Use of phenylene bis-diphenyltriazine for protecting the skin barrier function and the skin microbiota

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 the use thereof in strengthening the skin barrier and / or preventing and / or reducing damage to the barrier function of the skin. The present invention further relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine, or a composition comprising same, for the use thereof in protecting the skin microbial component and / or maintaining the equilibrium of the skin microbial component.

Description

[0001] USE OF PHENYLENE BIS-DIPHENYLTRIAZINE FOR THE PRESERVATION OF SKIN BARRIER FUNCTION AND MICROBIOTA

[0002] Field of invention

[0003] The field of 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 strengthening the skin barrier and / or preventing and / or reducing the impairment of the skin barrier function.

[0004] The invention also relates to the protection of the cutaneous microbial component and / or the maintenance of a balance of the cutaneous microbiota through the use of 5, 6, 5', 6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine.

[0005] State of the art

[0006] The skin is much more than an external envelope; it is in fact a true organ necessary for life. It constitutes a platform of exchange between our internal environment and the external environment and is therefore exposed to multiple attacks and variations to which it constantly adapts. The skin therefore ensures, among other things, a true barrier function, previously attributed solely to its structure and composition.

[0007] The skin is composed of cells grouped together to form a tissue that is both strong and flexible. These cells are divided into three layers: the hypodermis, the dermis, and the epidermis. The hypodermis is the deepest layer of the skin. It is made up of white adipose tissue that protects the body from shocks, builds up an energy reserve, and thermoregulates the body. The dermis is the layer between the hypodermis and the epidermis. It is the thickest layer of the skin. The dermis houses blood and lymphatic vessels, nerves, sweat glands that produce sweat, and pilosebaceous follicles. It is mainly composed of macromolecules, fibroblast cells, and immune system cells.

[0008] The epidermis is the thinnest surface of the skin. It is composed of 90% keratinocytes, which synthesize keratin and, through their differentiation, provide impermeability and protection to the skin. The epidermis is made up of four main layers: the basal layer (stratum basale), made up of keratinocytes with large nuclei, which ensure the constant renewal of the epidermis; the spinous layer (stratum spinosum), composed of large keratinocytes, which gradually flatten towards the upper layers; the granular layer (stratum granulosuni), composed of flattened keratinocytes, which transform the keratinocytes into comeocytes (anucleated cells); and finally the horny layer (stratum corneum), the upper layer composed of comeocytes that will desquamate.

[0009] The epidermis is not only composed of comeocytes, but also of lipids between these different cells. Lipids are distributed in the form of lipid bilayers. The main classes of these lipids are ceramides, cholesterol, and free fatty acids. They partially ensure the skin's barrier function.

[0010] Sebum is a hydrolipidic film produced by the sebaceous glands. It is excreted on the surface of the skin where it forms a protective layer and also serves as a substrate for the skin microbiota. Sebum is predominantly lipophilic and anaerobic, and therefore helps preserve hydrophobic and anaerobic microbial species. It also protects the skin by lubricating and acidifying it to regulate skin pH.

[0011] The skin microbiota also plays a key role in the skin's protective functions. Also called skin flora, it is located in the epidermis and is made up of microorganisms such as bacteria, viruses, fungi, and parasites. The skin microbiota develops as we age, reaching an average of 1,000 billion bacteria and 1,000 species of viruses, parasites, and fungi. For bacteria, the most well-known and studied strains are Staphylococcus aureus, Staphylococcus epidermidis, and Cutibacterium acnes. Some are aerobic and therefore live with oxygen, while others are anaerobic and live deeper in the stratum corneum without oxygen. Some of these bacteria produce fatty acids, others antimicrobial peptides, and in some cases, even amino acids. Most of these bacteria use lipids from sebum to grow and produce these compounds.

[0012] The skin microbiota varies quantitatively and qualitatively from one person to another. Variables such as age, sex, immune system, pH, temperature, and humidity can alter the composition of the skin microbiota. For example, the use of cosmetic or pharmaceutical products creates differences. However, two distinct categories can be identified within the skin microbiota: the "resident" flora and the "transient" flora.

[0013] As its name suggests, resident skin flora lives in complete symbiosis with the skin. We speak of commensal organisms. It is important for defense against pathogenic microorganisms, because the space it occupies saturates the area and prevents the attachment of unwanted organisms.

