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

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

[0001] USE OF PHENYLENE BIS-DIPHENYLTRIAZINE FOR THE PRESERVATION OF SKIN IMMUNE DEFENSES

[0002] Field of T invention

[0003] The invention relates to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine (phenylene bis-diphenyltriazine), as well as a composition comprising it, for its use in the preservation of the immune defenses of the skin, in particular the preservation of innate immunity.

[0004] Technical background

[0005] The skin is much more than an external covering; it is in fact a true organ necessary for life. It is a platform for exchange between the body and the external environment, and is therefore exposed to multiple physical, chemical, and microbiological attacks, against which it constitutes the first line of anatomical defense. The skin therefore ensures, among other things, a true barrier function.

[0006] 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 a supportive connective tissue; and (iii) the epidermis, the superficial layer, which mainly comprises keratinocytes. The epidermis is separated from the external environment by the horny layer (stratum corneum), a protective barrier rich in keratinocytes. 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 the host to be defended against attacks of various kinds.

[0007] The cutaneous immune system is based on different resident cells with specific and varied functions depending on their location, recruited specialized cellular actors (leukocytes) and soluble mediators (cytokines and chemokines).

[0008] The dermis is home to fibroblasts, mast cells, macrophages and dendritic cells, which participate directly or indirectly in skin immunology.

[0009] Within the epidermis, two types of cells play a major role in cutaneous immunity, whether innate or adaptive.

[0010] - 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. - Langerhans cells are dendritic cells that act as true 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.

[0011] The cutaneous immune system can be disrupted by various intrinsic or extrinsic factors, such as aging or UV radiation.

[0012] The field of photoprotection remains a major public health issue to prevent 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 visible blue light, and infrared via damage to macromolecules leading to DNA lesions, oxidative stress, lipid peroxidation and degradation of the dermal matrix.

[0013] To assess the impact of sun exposure, the skin 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 to reproduce the complexity of skin physiology, and have demonstrated, quite unexpectedly, that the sunscreen phenylene bis-diphenyltriazine has the capacity to prevent and / or reduce the alteration of the skin's immune system.

[0014] Description of the invention

[0015] 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.

[0016] 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), but also high-energy visible blue light. In the remainder of the 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.

[0017] The term "sunscreen" refers to a substance capable of filtering solar radiation to protect a surface, typically skin or hair, from the harmful effects of this radiation.

[0018] 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.

[0019] By "UVA radiation" or simply "UVA" is meant ultraviolet rays with an X-ray wavelength between 320 and 400 nm.

[0020] By "UVB radiation" or simply "UVB" is meant ultraviolet rays with an X-ray wavelength between 290 and 320 nm.

[0021] A sunscreen is called a “UVA filter” or “UVB filter” depending on whether it filters mainly UVA or UVB rays.

[0022] A so-called “broad band” or “broad spectrum” sun filter filters both UVA and UVB rays.

[0023] Depending on the radiation filtration mechanism, that is to say depending on whether the radiation is absorbed and / or reflected, or even diffused by the solar filter, we distinguish, strictly speaking:

[0024] - filters in the strict sense, which mainly absorb radiation, and

[0025] - screens, which absorb and reflect radiation.

[0026] However, in the remainder of the description, the term "solar filter", sometimes abbreviated to "filter", will be used interchangeably, whether it is a filter or a screen.

[0027] A sunscreen can be "lipo-soluble" or "water-soluble", depending on whether it dissolves more easily in lipids or in water, or "insoluble". A non-soluble sunscreen is typically in particulate form, and can nevertheless be incorporated into a sunscreen composition, in particular in a dispersed form, in particular water-dispersed when it is dispersed in an aqueous phase.

[0028] Ua 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 total weight of the dispersion.

[0029] Advantageously, the process for preparing the aqueous dispersion consists of grinding the insoluble organic filter in the form of 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 allows better dispersion of the particles. These techniques are well known to those skilled in the art. The grinding apparatus may be, for 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, non-ionic or amphoteric surfactants, emulsifiers and dispersants such as PPG-1-PEG-9 Lauryl Glycol Ether (Eumulgin® L, marketed by BASF).

[0030] In a particular embodiment, the size D50 of the phenylene bis-diphenyltriazine particles is between 100 and 1,000 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.

[0031] By "size D50" or "median" is meant the size for which the cumulative function F(D) is equal to 50%, F(D) being defined according to the following relation: in which: f(D) is the particle size distribution in number, and

[0032] D is a size class.

[0033] The D50 value can be determined using a Mastersizer 3000 laser diffraction granulometer in wet conditions.

