5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for the treatment and / or prevention of pre-cancerous or cancerous skin lesions

Abstract

The present invention relates to 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine or a composition comprising it for use in the prevention and / or treatment of a pre-cancerous or cancerous skin lesion; or for use in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

Description

Title of the invention: 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the treatment and / or prevention of a pre-cancerous or cancerous skin lesion TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to the 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine, and a composition comprising it, for use in the prevention and / or treatment of a precancerous skin lesion such as actinic keratosis or a cancerous skin lesion; or in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells. STATE OF THE ART

[0002] Excessive sun exposure disrupts the proper functioning of skin tissue and causes damage of varying severity depending on the duration and frequency of exposure. Overexposure to ultraviolet (UV) radiation, whether solar or artificial, has major deleterious effects on living systems. These biological effects are primarily linked to ultraviolet B and A (UVB and UVA). In humans, UV radiation is responsible for erythema, immunosuppression, and, in the long term, leads to the appearance of skin wrinkles (photoaging) and, more seriously, to the formation of skin cancers. The toxicity of UV radiation is linked to its absorption by various molecules present in the skin. The compounds that absorb photons are called chromophores. They can be naturally present in skin tissue (DNA, melanin) or of external origin (xenobiotics, medications).

[0003] The ability of UV radiation to induce skin tumors is primarily explained by its genotoxic and mutagenic properties. Indeed, sunlight is a proven cause of the development of skin cancers, particularly squamous cell and basal cell carcinomas involving keratinocytes. A number of experimental studies reveal that UVB (280-320 nm) constitutes the most harmful part of the solar spectrum (Marzouki et al. 2017). Although they are minor components of solar radiation (<5% of total UV), UVB is directly absorbed by DNA. It induces photochemical reactions on the DNA double helix and modifies the chemical structure of the pyrimidine bases (C and T), which are found as photoproducts of two main types: cy dimers Clobutane pyrimidine dimer (CPD) and the photoproducts of (6-4)pyrimidone (6-4PP) and their Dewar valence isomers can form at any of the four possible bipyrimidine sequences (TT, TC, CT, and CC), but in varying proportions. These lesions induce slight distortion of the DNA double helix, causing genomic instability. During replication, the presence of these lesions can lead to the incorporation of an incorrect nucleotide, resulting in the formation of a mutation. Mutations caused by UV radiation are characterized by a very high frequency of transitions in dipyrimidine sequences containing cytosines. The most frequent are C→T and CC→TT transitions. If this damage is not properly repaired, it is a source of mutations that constitute the first step toward tumor formation. UVB rays are therefore capable of initiating a process of carcinogenesis. However, the mutagenic potential of UVA rays should not be overlooked, as they have been shown to also induce the formation of CPDs in DNA, even though they are much less powerful than UVB rays. UVA rays are at least twenty times more intense than UVB rays in solar radiation but are two to three orders of magnitude less damaging to DNA.

[0004] Solar radiation is one of the few environmental carcinogens capable of inducing all three phases of carcinogenesis: initiation, promotion, and progression. CPD photolesions are suspected of being responsible for the majority of DNA mutations during photocarcinogenesis and are relatively resistant to cellular repair. Sun-induced immunosuppression may also promote immune tolerance to tumor cells, and the decreased repair and regeneration capacity of the skin during photoaging could contribute to tumor development. If these lesions are not properly repaired, they are a source of mutations that constitute the first step toward tumor formation.

[0005] Chronic UV exposure is initially responsible for the formation of benign precancerous lesions (actinic keratoses) which can degenerate into skin cancers, the number of which is increasing worldwide. Their frequency varies according to their cellular origin: epithelial carcinomas or melanomas. Epithelial cancers include basal cell carcinomas, which result from an alteration of the keratinocytes in the basal layer of the epidermis, and squamous cell carcinomas, which are dependent on suprabasal cells (squamous cell carcinomas). Carcinomas represent 90% of skin cancers, with 70% being basal cell carcinomas and 20% squamous cell carcinomas.

[0006] Actinic keratoses, also called solar keratoses or pre-epitheliomatous keratoses, are pre-cancerous skin lesions resulting from the proliferation Actinic keratoses are characterized by the formation of atypical keratinocytes. Their prevalence varies from 6% to 60%, depending on key factors such as age, phototype, and other risk factors like immunosuppression or working outdoors (Dréno et al. 2014). Actinic keratoses are very common and are constantly increasing due to the aging population.