[0014] Transient flora does not establish itself permanently on the surface of the skin; it varies throughout the day, depending on the activities carried out and changes in environmental conditions. It can be present for a few hours or a few days. The microorganisms that compose it are mostly harmless, called saprophytes. This flora can also be made up of opportunistic pathogenic bacteria and cause diseases such as skin disorders if the host's defenses weaken. One of the most common transient species is S. aureus, implicated in atopic dermatitis.

[0015] The microorganisms present on the skin and making up the resident flora are not opportunistic; they perform very useful functions for the protection of the body. Indeed, the skin microbiota plays a barrier role and protects its host. Consequently, alteration of the skin microbiota, due to exogenous or endogenous factors, promotes skin disorders including alteration of the barrier function and / or skin infections.

[0016] Under the effect of natural desquamation, allowing the renewal of the epidermis, as well as personal hygiene practices, the skin microbiota must continually renew itself. Environmental factors will play an important role in the effectiveness of this renewal. Too frequent washing can attack the hydrolipidic film and deteriorate the re-adhesion of the skin flora. The use of creams, lotions, cleansers, deodorants, antibiotics or antiperspirants can have a significant impact on the composition of skin microbial communities, in particular the excessive and / or prolonged use of antibacterial soaps. We speak of dysbiosis when there is an imbalance of the microbiota. It is therefore important to use suitable cosmetic products to maintain a diversity of the skin flora.

[0017] It is clear that the quality of the skin barrier and mucous membranes depends on complex endogenous biological mechanisms involving numerous growth and differentiation factors, adhesion molecules, hormones and lipid metabolism enzymes.

[0018] Thus, an alteration of the skin barrier and / or a break in the continuity of the skin surface can occur in the presence of external aggressions such as irritants (detergents, acids, bases, oxidants, reducers, concentrated solvents, toxic gases or fumes), mechanical stress (friction, shocks, abrasion, tearing of the surface, projection of dust, particles, shaving or hair removal), thermal or climatic imbalances (cold, dryness, radiation), or even xenobiotics (undesirable microorganisms, allergens), or internal aggressions such as psychological stress. These aggressions cause lipid deficiencies, in particular for ceramides. These changes in lipid ratios will modify the organization of the lipid cement and lead to an alteration of the barrier function, thus increasing the transepidermal water loss and a modification of the natural hydration factors.These changes will lead to dehydration of the skin as well as dry skin and can also worsen cases of atopic dermatitis, sensitive or reactive skin sensations.

[0019] This alteration of the skin barrier can notably result in skin discomfort and unpleasant sensory phenomena, including tingling, tightness, heating and itching. These sensations of skin discomfort are more frequent in the most exposed areas of the body, namely the hands, feet, face and scalp. They can occur in particular on areas subject to certain daily or frequently repeated hygiene gestures such as shaving, hair removal, cleansing with toiletries or household products, the application of adhesives with dressings or patches, and the fixing of prostheses, or in the case of sporting, professional or simply lifestyle gestures and the use of clothing, tools or equipment generating localized friction. They can also be amplified by psychological stress.

[0020] As discussed previously, the skin is covered with a protective film, called the hydrolipidic film. It constitutes the outermost barrier, but also the most fragile and most easily disrupted. It is largely composed of fatty substances excreted by the sebaceous glands and lipids resulting from the degradation of cells (squalene, waxes, triglycerides, free fatty acids, cholesterol esters) during the keratinization of horny cells, as well as hydrophilic compounds, such as water from sweat, glycerol, urea, natural skin moisturizing factors, salts, and metabolites of the skin flora. This surface film is highly exposed and very sensitive to environmental stresses, hygiene habits, skin condition, and exposure to UV radiation.

[0021] The microbiota can significantly modify the composition of sebum, degrade triglycerides and modify free fatty acid ratios, particularly during stress or pathology.

[0022] It is therefore important to preserve and even strengthen this skin barrier function, especially for the most sensitive skin.

[0023] There is still a need for agents to strengthen the skin barrier and / or prevent and / or reduce an alteration of the skin barrier function.

[0024] To assess the impact of external factors, such as sun exposure, the skin ecosystem, i.e. the skin, the hydrolipidic film and the microbiome, must be studied as a whole to understand how its components interact with each other and contribute to responding to external stress.

[0025] When chronically exposed to sunlight, the skin will not only suffer medical problems such as sunburn and even skin cancer, but it also influences its phenotypic appearance by inducing photoaging.