[0034] Topical application of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine prevents and / or reduces the alteration of the cutaneous immune system. It thus makes it possible to protect and preserve cutaneous immunity, in particular innate immunity, in particular against external stress, such as exposure to UV radiation. In particular, the inventors have surprisingly demonstrated that phenylene bis-diphenyltriazine acts specifically on branched-chain amino acids and other lipid markers by limiting the concentration imbalances of these markers in irradiated skin. These markers are well known for their involvement in the inflammatory response (see, e.g., 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.

[0035] Phenylenes bis-diphenyltriazine therefore helps preserve the skin's immune defenses, in particular its natural immune defenses, that is to say the immune defenses intrinsically present in a subject's skin, particularly when it is subjected to an attack, such as exposure to UV radiation. The inventors also surprisingly demonstrated that phenylene bis-diphenyltriazine acts specifically on arachidonic acid and aromatic amino acids.

[0036] Arachidonic acid is known as a precursor of metabolites that modulate the immune response. These metabolites include 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 arachidonic acid concentration induced by UV radiation on the skin, and thus to preserve the immune defenses of a subject's skin.

[0037] 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 a subject's skin.

[0038] The present invention also relates to a method for preventing and / or decreasing the 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.

[0039] It further relates to a method for preserving the immune defenses of the skin, in particular its natural immune defenses, and therefore to 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'-(1,4-phenylene)-bis[1,2,4]triazine.

[0040] 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 at least one cosmetically and / or pharmaceutically acceptable excipient, for the same uses as those presented above.

[0041] In a particular embodiment, the composition for use according to the invention is in the form of an emulsion. For the purposes of the present invention, the term "emulsion" means 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.

[0042] These emulsions can be more or less fluid and come in the form of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, or possibly an aerosol, a mousse or a spray, and can 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, 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 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 of 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 may be combined with one or more other sunscreens, to constitute a photoprotective system which allows, after application to a surface (skin, hair, etc.), by mechanisms of absorption and / or reflection and / or diffusion of UVA and / or UVB radiation, to prevent, or at least limit, 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 chosen from the following filters (i) to (v):

[0048] (i) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (CAS No. 302776-68-7), also known as diethylamino hydroxybenzoyl hexyl benzoate or DHHB, marketed by BASF under the name Uvinul A Plus®.

[0049] It is a liposoluble UVA filter, having a maximum absorption wavelength λmax 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.

[0050] (ii) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-l,3,5-triazine (CAS No. 187393-00-6), also known as bis-ethylhexyloxyphenol methoxyphenyl triazine or BEMT, marketed by BASF under the name Tinosorb S®.

[0051] It is a liposoluble broadband filter, having two absorption peaks at 310 nm and 340 nm.

[0052] 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.

[0053] (iii) 4-tert-butyl-4-methoxydibenzoylmethane or butyl methoxydibenzoylmethane (chemical name: l,4-(l,l-dimethylethyl)phenyl-3-(4-methoxyphenyl)- 1,3 -propanedione; CAS No.: 70356-09-1), also known as avobenzone or BMDBM, marketed in particular by DSM under the name Parsol 1789®.

[0054] It is a liposoluble UVA filter, with a maximum absorption wavelength Àmax equal to 357 nm.

[0055] In a particular embodiment, the BMDBM represents between 1% and 10%, for example between

[0056] 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 4-[[4,6-bis[[4-(2-ethylhexoxy-oxomethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzoic acid 2-ethylhexyl ester; CAS No.: 88122-99-00), marketed by BASF under the name Uvinul T 150®.

[0058] It is a liposoluble UVB filter, with a maximum absorption wavelength λmax equal to 314 nm.

[0059] 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 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]-1,3,5-triazine-2,4-diyl]diimino]bis-, bis(2-ethylhexyl)benzoate; CAS No.: 154702-15-5), marketed by 3V Sigma under the name Uvasorb HEB®.

[0060] It is a liposoluble UVB filter, with a maximum absorption wavelength λmax equal to 310 nm.

[0061] 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.

[0062] 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):

[0063] (vi) methylene bis-benzotriazolyl tetramethylbutylphenol (chemical name: 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(l,l,3,3-tetramethylbutyl)phenol; CAS No.: 103597-45-1) also known as MBBT, marketed by BASF under the name Tinosorb M®.

[0064] It is a broadband filter, having two absorption peaks at 306 nm and 348 nm, of non-soluble type.

[0065] MBBT typically comes in the form of an aqueous dispersion, comprising between 40% and 60%, typically 50% by weight of active ingredient relative to the total weight of the dispersion.

[0066] 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.