[0007] Clinically, actinic keratoses are often more palpable than visible, giving a rough appearance under the finger, often small, sometimes isolated or, conversely, multiple, in large, poorly defined areas. The lesions vary in size from 2 mm to large plaques, but most measure between 2 and 6 mm in diameter. Actinic keratoses may be light-colored, dark-pigmented, erythematous, or bronze. Actinic keratoses of the head and neck are flat, while those on the backs of the hands or forearms are often thicker.

[0008] Actinic keratoses are very common on sun-exposed areas, particularly in fair-skinned individuals. Actinic keratoses develop under the influence of UV radiation, primarily UVB but also UVA. This radiation causes damage to the DNA of keratinocytes, the cells that make up the epidermis.

[0009] The theory of somatic mutagenesis indicates that malignant transformation of cells is closely linked to the formation of DNA damage and the risk that this damage may lead to mutations that promote uncontrolled cell growth. Certain changes in the genetic information of somatic cells (point mutations and / or chromosomal rearrangements) are a primary cause of malignant cell transformation. The accumulation of these alterations in important genes that play a role in maintaining cell integrity, such as cell cycle control, repair, and apoptosis, can lead to the uncontrolled proliferation of abnormal cells and the formation of a tumor.

[0010] Mutation spectra, particularly in the tumor suppressor gene p53, have made it possible to identify mutations in a given cancer type based on their nucleotide position. The most frequently mutated positions differ depending on the cancer. The p53 gene is very frequently mutated in more than 50% of human tumors and exhibits a mutation spectrum or signature specific to UVB. Tumor analysis has revealed "hot spots" of greater sensitivity to UV radiation, thus reflecting the signature of sun exposure. Finally, it has recently been shown that the genome of human keratinocytes also exhibits "hypersensitivity zones" of CPD mutations to UVB, particularly in the promoters of genes encoding transcription factors of the ETS family, with a sensitivity up to 550 times greater than in the average genome. Thus, when these mutations affect genes that are involved in During tumor elimination and DNA repair, these cells lose their protective function against cancer cells. This contributes to the emergence of abnormal, so-called "atypical" keratinocytes that proliferate, clinically manifesting as actinic keratoses. Natural UV radiation, as well as artificial UV radiation delivered in beauty salons, is responsible for their development.

[0011] The main risk of actinic keratoses is their progression to an invasive lesion such as cutaneous squamous cell carcinoma. There is a continuum ranging from actinic keratosis to carcinoma in situ (or Bowen's disease), and finally to invasive squamous cell carcinoma. However, actinic keratoses can also regress spontaneously or remain stable (Wemer et al. 2013). Their potential for malignant transformation (squamous cell carcinoma) is approximately 10% of cases. Studies have clearly demonstrated that, in humans, sunlight can act as both an initiator and a promoter of non-melanoma skin cancer. The exact number of actinic keratoses that will induce carcinomas depends on additional factors that promote conversion.

[0012] Treatment options for actinic keratoses depend on their number, depth, and extent. Cryotherapy is the preferred treatment method for isolated or small lesions. The main immediate side effects are pain, edema, and blistering. In the long term, hyperpigmented or hypopigmented scars may persist. Photo-directed treatment with porphyrins and light (photodynamic therapy) can be useful in managing larger actinic keratoses. The main limitations of photodynamic therapy are the need for a specific lamp by the dermatologist and the pain experienced during the procedure, which can sometimes be unbearable and necessitate stopping the treatment.Full-thickness elliptical excision for actinic keratosis is rarely performed by dermatologists, but is routinely performed by plastic surgeons, general surgeons, and general practitioners. This form of therapy is considered inappropriate by most health authorities and is therefore discouraged.