[0026] 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.

[0027] Therefore, there is still a need for balanced photoprotection that covers the solar spectrum from UV to visible and infrared radiation.

[0028] There are many sunscreens on the market that are anti-UVB and / or anti-UVA.

[0029] But it is necessary to protect the skin beyond UV and 400 nm, particularly against high-energy visible light or blue light (400-450 nm). Ultra-broad spectrum sunscreens are therefore preferred. Phenylenese bis-diphenyltriazine, a sunscreen approved by the Scientific Committee for Consumer Safety, meets these needs.

[0030] The present invention stems from the observation that in addition to being highly safe for the consumer and the environment, phenylene bis-diphenyltriazine respects the skin ecosystem, and in particular the skin flora.

[0031] Indeed, the inventors have demonstrated, quite unexpectedly, that the phenylene bis-diphenyltriazine sunscreen has the capacity to protect the skin barrier function, and even to strengthen it effectively against solar radiation, but also to promote the maintenance of a balance of the skin microbiome.

[0032] Summary of the invention

[0033] According to a first aspect, 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 strengthening the skin barrier and / or preventing and / or reducing the alteration of the barrier function of the skin.

[0034] According to a second aspect, 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 protecting the cutaneous microbial component and / or maintaining the balance of the cutaneous microbial component.

[0035] Detailed description

[0036] For the purposes of the present invention, the term "skin barrier function" means the protective function of the epidermis, in particular against external aggressions, and the regulation of insensible loss of water and ions. This barrier function involves the various constituents of the skin, including in particular lipids, including those of sebum, and the skin microbiota.

[0037] Lipids are organized in the form of lipid bilayers between the cells of the epidermis. The main classes of these lipids are ceramides, cholesterol, and free fatty acids. They partially ensure the skin's barrier function. Sebum is a hydrolipidic film produced by the sebaceous glands. It is excreted on the surface of the skin where it forms a protective layer and also serves as a substrate for the skin microbiota. This layer also helps protect against external aggressions and prevent water loss, thus limiting skin dehydration.

[0038] The inventors have, surprisingly, demonstrated the direct effects of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine on the lipid component of the skin. In particular, the authors have shown in the examples that 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine makes it possible to very significantly dampen the imbalances in the lipid fraction of the skin induced by UV radiation, and thus to preserve the barrier function and hydration of the skin.

[0039] For the purposes of the present invention, the term "cutaneous microbial component" means a set of microorganisms composed of at least four different genera of bacteria present on the skin of a subject, preferably a human subject. Preferably, the microbial component comprises at least four, five, six, seven, eight, nine, or ten genera of microorganisms selected from the genera Cutibacterium, Staphylococcus, Streptococcus, Burkholderia, Finegoldia, Gemella, Veillonella, Kocuia, Corynebacterium, Methylobacterium, and Brevibacterium, more preferably the set of genera described above. Preferably, the microbial component comprises at least the following genera: Cutibacterium, Staphylococcus, Streptococcus, and Burkholderia. The microbial component may also comprise one or more genera or species of fungi and / or viruses.

[0040] Preferably, the microbial component corresponds to the microbiota of a subject's skin. By "microbiota" we mean the set of microorganisms that are present in an environment. The skin microbiota therefore corresponds to the set of microorganisms present on the skin. The skin microbiota also plays a key role in the protective functions of the skin. It also participates in the regulation of the skin's pH. Of course, the composition of the microbiota can vary depending on the skin site. Preferably, the skin microbial component corresponds to the microbiota of a subject's facial skin.

[0041] The inventors have shown that, surprisingly, the microbial component is not affected by ultraviolet radiation irradiation in the presence of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine. These irradiations lead to an imbalance of the skin microbiota and the proliferation of certain species including C. acnes, as shown by the metabolome analysis carried out in the examples. The presence of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine makes it possible to very significantly dampen the imbalance induced by UV radiation and to prevent the proliferation of certain microorganisms.

[0042] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine therefore specifically helps to preserve the skin's barrier function and skin hydration.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] By "UVA radiation" or simply "UVA" is meant ultraviolet rays with a wavelength  between 320 and 400 nm.

[0047] By "UVB radiation" or simply "UVB" is meant ultraviolet rays with a wavelength  between 290 and 320 nm.

[0048] A sunscreen is called a “UVA filter” or “UVB filter” depending on whether it filters mainly UVA or UVB rays.

