed epidermis with microbiota and sebum from 18 distinct donors are studied (untreated / unirradiated; formulation A / unirradiated; formulation A / irradiated; formulation B / unirradiated; formulation B / irradiated).

[0133] The reconstructed epidermis is irradiated with 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 fitted with a UV filter to eliminate wavelengths below 290 nm. The irradiance in the UV spectrum is approximately 70 W / m² from 290 to 400 nm. The skin models are exposed to a single acute dose of UV of 16.5 J / cm2 (approximately 45 min) and the irradiation chamber is maintained at 37 °C using ice water and an airflow.

[0134] Formulation A or B is applied at a dose of 2 mg / cm² to the surface of the reconstructed epidermis. After irradiation with the full solar spectrum (up to 790 nm), the model is maintained in culture for 24 hours at 32°C and 60% humidity.

[0135] At the end of the experiment, the surface of the reconstructed epidermis is washed twice with 100 pL of physiological saline and then dried with a cotton swab. This step aims to recover the skin microbiota and the hydrolipidic film. The reconstructed epidermis is separated from the insert and weighed to standardize the results obtained with the metabolomics approach. The reconstructed epidermis is ground, and 108 samples are extracted. Briefly, the samples are ground in 2 x µL of acetonitrile / water 1 / 9 (v:v) using a fastprep with Lysing Matrix M tubes, 6 cycles of 20 seconds at strength 4, with 2 min on ice between each cycle. A volume of 800 pL of each sample was evaporated to dryness with a SpeedVac and then normalized in 220 pL of D2O. The samples were analyzed by NMR and then mass spectrometry.

[0136] The 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 1H resonance frequency, using a 5 mm 1H-13C-15N-31P inverse-detection cryosprobe attached to a Cryoplatform (the pre-amplification unit). The 1H NMR spectra are acquired using the NOESY 1D experiment with pre-saturation for water suppression (noesyprld), with a mixing time of 100 ms.

[0137] After NMR analysis, the samples are transferred from the NMR tubes to the UHPLC vials. The samples are centrifuged at 9000 g for 5 min. A volume of 10 pL is then injected into the Waters ACQUITY UHPLC system (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% of B, 30–34 min: 100% of B. Separation is carried out at 30°C using 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 desolvation gas flow rate of 600 L / h in negative mode. High-resolution mass spectra are obtained. Acquired with a Waters Synapt G2-Si mass spectrometer (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.

[0138] Structural identifications of 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).

[0139] Data analysis:

[0140] Statistical analysis and network mapping are carried out by the MetaboHUB-MetaToul-AXIOM platform.

[0141] The data are normalized to allow the quantification of signals detected in several samples.

[0142] Principal component analysis is first applied to verify the validity of the acquisition, to detect potential outliers and internal clusters.

[0143] In a biological context, confounding factors are commonly 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 treatment groups can be found. Discriminant analysis using orthogonal partial least squares (O-PLS-DA) aims to eliminate this unwanted 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 = 1) was used to find discriminant features.

[0144] For each discriminating characteristic, a univariate Wilcoxon test and a false discovery rate (FDR) correction are performed to take into account multiple tests (FDR-corrected p-value threshold = 0.05).

[0145] Multivariate analyses are performed using SIMCA vl5 software (Umetrics, Umeå, Sweden). The mixOmics package (Rohart et al., 2017) is used to perform multilevel analyses.

[0146] To create the metabolic network, freely accessible software, Toxalim: MetExplore, is developed and used by INRAE. This web server allows for the linking of metabolites identified in untargeted metabolomics experiments within the context of genome-wide reconstructed metabolic networks. The analysis pipeline includes mapping metabolomics data onto an organism's specific metabolic network, followed by the application of graph-based methods and advanced visualization tools to enhance data analysis.

[0147] All samples are discriminated from the NMR data according to the factors of treatment and irradiation. From this significant discrimination, 52 characteristics are discriminating (VIP >1) significant (p value corrected by the FDR of the Mann Whitney test <0.05).

[0148] a)Ctabolism of amino acids

[0149] The following tables report the observed variations (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.