[0013] For patients with multiple lesions or lesions in the field of malignant transformation, topical agents (5-fluorouracil, imiquimod, masoprocol, tretinoin, ingenol mebutate, diclofenac) are also frequently prescribed. These topical agents have been shown to effectively treat actinic keratoses but cause side effects, mainly local, such as pain, burning sensation, erythema, edema, or persistent scarring. Dermabrasion, chemical peels, and carbon dioxide laser resurfacing can also be used in the treatment of extensive actinic keratoses, as well as surgery, which remains the gold standard treatment for suspicious or treatment-resistant lesions. This procedure is usually preceded by a biopsy. Surgery also allows for control of the excision margins, but does not prevent the recurrence of actinic keratosis at the scar border. Treatments do exist, but they are relatively intensive and have numerous potential side effects.

[0014] Eliminating these pre-cancerous lesions undoubtedly reduces the risk of developing squamous cell carcinomas and is therefore appropriate for optimal patient care.

[0015] There is therefore still a need for treatments of pre-cancerous or cancerous skin lesions. Summary of the invention

[0016] 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 the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or of a cancerous skin lesion.

[0017] The present invention also relates to the use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or of a cancerous skin lesion.

[0018] The present invention also relates to the use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the preparation of a drug or a cosmetic or pharmaceutical composition (e.g. dermatological) intended for the prevention and / or treatment of a precancerous skin lesion, such as actinic keratosis, or a cancerous skin lesion.

[0019] The present invention also relates to a method for preventing and / or treating a precancerous skin lesion, such as actinic keratosis, or a cancerous skin lesion, comprising administering to a person in need an effective amount of 5,6,5' ,6' -tetraphenyl-3,3' -( 1,4-phenylene)-bis[ 1,2,4]triazine.

[0020] The present invention also relates to a composition, preferably a cosmetic or pharmaceutical (e.g. dermatological) 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 its use in the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or a cancerous skin lesion.

[0021] The present invention also relates to the use of a composition, preferably a cosmetic or pharmaceutical (e.g., dermatological) composition, comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and less a cosmetically and / or pharmaceutically acceptable excipient for the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or a cancerous skin lesion.

[0022] The present invention also relates to the use of a composition, preferably a cosmetic or pharmaceutical (e.g. dermatological) 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 preparation of a medicinal product intended for the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or a cancerous skin lesion.

[0023] The present invention also relates to a method for the prevention and / or treatment of a pre-cancerous skin lesion, such as actinic keratosis, or of a cancerous skin lesion comprising administering to a person in need an effective amount of a composition, preferably a cosmetic or pharmaceutical (e.g. dermatological) 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.

[0024] The present invention also relates to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for its use in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0025] The present invention also relates to the use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the repair of DNA damage in skin cells and / or for the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0026] The present invention also relates to the use of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine for the preparation of a drug or a cosmetic or pharmaceutical composition (e.g. dermatological) intended for the repair of DNA damage in skin cells and / or for the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0027] The present invention also relates to a method of repairing DNA damage in skin cells and / or preventing and / or reducing a deficiency in DNA damage repair in skin cells comprising administering to a person in need an effective amount of 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine.

[0028] The present invention also relates to a composition, preferably a cosmetic or pharmaceutical (e.g., dermatological) 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 its use in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0029] The present invention also relates to the use of a composition, preferably a cosmetic or pharmaceutical (e.g., dermatological) 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 repair of DNA damage in skin cells and / or for the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0030] The present invention also relates to the use of a composition, preferably a cosmetic or pharmaceutical (e.g. dermatological) 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 preparation of a medicinal product intended for the repair of DNA damage in skin cells and / or for the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

[0031] The present invention also relates to a method for repairing DNA damage in skin cells and / or preventing and / or reducing a deficiency in DNA damage repair in skin cells, comprising administering to a person in need an effective amount of a composition, preferably a cosmetic or pharmaceutical (e.g., dermatological) 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.

[0032] The present invention also relates to a method of therapeutic treatment of skin prone to actinic keratosis consisting of the application of 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine, or of a composition, preferably a cosmetic or pharmaceutical (e.g. dermatological) 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, before exposure of the skin to radiation, in particular sunlight, in order to prevent the deficiency in repair of DNA damage in skin cells. DETAILED DESCRIPTION OF THE INVENTION

[0033] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine

[0034] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine (CAS No.: 55514-22-2, trade name: Triasorb™), also known as bis-diphenyltriazine, is a sunscreen, more particularly a broad-spectrum sunscreen Ultra-broad-spectrum capable of filtering the harmful part of the solar spectrum, which includes UV radiation (UVB and UVA), as well as high-energy visible blue light. In the following description, the names 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine and phenylene bis-diphenyltriazine are used interchangeably.