[0049] A so-called “broad band” or “broad spectrum” sun filter filters both UVA and UVB rays.

[0050] 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:

[0051] - filters in the strict sense, which mainly absorb radiation, and

[0052] - screens, which absorb and reflect radiation. 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.

[0053] 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.

[0054] Phenylenese bis-diphenyltriazine is a non-soluble type filter. In particular, it is 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.

[0055] 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).

[0056] In a particular embodiment, the size D50 of the phenylene bis-diphenyltriazine particles is between 100 and 1000 nm, more particularly between 100 and 500 nm, even more particularly between 120 and 400 nm, in particular between 120 and 250 nm, in particular between 120 and 200 nm, typically between 150 and 200 nm.

[0057] 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: [Math. 1] in which: f(D) is the particle size distribution in number, and

[0058] Di is a size class.

[0059] The D50 value can be determined using a Mastersizer 3000 laser diffraction granulometer in wet conditions.

[0060] In a particular embodiment of the present invention, 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine is used to maintain hydration of the skin barrier.

[0061] In another particular embodiment, it is used for the prevention and / or reduction of sensations of tingling, tightness and / or heating, redness and / or irritation of the skin.

[0062] The present invention also relates to the use, in particular cosmetic and non-therapeutic, of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for strengthening the skin barrier and / or preventing and / or reducing the alteration of the skin barrier function.

[0063] It further relates to such use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for maintaining hydration of the skin barrier.

[0064] It further relates to such use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the prevention and / or reduction of sensations of tingling, tightness and / or heating, redness and / or irritation of the skin.

[0065] The present invention further relates to the use, in particular cosmetic and non-therapeutic use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine in the protection of the cutaneous microbial component and / or the maintenance of the balance of the cutaneous microbial component.

[0066] The present invention also relates to a method for strengthening the skin barrier and / or preventing and / or reducing the impairment of the skin barrier function, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine.

[0067] It further relates to a method for maintaining the hydration of the skin barrier, and a method for preventing and / or reducing sensations of tingling, tightness and / or heating, redness and / or irritation of the skin, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine.

[0068] The present invention further relates to a method for protecting the skin microbial component and / or maintaining the balance of the skin microbial component, comprising the topical application of an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine.

[0069] 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.

[0070] In a particular embodiment, the composition for use according to the invention is in the form of an emulsion.

[0071] For the purposes of the present invention, the term "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 an oily phase. This is, for example, an oil-in-water or water-in-oil or multiple emulsion, preferably an oil-in-water emulsion.

[0072] 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.

[0073] The composition for use according to the invention is intended for topical application to the skin.

[0074] 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.

[0075] 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. 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.

[0076] 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):

[0077] (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®.

[0078] It is a liposoluble UVA filter, with a maximum absorption wavelength Xmax equal to 354 nm.

[0079] 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.

[0080] (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®.

[0081] It is a liposoluble broadband filter, having two absorption peaks at 310 nm and 340 nm.

[0082] 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.

[0083] (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 in particular by DSM under the name Parsol 1789®.

[0084] It is a liposoluble UVA filter, with a maximum absorption wavelength Xmax equal to 357 nm.

[0085] 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.

[0086] (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®.

[0087] It is a liposoluble UVB filter, with a maximum absorption wavelength Xmax equal to 314 nm.

[0088] 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.

[0089] (v) diethylhexyl butamido triazone or DBT (chemical name: 4,4'-[[6-[[4-[[(l,1-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®.

[0090] It is a liposoluble UVB filter, with a maximum absorption wavelength Xmax equal to 310 nm.

[0091] 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.

[0092] 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):

[0093] (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®. It is a broadband filter, with two absorption peaks at 306 nm and 348 nm, of the non-soluble type.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] (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®.

[0098] It is essentially a UVB filter, with a maximum absorption wavelength of  ma x equal to 310 nm, non-soluble type.

[0099] TBPT is typically 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] In a particular embodiment, the composition for use according to the invention does not comprise any water-soluble filter.

[0104] 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.

[0105] In a particular embodiment, the composition for use according to the invention comprises one or more particulate inorganic filters, such as titanium dioxide (TiCh) or zinc oxide (ZnO).

[0106] 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.

[0107] In another particular embodiment, the composition for use according to the invention does not comprise any particulate inorganic filter.

[0108] 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.