[0067] 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.

[0068] (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®.

[0069] It is a primarily UVB filter, with a maximum absorption wavelength λmax equal to 310 nm, of the 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.

[0070] 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.

[0071] 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.

[0072] In a particular embodiment, the composition for use according to the invention does not comprise ethylhexyl salicylate, octocrylene, ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, homosalate, para-aminobenzoic acid (PABA), octyl dimethyl PABA, 3-methylbenzylidene camphor, 4-methylbenzylidene camphor, benzophenone-3 and / or benzophenone-4.

[0073] In a particular embodiment, the composition for use according to the invention does not comprise any water-soluble filter.

[0074] The absence of water-soluble filters is particularly advantageous, in that water-soluble filters are, generally speaking, more easily assimilated by marine organisms than liposoluble or non-soluble filters. Consequently, the Applicant's choice of using only liposoluble or particulate filters, in particular water-dispersed ones, makes it possible to minimize the impact of the composition according to the invention on the marine environment.

[0075] 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).

[0076] The particulate inorganic filter(s) optionally present in the composition according to the invention typically have a particle size D50 of between 15 nm and 150 nm.

[0077] In another particular embodiment, the composition for use according to the invention does not comprise any particulate inorganic filter.

[0078] 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 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.

[0079] In an advantageous embodiment, the photoprotective system consists of:

[0080] (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine,

[0081] (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-l,3,5-triazine,

[0082] (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and

[0083] (d) ethylhexyl triazone or diethylhexyl butamido triazone.

[0084] In particular, (d) corresponds to ethylhexyl triazone.

[0085] 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 total weight of the composition, the 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.

[0086] 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 may 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. The term "pharmaceutically and / or cosmetically acceptable excipient" means any cosmetically and / or pharmaceutically acceptable adjuvant allowing the manufacture, preservation or administration of the composition.

[0087] The compositions for use according to the invention may thus comprise conventional pharmaceutical or dermatological adjuvants notably chosen from liquid lipophilic compounds, emulsifiers, consistency agents, water-retentive agents, texturizing 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-sun compositions.

[0088] 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.

[0089] By "liquid lipophilic compound" is meant a compound which has an affinity for apolar substances such as lipids, and is in liquid form, particularly at 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 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 chain(s), 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 may 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 combinations thereof.,

[0090] The liquid lipophilic emollient(s) are chosen in particular from C12-C15 alkyl benzoate, caprylic / capric triglycerides and dicaprylyl carbonate.

[0091] 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.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 preferentially 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 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.

[0092] The composition may also comprise 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 dioctyl sodium 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.;

[0093] The emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.

[0094] In a particular embodiment, the composition for use according to the invention does not comprise an ethoxylated emulsifier and / or comprising a PEG chain.

[0095] 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 oxyalkenyl silicone / polysiloxane / polyalkyl / polyether copolymers and derivatives.

[0096] The composition may also comprise 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 myristyl 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; crosslinked polyacrylates or homopolymers of 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.

[0097] 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.

[0098] In a particular embodiment, the composition does not comprise a consistency agent chosen from acrylates and their derivatives.

[0099] The composition may also comprise one or more water-retentive agents selected 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).

[0100] Preferably, the composition for use according to the invention comprises VP / eicosene copolymer as a water-retentive agent.

[0101] The composition may also comprise one or more texturizing 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.

[0102] In a particular embodiment, the composition for use according to the invention does not comprise a texturizing agent chosen from nylon derivatives and polymethyl methacrylate (PMMA).

[0103] 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 an amount 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.

[0104] In another particular embodiment, the composition is free of ethanol and isopropanol.

[0105] 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 the present invention, the term "volatile ingredients" means non-alcoholic volatile organic or inorganic compounds such as esters, silicones or volatile alkanes, characterized by a flash point below 60°C.For the purposes of the present invention, the term "flash point" (denoted PE) means 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 with a flame or a hot spot, but insufficient for combustion to propagate by itself in the absence of the so-called pilot flame. According to Regulation (EC) No 1272 / 2008 on the classification, labeling and packaging of substances and mixtures, a substance with a PE such that 23°C < PE < 60°C belongs to category 3 "low flammability".

[0106] Volatile esters include isohexyl neopentanoate. Volatile silicones include cyclopentasiloxane. Volatile alkanes include isohexadecane.

[0107] In another particular embodiment, the composition for use according to the invention is free of volatile ingredients within the meaning of the present invention.

[0108] The composition may also comprise alkalizing or acidifying agents, and more particularly acids and bases for adjusting the pH range of said composition. The bases may be mineral (soda, potash, ammonia, etc.) or organic, such as mono-, dion triethanolamine, an aminomethylpropanediol, N-methyl-glucamine, 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.