[0035] 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.

[0036] By "UVA radiation" or simply "UVA", we mean ultraviolet rays having an X wavelength between 320 and 400 nm.

[0037] By "UVB radiation" or simply "UVB", we mean ultraviolet rays having an X wavelength between 290 and 320 nm.

[0038] By “high energy visible blue light” or “HEV”, we mean rays having an X wavelength between 400 and 450 nm, in particular between 400 and 450 nm.

[0039] The term “sunscreen” refers to a substance capable of filtering solar radiation to protect a surface, typically the skin or hair, against the harmful effects of this radiation.

[0040] Depending on the radiation filtration mechanism, that is, depending on whether the radiation is absorbed and / or reflected, or even diffused by the solar filter, we can strictly distinguish: - filters strictly speaking, which mostly absorb radiation, and - screens, which absorb and reflect radiation.

[0041] However, in the remainder of this description, the term "sunscreen," sometimes abbreviated as "filter," will be used interchangeably to refer to both a filter and a screen. The term "UV filter" may also be used instead of "sunscreen."

[0042] A sunscreen is described as a "UVA filter" or "UVB filter" depending on whether it filters mostly UVA or UVB.

[0043] A "broadband" or "broad spectrum" solar filter filters both UVA and UVB rays. An "ultra-broadband" or "ultra-broad spectrum" solar filter is a broadband solar filter as defined above that also filters high-energy visible blue light.

[0044] A sunscreen filter can be "lipid-soluble" or "water-soluble," depending on whether it dissolves more readily in lipids or in water, or even "insoluble." An insoluble sunscreen filter is typically in particulate form and can nevertheless be incorporated into a sun protection composition, particularly in a dispersed form, especially a water-dispersed form when dispersed in an aqueous phase.

[0045] Phenylene bis-diphenyltriazine is an insoluble type filter. In particular, it is a water-dispersible filter, which typically takes the form of an aqueous dispersion, comprising between 20% and 50%, in particular between 40% and 50% by weight of active material relative to the total weight of the dispersion.

[0046] Advantageously, the process for preparing the aqueous dispersion consists of grinding the insoluble organic filter into particles using a grinding apparatus and in the presence of a grinding aid. Conventionally, wet grinding processes are used (wet grinding, wet mixing), and the grinding aid allows for better particle dispersion. These techniques are well known to those skilled in the art. The grinding apparatus can be, for example, a micro-bead mill, a vibrating mill, or a ball mill. Depending on the grinding process, the grinding aid is chosen from the group consisting of anionic, nonionic, or amphoteric surfactants, emulsifiers, and dispersants such as PPG-1-PEG-9 Lauryl Glycol Ether (Eumulgin® L, marketed by BASF).

[0047] In a particular embodiment, the D50 size of the bis-diphenyltriazine phenylene particles is between 100 and 1000 nm, more particularly between 100 and 500 nm, even more particularly between 120 and 400 nm, especially between 120 and 250 nm, particularly between 120 and 200 nm, typically between 150 and 200 nm.

[0048] By "size D50" or "median" of particles, we mean the size for which the cumulative function F(D) is equal to 50%, F(D) being defined according to the following relation:

[0049] [Math.l] F(Di) = lf(D)dD o

[0050] in which:

[0051] f(D) is the number size distribution of the particles, and

[0052] Di is a size class.

[0053] The value of the D50 size can be determined by laser diffraction, in particular using a Mastersizer 3000 laser diffraction particle size analyzer, more particularly in liquid mode. Composition

[0054] The composition according to the invention comprises 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine, as defined above, and at least one cosmetically and / or pharmaceutically acceptable excipient.

[0055] In the present invention, "cosmetically and / or pharma- "Ceutically acceptable" means that which is useful in the preparation of a composition that may have 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.

[0056] By "cosmetically and / or pharmaceutically acceptable excipient" is meant any cosmetically and / or pharmaceutically acceptable adjuvant enabling the manufacture, preservation or administration of the composition.

[0057] In a particular embodiment, the composition for use according to the invention is in the form of an emulsion, preferably oil-in-water.