[0109] In an advantageous embodiment, the photoprotective system consists of:

[0110] (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine,

[0111] (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-l,3,5-triazine,

[0112] (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and

[0113] (d) ethylhexyl triazone or diethylhexyl butamido triazone.

[0114] In particular, (d) corresponds to ethylhexyl triazone.

[0115] In this particular embodiment, the composition for use according to the invention does not comprise any sunscreen other than those constituting the photoprotective system, and 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 sunscreen (d), chosen from EHT and DBT, preferably 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.,

[0116] 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.

[0117] The compositions for use according to the invention may thus comprise conventional pharmaceutical or dermatological adjuvants, in particular 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 E and C, alpha-hydroxy acids, active agents (in particular softeners, moisturizing agents, antioxidants) or any other ingredient usually used for the manufacture of anti-sun compositions.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.

[0118] 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 It 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.,

[0119] The liquid lipophilic emollient(s) are chosen in particular from C12-C15 alkyl benzoate, caprylic / capric triglycerides and dicaprylyl carbonate.

[0120] 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.

[0121] 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.

[0122] 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.;

[0123] The emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.

[0124] In a particular embodiment, the composition for use according to the invention does not comprise an ethoxylated emulsifier and / or comprising a PEG chain.

[0125] 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.

[0126] 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, camauba 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.

[0127] 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.

[0128] In a particular embodiment, the composition does not comprise a consistency agent chosen from acrylates and their derivatives.

[0129] 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).

[0130] Preferably, the composition for use according to the invention comprises VP / eicosene copolymer as a water-retentive agent.

[0131] 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.

[0132] 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).

[0133] The composition may also comprise coloring pigments, in particular chosen from CI77891, CI77491, CI77492 and CI77499 (INCI designations).

[0134] 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.

[0135] In another particular embodiment, the composition is free of ethanol and isopropanol.

[0136] 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".

[0137] Volatile esters include isohexyl neopentanoate. Volatile silicones include cyclopentasiloxane. Volatile alkanes include isohexadecane.

[0138] In another particular embodiment, the composition for use according to the invention is free of volatile ingredients within the meaning of the present invention.

[0139] 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-, di- or 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.

[0140] 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.

[0141] In a particular embodiment, the composition for use according to the invention is free of silicone.

[0142] EXAMPLES

[0143] The following abbreviations are used:

[0144] [Table 1]

[0145] RHE model + microbiota + sebum

[0146] The inventors developed a reconstructed human epidermis model colonized by skin microbiota and donor sebum to replicate the complexity of the skin ecosystem. This model closely approximates the reality of skin physiology and allows for the study of interactions between the skin and the microbiota.

[0147] 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).

[0148] Briefly, the 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.

[0149] 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.

[0150] At the end of the reconstruction, the microbiota and sebum from healthy volunteers are inoculated.

[0151] - Preparation of sebum

[0152] 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. 1100 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.

[0153] - Preparation of the microbiota

[0154] 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.

[0155] The sebum / microbiota mixture (22 pL) is deposited on the surface of the reconstructed human epidermis and spread using a finger cot.

[0156] The reconstructed human epidermis thus obtained are incubated at 32°C, 5% CO2, 60% humidity for 24 hours.

[0157] Formulations

[0158] The following formulations were tested in Examples 1 and 2 described below.

[0159] Formulation A

[0160] [Table 2]

[0161]

[0162] Formulation B

[0163] [Table 3] Formulation C

[0164] [Table 4]

[0165] Example 1: Effect of phenylene bis-diphenyltriazine on ceramide synthesis Ceramides are the most abundant class of lipids in the human stratum corneum, representing 50% of the total lipids. They are composed of a fatty acid chain of varying length linked to a sphingosine base, also of varying length. Ceramides are subclassified according to the type of fatty acid and sphingosine base: A = hydroxy fatty acid, EO = ester-linked hydroxy fatty acid, N = non-hydroxy fatty acid, P = phytosphingosine, S = sphingosine, H = 6-hydroxy-sphingosine, and dS = dihydrosphingosine, (van Smeden, Janssens, Gooris, et al., 2014). The most abundant subclasses in the human stratum corneum, in samples collected from the inner forearm, are [NP] and [NH], with relative compositions of 22.1–24.2% and 14.5–23.7% of total ceramides, respectively.