[0109] The composition for use according to the invention may further comprise additional active agents chosen 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, sebum-regulating or anti-seborrheic agents, astringent agents, healing agents, anti-inflammatory agents, anti-acne agents, and mixtures thereof.

[0110] In a particular embodiment, the composition for use according to the invention is free of silicone.

[0111] 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 α-, β-, γ- and δ-tocopherol or tocotrienol. The term "tocopherol" usually designates α-tocopherol. Among the tocopherol derivatives, mention may in particular be made of ester derivatives, such as tocopherol acetate, and glycosylated derivatives, such as tocopheryl glucoside (INCI: tocopheryl glucoside).

[0112] 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.

[0113] EXAMPLES

[0114] RHE model + microbiota + sebum

[0115] The inventors developed a reconstructed human epidermis (RHE) model colonized by donor skin microbiota and sebum to replicate the complexity of the skin ecosystem. This model approximates the reality of skin physiology and allows for the study of interactions between the skin and the microbiota.

[0116] 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, cells (keratinocytes) were isolated from the skin excisions, then cultured before being seeded on culture inserts immersed in culture medium, then the culture inserts were placed at the air / liquid interface in an incubator at 37°C in a humidified atmosphere with 5% CO2, to form the stratum corneum.

[0117] 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.

[0118] At the end of the reconstruction, the microbiota and sebum from healthy volunteers are inoculated.

[0119] - Preparation of sebum

[0120] 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 collected sebum is controlled (e.g. 1,100 mg for a preparation) and the sebum is then taken up in 20 ml of hexane. 100 vials of sebum are prepared 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 pL of absolute ethanol (Fischer Scientific, Illkirch, France) and diluted to 1 / 20 eme in physiological serum.

[0121] - Preparation of the microbiota

[0122] 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 rubbed energetically on the donor's forehead for 40 seconds. Each swab was then placed in a tube for centrifugation. After centrifugation, a colorless liquid was collected (approximately 60 pL) and its volume was adjusted to 120 pL with physiological saline. Each microbiota was then mixed with the sebum in order to carry out the deposition.

[0123] The sebum / microbiota mixture (22 pL) is deposited on the surface of the reconstructed human epidermis and spread using a finger cot.

[0124] The reconstructed human epidermis thus obtained are incubated at 32°C, 5% CO2, 60% humidity for 24 hours.

[0125] Formulations

[0126] The following formulations were evaluated in the experiments described below. Formulation A

[0127] Table 1 Formulation B

[0128] Table 2

[0129] Effect of phenylene bis-diphenyltriazine against the deleterious effects of UV radiation on skin immune defenses: a metabolomic approach

[0130] Methods

[0131] 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).

[0132] The reconstructed epidermis are 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 spectra is approximately 70 W / m 2 from 290 to 400 nm. 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 iced water and an air flow.

[0133] Formulation A or B is applied at a dose of 2 mg / cm 2 on the surface of the reconstructed epidermis. After irradiation with the total solar spectrum (up to 790 nm), the model is kept in culture for 24 hours at 32°C and 60% humidity.

[0134] At the end of the experiment, the surface of the reconstructed epidermis was washed twice with 100 μL of physiological saline, and then dried with a cotton swab. This step aims to recover the skin microbiota as well as the hydrolipidic film. The reconstructed epidermis were separated from the insert and weighed to standardize the results obtained with the metabolomic approach. The reconstructed epidermis were ground and 108 samples were extracted. Briefly, the samples were ground in 2 x ImL of acetonitrile / water 1 / 9 (v:v) with a 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 μL of each sample was evaporated to dryness with a SpeedVac and then standardized in 220 μL of D2O. The samples were analyzed by NMR then mass spectrometry.

[0135] 1H NMR spectra were 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 cryoprobe with inverse detection attached to a Cryoplatform (the preamplification unit). 1H NMR spectra were acquired using the 1D NOESY experiment with pre-saturation for water suppression (noesyprld), with a mixing time of 100 ms.

[0136] After NMR analyses, samples were transferred from NMR tubes to UHPLC vials. Samples were centrifuged at 9000 g for 5 min. A volume of 10 pL was 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 was used: 0-30 min: 0% to 100% B, 30-34 min: 100% B. Separation was performed at 30°C with a Hypersil Gold C18 column (100 x 2.1 mm, 1.9 μm) from Thermo Scientific (Les Ulis, France).The following electrospray parameters were applied: capillary voltage of 0.5 kV, sample 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, sample 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 were 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.