[0058] For the purposes of this invention, "emulsion" means any type of emulsion obtained by dispersing a discontinuous internal phase in a continuous external phase, one of these phases being an aqueous phase and the other an oily phase. This includes, for example, an oil-in-water or water-in-oil emulsion, or a multiple emulsion, preferably an oil-in-water emulsion.

[0059] The emulsion can be more or less fluid and may be presented in particular in the form of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, or possibly an aerosol, a foam or a spray, and may also be water-resistant.

[0060] The composition for use according to the invention is intended more particularly for topical application on the skin.

[0061] In a particular embodiment, phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the total weight of the composition.

[0062] It is understood that these mass percentages, as well as all those indicated in the description, are expressed as a percentage of the mass of active material relative to the total mass of the composition.

[0063] In the composition according to the present invention, phenylene bis-diphenyltriazine can be associated with one or more other sunscreens, to constitute a photoprotective system which, after application to a surface (skin, hair, etc.), by mechanisms of absorption and / or reflection and / or diffusion of UVA and / or UVB radiation, prevents, or at least limits, the contact of said radiation with said surface.

[0064] The photoprotective system constituting a composition according to the invention preferably comprises one or more liposoluble sunscreens selected from the following filters (i) to (v):

[0065] (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®. This is a liposoluble UVA filter, having a maximum absorption wavelength Xmax equal to 354 nm. In a particular embodiment, DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, in particular between 5% and 7%, notably between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition.

[0066] (ii) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine (CAS No. 187393-00-6), also known as bis-ethylhexyloxyphenol methoxyphenyl triazine or BEMT, marketed by BASF under the name Tinosorb S®. This is a fat-soluble broadband filter, having two absorption peaks at 310 nm and 340 nm. In one particular embodiment, 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.

[0067] (iii) 4-tert-butyl-4-methoxydibenzoylmethane or butyl methoxydibenzoylmethane (chemical name: 1,4-(1,l-dimethylethyl)phenyl-3-(4-methoxyphenyl)-l,3-propanedione; CAS No.: 70356-09-1), also known as avobenzone or BMDBM, marketed notably by DSM under the name Parsol 1789®. This is a liposoluble UVA filter, having a maximum absorption wavelength Xmax equal to 357 nm. 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.

[0068] (iv) ethylhexyl triazone or EHT (chemical name: 2-ethylhexyl ester of 4-[[4,6-bis[[4-(2-ethylhexoxy-oxomethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzoic acid; CAS No.: 88122-99-00), marketed by BASF under the name Uvinul T 150®. This is a liposoluble UVB filter, having a maximum absorption wavelength Xmax of 314 nm. In one particular embodiment, EHT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, in particular between 3.5% and 4.5% by weight relative to the total weight of the composition.

[0069] (v) diethylhexyl butamido triazone or DBT (chemical name: 4,4'-[[6-[[4-[[(l,l-dimethylethyl)amino]carbonyl]phenyl]amino]-l,3,5-triazine-2,4-diyl ]diimino]bis-, bis(2-ethylhexyl)benzoate; CAS No.: 154702-15-5), marketed by 3V Sigma under the name Uvasorb HEB®. This is a liposoluble UVB filter, having a maximum absorption wavelength Xmax of 310 nm. In one particular embodiment, 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.

[0070] The photoprotective system constituting a composition according to the invention may further comprise one or more additional particulate organic UV filters, in addition to phenylene bis-diphenyltriazine, selected from the following filters (vi) and (vii):

[0071] (vi) methylene bis-benzotriazolyl tetramethylbutylphenol (chemical name: 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol; CAS No.: 103597-45-1) also known as MBBT, marketed by BASF under the name Tinosorb M®. This is a broadband filter, having two absorption peaks at 306 nm and 348 nm, of the non-soluble type. MBBT typically comes 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. In one particular embodiment, MBBT represents between 1% and 7%, typically between 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. In one particular embodiment, the D50 size of MBBT particles is between 50 nm and 250 nm, in particular between 60 nm and 150 nm.