[0166] Indicators of dry skin, including conductance, dryness, roughness, and scaling, have been shown to be strongly correlated with lower levels of total ceramides and lower levels of CER[NP] and CERfNH] (Ishikawa et al., 2013). Decreased levels of CER[NP], total ceramides, and CERfNH] have also been linked to skin dryness in volunteers during winter (Ishikawa et al., 2013; Pappas et al., 2018).

[0167] Deficiencies in CERfEOS] and CERfEOH] are frequently correlated with an absence of long-phase periodicity (lamellar organization of the stratum corneum) in dry skin, and associated with abnormalities in the lamellar architecture of the stratum corneum (Schreiner et al., 2000).

[0168] Ultra-long-chain ceramides (Cer EO) are essential for the formation of the long-period lamellar phase and the maintenance of barrier function. The decrease in ultra-long-chain ceramides and free fatty acids leads to less dense and less organized lipid lamellae (Kessner et al, 2008). This creates gaps in the lipid arrangement of the extracellular spaces between comeocytes, reduces the skin barrier function, and increases its permeability. In fact, the decrease in ultra-long-chain ceramides has been linked to increased transdermal water loss, particularly in atopic patients (Di Nardo et al, 1998).

[0169] Methods

[0170] Two groups of eighteen reconstructed epidermis with microbiota and sebum from 18 separate donors were studied. In one of the two groups, phenylene bis-diphenyltriazine (formulation A) was applied to the RHE at a dose of 2 mg / cm 2on the surface of human skin explants.

[0171] After 24 h of incubation, the reconstructed epidermis are frozen in liquid nitrogen and stored at -80°C.

[0172] At the end of the experiment, the surface of the reconstructed epidermis is washed with physiological saline and then dried. This step aims to recover the skin microbiota as well as the hydrolipidic film to analyze them separately from the reconstructed epidermis. The reconstructed epidermis are ground using a Fast-prep method (Matrix M, power, 20 sec, 6 times) then homogenized by ultrasound before analysis. The samples are frozen in liquid nitrogen and stored in Eppendorf test tubes at -80°C. At the end of the study, the samples are collected for ceramide analysis.

[0173] HPLC parameters

[0174] - Column: Agilent Poroshell 120 EC-C8 2.1 x 100 mm, 2.7pm

[0175] - Mobile phase: A: 20 mM ammonium formate pH 5 (adjusted with HCOOH); B: methanol

[0176] - Passer temperature: 40°C

[0177] - Column temperature: 60°C

[0178] - Flow rate: 0.2 mL / min

[0179] - Injection volume: 10 uL

[0180] - Gradient:

[0181] [Table 5]

[0182] Mass spectrometer parameters (ESI)

[0183] - Equipment: Agilent 6490 Triple Quadrupole

[0184] - Full Scan m / z mode from 150 to 1400 amu

[0185] - Scanning time: 250 scans / min

[0186] - Fragmentation: 380 V

[0187] - Cell Acc.: 5 V - Polarity: negative

[0188] - Nebulizer: 40 psi

[0189] - Curtain gas temperature and flow rate: 400°C, 10 L / min

[0190] - Capillary: 4000 V

[0191] - Charging voltage: 1500 V

[0192] Results

[0193] - Ceramide EOH:

[0194] Cer EOH ratio / total ceramide content

[0195] [Table 6]

[0196] *: P<0.05, T test versus control group

[0197] - Ceramide NH:

[0198] Cer NH ratio / total ceramide content

[0199] [Table 7]

[0200] *: P<0.05, T test versus control group

[0201] Discussion

[0202] Ceramides are present as the dominant lipids in the stratum corneum, and play a crucial role in barrier function and therefore in limiting dehydration and water retention. Based on the important properties of ceramides, emphasis has been placed on two subclasses of ceramides, which play a prominent role in barrier function.

[0203] The inventors demonstrated that the application of phenylene bis-diphenyltriazine induces a statistically significant synthesis of EOH and NH ceramides.

[0204] These results demonstrate that phenylene bis-diphenyltriazine strengthens the epidermal barrier function by promoting esterified ceramides and helps prevent skin dryness by increasing CER NH in particular. Example 2: Protective effect of phenylene bis-diphenyltriazine against the harmful effects of UV radiation on the barrier function, hydration and microbiota of the skin

[0205] Methods

[0206] Six groups of eighteen reconstructed epidermis with microbiota and sebum from 18 distinct donors are studied (untreated / unirradiated; untreated / irradiated; formulation A / unirradiated; formulation A / irradiated; formulation B / unirradiated; formulation B / irradiated.