[0137] Structural identifications of discriminating metabolites were performed on an LTQ Orbitrap XL mass spectrometer (Thermo Scientific, Les Ulis, France) coupled to a U3000 liquid chromatography system (Thermo Scientific, Les Ulis, France).

[0138] Data analysis:

[0139] Statistical analysis and network mapping are performed by the MetaboHUB-MetaToul-AXIOM platform.

[0140] The data are normalized to allow quantification of signals detected in multiple samples.

[0141] Principal component analysis is first applied to check the validity of the acquisition, to detect potential outliers and internal clusters.

[0142] 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... 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. Orthogonal partial least squares discriminant analysis (O-PLS-DA) aims to eliminate this unwanted variation. A permutation test is performed to assess the robustness of PLS-DA models. The Variable Importance in Projection (VIP) value (threshold=l) was used to find discriminating features.

[0143] For each discriminating characteristic, a univariate Wilcoxon test and a false discovery rate (FDR) correction are performed to account for multiple testing (FDR-corrected p-value threshold = 0.05).

[0144] Multivariate analyses were performed using SIMCA vl5 software (Umetrics, Umeå, Sweden). The mixOmics package (Rohart et al., 2017) was used to perform multilevel analyses.

[0145] To create the metabolic network, INRAE ​​developed and used a freely available software package, Toxalim: MetExplore. This is a web server that offers the possibility to link metabolites identified in untargeted metabolomics experiments in the context of reconstructed genome-wide 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.

[0146] All samples are discriminated from NMR data according to treatment and irradiation factors. From this significant discrimination, 52 features are discriminating (VIP >1) significantly (p-value corrected by the FDR of the Mann Whitney test <0.05). a) Amino acid metabolism

[0147] 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.

[0148] - Branched-chain amino acids (BCAA)

[0149] Table 3 : Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: not significant

[0150] - Aromatic amino acids

[0151] Table 4

[0152] BCAAs, aromatic amino acids and their metabolites play an important role in the immune response.

[0153] 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 to prevent and / or reduce the alteration of the cutaneous immune system. b) Lipid metabolism

[0154] - Arachidonic acid

[0155] Arachidonic acid and its metabolites are well known as modulators of immune responses. The following table shows arachidonic acid concentrations in reconstructed epidermis, determined by liquid chromatography-mass spectrometry (LC / MS).

[0156] LC Settings:

[0157] - Column: Waters XTERRA RP 18 3.5pm 4.6 x 250 mm

[0158] - Mobile phase: methanol / heptane / chloroform / acetic acid (90 / 10 / 1 / 0.1)

[0159] - Passer temperature: 10°C

[0160] - Column temperature: 25°C

[0161] - Flow rate: 0.5 mL / min

[0162] - Injection volume: 10 pL

[0163] - Pressure: 77 bars

[0164] - Elution time: 12 min

[0165] MS (ESI) parameters:

[0166] - Equipment: Agilent - Scanning time: 50 scans / min

[0167] - Fragmentation: 380 V

[0168] - Cell Acc.: 5 V

[0169] - Polarity: negative

[0170] - Nebulizer: 20 psi

[0171] - Gas temperature: 200°C

[0172] - Curtain gas temperature and flow rate: 250°C, 11 L / min

[0173] - Capillary: 3000 V

[0174] - Charging voltage: 1500 V

[0175] Results :

[0176] Table 5

[0177] *P<0.05 versus Irradiated group

[0178] UV radiation induces a significant decrease in the concentration of arachidonic acid in reconstructed epidermis. Topical application of a formulation comprising phenylene bis-diphenyltriazine associated (B) or not (A) with other sunscreens allows maintaining an arachidonic acid level equivalent to a control group, despite exposure to UV radiation.

[0179] - Other lipid markers

[0180] 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.

[0181] Table 6 NI: Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: not significant

[0182] 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 cutaneous immune system.

[0183] All the above results allow us to conclude that phenylene bis-diphenyltriazine can effectively combat disorders of the cutaneous immune system caused by UV radiation, and thus preserve the skin's immune defenses, particularly innate immunity.

Claims

DEMANDS 1. 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.

2. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,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 its 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'-(l,4-phenylene)-bis[l,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 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 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 represents between 1% and 10% by weight relative to the total weight of the composition.

9. Composition for use according to any one of claims 3 to 8, characterized in that the sunscreen (d) represents between 1% and 6% by weight relative to the total weight of the composition.

10. Composition for its use according to any one of claims 3 to 9, characterized in that the sunscreen (d) is ethylhexyl triazone.

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