[0150] - Branched-chain amino acids (BCAAs)

[0151] [Tables3] MS Negative NI CTRL vs. IR CTRL NI FA vs. IR FA NI FB vs. IRFB L-Isoleucine -1.60 ns ns L-Leucine -0.78 -0.14 ns

[0152] NI: Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: Not significant

[0153] - Aromatic amino acids

[0154] [Tables4] NI CTRL NMR vs. IR CTRL NI FB vs IRFB L-Phenylalanine -0.18 0.20 Indole acetic acid -0.10 ns L-Tryptophan -0.13 ns Tyrosine 2.52 ns

[0155] BCAAs, aromatic amino acids and their metabolites play an important role in the immune response.

[0156] The above results demonstrate that topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to very significantly dampen the imbalances induced by UV radiation, and thus to prevent and / or reduce the alteration of the cutaneous immune system.

[0157] b) Lipid metabolism

[0158] - Arachidonic acid

[0159] 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 phase-shift chromatography liquid - mass spectrometry (LC / MS).

[0160] LC parameters:

[0161] - Column: Waters XTERRA RP18 3.5pm 4.6 x 250 mm

[0162] - Mobile phase: methanol / heptane / chloroform / acetic acid (90 / 10 / 1 / 0.1)

[0163] - Pass-through temperature: 10 °C

[0164] - Column temperature: 25 °C

[0165] - Flow rate: 0.5 mL / min

[0166] - Injection volume: 10 pL

[0167] - Pressure: 77 bars

[0168] - Elution time: 12 min

[0169] MS (ESI) Parameters:

[0170] - Equipment: Agilent

[0171] - Scanning time: 50 scans / min

[0172] - Fragmentation: 380 V

[0173] - Cell Acc.: 5 V

[0174] - Polarity: negative

[0175] - Nebulizer: 20 psi

[0176] - Gas temperature: 200°C

[0177] - Curtain gas temperature and flow rate: 250 °C, 11 L / min

[0178] - Capillary: 3000 V

[0179] - Charging voltage: 1500 V

[0180] Results:

[0181] [Tables5] Average Group (pg / mL) Non-irradiated 0.003211 * Irradiated 0.001606 Non-irradiated + Formulation A 0.003589 * Irradiated + Formulation A 0.003589* Non-irradiated + Formulation B 0.002928* Irradiated + Formulation B 0.003361*

[0182] *P<0.05 versus Irradiated group

[0183] UV radiation induces a significant decrease in the concentration of arachidonic acid in reconstructed epidermis. Topical application of a formulation comprising phenylene bis-diphenyltriazine, with or without (A) other sunscreens, helps maintain a level of arachidonic acid. equivalent to a control group, despite exposure to UV radiation.

[0184] - Other lipid markers

[0185] The following table reports the observed variations (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.

[0186] [Tableauxô] NMR NI CTRL vs. IR CTRL NI FA vs. IR FA NI FB vs. IRFB Azelaic acid 0.57 ns ns Acetate 1.80 ns ns Formate 1.65 ns ns

[0187] NI: Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: Not significant

[0188] These results demonstrate that topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens makes it possible to very significantly dampen the imbalances induced by UV radiation, and thus to prevent and / or reduce the alteration of the cutaneous immune system.

[0189] The above results together lead to the conclusion that phenylene bis-diphenyltriazine makes it possible to effectively combat disorders of the cutaneous immune system caused by UV radiation, and thus to preserve the immune defenses of the skin, in particular innate immunity.

Claims

Demands

1. 5,6,5' ,6' -tetraphenyl-3,3' -( 1,4-phenylene)-bis[l,2,4]triazine for its use in preserving the immune defenses of the skin.

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 comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and at least one cosmetically and / or pharmaceutically acceptable excipient, in the preservation of the skin's immune defenses.

4. Composition for its use according to claim 3, for the preservation of innate immunity.

5. Composition for use according to claim 3 or 4, characterized in that it comprises a photoprotective system consisting of: (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine, (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and (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 sunscreens other than those constituting said photoprotective system.

6. Composition for use according to any one of claims 3 to 5, characterized in that 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine represents between 1% and 5% by weight relative to the total weight of the 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 for its use according to any one of claims 3 to 7, characterized in that hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate constitutes between 1% and

9. 10% by weight relative to the total weight of the composition. Composition for its use according to any one of claims 3 to 8, characterized in that the sunscreen (d) represents

10. between 1% and 6% by weight relative to the total weight of the composition. Composition for its use according to any one of claims 3 to 9, characterized in that the sunscreen (d) is ethylhexyl triazone.