[0207] 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.

[0208] 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.

[0209] 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 to analyze them separately from the reconstructed epidermis.

[0210] At the end of the study, 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 strength 4, with 2 min on ice between each cycle. A volume of 800 uL of each sample was evaporated to dryness with a SpeedVac and then normalized in 220 uL of D2O. The samples were analyzed by NMR and then mass spectrometry.

[0211] 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 inverse-detection 1H-13C-15N-3 IP cryoprobe 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.

[0212] 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.

[0213] Structural identifications of discriminating metabolites were performed on an LTQ Orbitrap XL mass spectrometer (Thermo Scientific, Les Ulis, France) coupled with a U3000 liquid chromatography system (Thermo Scientific, Les Ulis, France). Data analysis:

[0214] Statistical analysis and network mapping are performed by the MetaboHUB-MetaToul-AXIOM platform.

[0215] The data are normalized to allow quantification of signals detected in multiple samples.

[0216] Principal component analysis is first applied to check the validity of the acquisition, to detect potential outliers and internal clusters.

[0217] 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.

[0218] 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).

[0219] Multivariate analyses were performed using SIM CA vl5 software (Umetrics, Umeå, Sweden). The mixOmics package (Rohart et al., 2017) was used to perform multilevel analyses.

[0220] To create the metabolic network, a freely available software is developed and used by INRAE, Toxalim: MetExplore (Cottret et al., 2018). It 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 and then applying graph-based methods and advanced visualization tools to enhance data analysis.

[0221] All samples are discriminated from NMR data according to treatment and irradiation factors. From this significant discrimination, 52 characteristics are discriminating (VIP >1) significantly (p-value corrected by the FDR of the Mann Whitney test <0.05). a) Barrier function and hydration: metabolomic approach

[0222] The following table reports the observed variations (Log 2 of variations) under the effect of UV irradiation for different discriminating metabolites of the barrier function and hydration of the skin, in the epidermis of the model. [Table 8]

[0223] ''il: Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: not significant 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 preserve the barrier function and hydration of the skin. b) Microbiota: metabolomic approach

[0224] The following table reports the observed variations (Log 2 of variations) under the effect of UV irradiation for different metabolites detected on the surface of the model in relation to the microbiota of the model.

[0225] [Table 9]

[0226] MI: Non-irradiated; IR: Irradiated; CTRL: Control; FA: Formulation A; FB: Formulation B; ns: not significant

[0227] 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 reduce the imbalances induced by UV radiation, and thus to maintain the balance of the cutaneous microbial component. Phenylenes bis-diphenyltriazine therefore exhibits a true symbiotic action. c) C. acne

[0228] Extraction of microbiota DNA from the surface of the skin model:

[0229] The DNA of microorganisms after growth on reconstructed epidermis is extracted using a Qiacube following the Qiagen QIAamp DNA Investigator Kit protocol.

[0230] Targeted sequencing:

[0231] The impact of “culture on reconstructed human epidermis” on the microbiota is evaluated by targeted sequencing.

[0232] Sequencing was performed on a MiSeq sequencer (Illumina) with primers adapted to each target. Sequence preprocessing was performed using a computer pipeline developed by INRAE ​​running under Mothur (version 1.44.0).

[0233] 16S Bacteria Sequencing:

[0234] The primers used target the variable regions VI-V3 of the 16S ribosomal RNA sequence of prokaryotes (bacteria and archaea). The preprocessing of the sequences is carried out by a computer pipeline developed by INRAE ​​running under Mothur (version 1.44.0).

[0235] Barcodes and primers as well as chimeras were removed from the sequence files during the filtering steps. Sequences with 100% homology between them were grouped into unique sequences, then into OTUs (operational taxonomy units: threshold of 97%) which will be identified subsequently.

[0236] Bioinformatics analysis of sequencing data allows the identification of microorganisms present at different taxonomic levels (phylum and genus). The analysis allowing phylogenetic affiliation up to the genus level was carried out using bioinformatics tools for processing large amounts of sequence data (Mothur). Identification was carried out on the basis of the Greengenes taxonomy for bacteria.

[0237] C. acnes is the most abundant bacterial species in the model microbiotas.

[0238] The inventors have demonstrated a significantly increased abundance under the effect of irradiation.

[0239] [Table 10]

[0240] '41: Non-irradiated; IR: Irradiated; CTRL: Control; LA: Formulation A; ns: not significant

[0241] These results demonstrate that the topical application of a formulation comprising phenylene bis-diphenyltriazine can significantly reduce imbalances induced by UV radiation, and thus protect the microbiota and maintain the balance of the cutaneous microbial component.

[0242] Example 3: Effect of a placebo formulation not including phenylene bis-diphenyltriazine against the deleterious effects of UV radiation on barrier function

[0243] A placebo formulation C is used, comprising the same components as those of formulations A and B except that it does not contain any sunscreen, and therefore does not contain phenylene bis-diphenyltriazine. This formulation is applied to reconstructed skin models, whether irradiated or not. This example shows that the components of the formulations other than sunscreens do not help preserve the skin's barrier function when the skin is irradiated.

[0244] Methods

[0245] Four groups of eighteen reconstructed epidermis with microbiota and sebum from 18 distinct donors are studied (untreated / unirradiated; untreated / irradiated; formulation C / unirradiated; formulation C / irradiated).

[0246] The reconstructed epidermis are irradiated according to the same protocol as that described in example 2.

[0247] Formulation C is applied at a dose of 2 mg / cm2 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.

[0248] At the end of the experiment, the reconstructed epidermis are recovered and treated according to the same protocol as that described in example 2.

[0249] The 1H NMR spectra of the samples obtained from the reconstructed epidermis are produced according to the same protocol as that described in Example 2.

[0250] The analysis of these spectra is carried out according to the same protocol as that described in example 2.

[0251] Results - Barrier function and hydration: metabolomic approach

[0252] The following table reports the observed variations (Log 2 of variations) under the effect of UV irradiation for different discriminating metabolites of the barrier function and hydration of the skin, in the epidermis of the model.

[0253] [Table 11]

[0254] NI: Non-irradiated; IR: Irradiated; CTRL: Control; FC: Formulation C; ns: not significant

[0255] These results demonstrate that topical application of the placebo formulation without sunscreen (formulation C) does not reduce imbalances induced by UV radiation. The placebo formulation therefore does not preserve the barrier function or hydration of the skin, unlike formulations A and B which contain phenylene bis-diphenyltriazine. These formulations very significantly dampen imbalances induced by UV radiation, and thus preserve the barrier function, skin hydration and the balance of the cutaneous microbial component.

[0256] These results taken into consideration with the results obtained in Example 2 clearly show that phenylene bis-diphenyltriazine is responsible for the effects on the preservation of the barrier function and hydration of the skin.

Claims

DEMANDS 1. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use in strengthening the skin barrier and / or preventing and / or reducing impairment of the skin barrier function, in particular for maintaining skin barrier hydration and / or for preventing and / or reducing sensations of stinging and / or tightness, redness and / or skin irritation.

2. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use according to claim 1, for maintaining skin barrier hydration.

3. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use according to claim 1 or 2, for the prevention and / or reduction of tingling and / or pulling sensations, redness and / or skin irritation.

4. 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use in protecting the cutaneous microbial component and / or maintaining the balance of the cutaneous microbial component.

5. Composition comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and at least one pharmaceutically acceptable excipient, for use in strengthening the skin barrier and / or preventing and / or reducing impairment of the skin barrier function, in particular for maintaining skin barrier hydration and / or preventing and / or reducing sensations of stinging and / or tightness, redness and / or skin irritation.

6. Composition for its use according to claim 5, for maintaining the hydration of the skin barrier.

7. Composition for its use according to claim 5 or 6, for the prevention and / or reduction of tingling and / or pulling sensations, redness and / or irritation of the skin.

8. Composition comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and at least one pharmaceutically acceptable excipient, for use in protecting the cutaneous microbial component and / or maintaining the balance of the cutaneous microbial component.

9. Composition for use according to any one of claims 5 to 8, 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%, in particular between 6% and 20%, notably between 7% and 18%, typically between 8% and 17% by weight of the composition relative to the total weight of the composition, said composition not comprising any sunscreens other than those constituting said photoprotective system.

10. Composition for its use according to claim 9, characterized in that the sunscreen (d) is ethylhexyl triazone.

11. Composition for its use according to claim 9 or 10, 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, - 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine represents between 1% and 4% by weight, - 1' hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate represents between 1% and 10% by weight, and - the sunscreen (d) represents between 1% and 6% by weight, relative to the total weight of the composition.

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