[0072] (vii) 2,4,6-tris(biphenyl-4-yl)-l,3,5-triazine (CAS No. 31274-51-8) also called trisbiphenyl triazine or TBPT, marketed by BASF under the name Tinosorb A2B®. This is a UVB filter, having a maximum absorption wavelength Xmax equal to 310 nm, of the non-soluble type. TBPT typically comes 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. In one particular embodiment, TBPT represents between 1% and 7%, in particular between 2% and 7%, notably between 2% and 6% by weight relative to the total weight of the composition. In one particular embodiment, the D50 size of TBPT particles is between 50 nm and 250 nm, in particular between 80 nm and 150 nm.

[0073] In a particular embodiment, the photoprotective system constituting a composition according to the invention may further comprise one or more particulate inorganic filters, such as titanium dioxide (TiO2) or zinc oxide. (ZnO).

[0074] The inorganic particulate filter(s) possibly present in the composition according to the invention typically have a particle size D50 between 15 nm and 150 nm.

[0075] In a particular embodiment, the composition 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.

[0076] In a particular embodiment, the composition according to the invention does not include any water-soluble filters. The absence of water-soluble filters is particularly advantageous, since water-soluble filters are generally more readily assimilated by marine organisms than fat-soluble or insoluble filters. Consequently, the Applicant's choice to use only insoluble (more specifically particulate, and in particular water-dispersed) or fat-soluble filters minimizes the impact of the composition according to the invention on the marine environment.

[0077] In another particular embodiment, the composition for use according to the invention does not include 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 / or all the UV filters present in the composition represent between 4% and 25% by weight, in particular between 6% and 20% by weight, notably between 7% and 18% by weight, typically between 8% and 17% by weight, relative to the total weight of the composition.

[0079] In an advantageous embodiment, the photoprotective system of the composition according to the invention consists 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-tri azine (BEMT), c. Hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate (DHHB), and d. ethylhexyl triazone (EHT) or diethylhexyl butamido triazone (DBT).

[0080] In particular, (d) corresponds to ethylhexyl triazone.

[0081] In this particular embodiment, phenylene bis-diphenyltriazine represents between 1% and 5%, in particular between 2% and 5%, in particular between 2% and 4%, typically between 3% and 4% by weight relative to the total weight of the composition; DHHB represents between 1% and 10%, for example between 3% and 10%, in particular between 4% and 9%, typically between 5% and 8%, for example between 5% and 7%. in particular between 6% and 7% or advantageously between 5% and 6% by weight, relative to the total weight of the composition; BEMT represents between 1% and 4%, in particular between 2% and 4%, especially between 2% and 3% by weight of the composition relative to the total weight of the composition; and EHT or DBT represents between 1% and 6%, typically between 2% and 5%, in particular between 3% and 5%, especially between 3.5% and 4.5% by weight relative to the total weight of the composition.

[0082] The compositions according to the invention may thus include cosmetically and / or pharmaceutically (e.g. dermatologically) acceptable excipients conventionally used in the art, in particular selected from liquid lipophilic compounds, water-miscible polyols, emulsifiers, consistency agents, water-retaining agents, texturizing agents, opacifiers, colour pigments, antifoaming agents, perfumes, preservatives, polymers, fillers, sequestrants, bactericides, odor absorbers, alkalizing or acidifying agents, surfactants, free radical scavengers, vitamins, alpha-hydroxy acids, active agents (in particular moisturizing agents, antioxidants) or any other ingredient commonly used for the manufacture of sunscreen compositions.

[0083] The composition may thus include a liquid lipophilic compound or a combination of several liquid lipophilic compounds, typically a liquid lipophilic emollient or a combination of liquid lipophilic emollients, in particular a liquid fat or a combination of liquid fats.

[0084] By "liquid lipophilic compound" is meant a compound which has an affinity for nonpolar substances such as lipids, and is in liquid form in particular at a temperature between 5°C and room temperature (between 20°C and 25°C). It typically comprises one or more polar chemical function(s) chosen from among the ester (-CO2-), alcohol (-OH), ether (-O-), carbonate (-OCO2-) and carboxylic acid (-CO2H) functions, and one or more lipophilic group(s), i.e. one or more aliphatic and / or aromatic hydrocarbon group(s), in particular one or more saturated or unsaturated, linear or branched hydrocarbon chain(s), comprising between 6 and 20 carbon atoms, for example between 7 and 18 carbon atoms, notably between 8 and 16 carbon atoms.It can be chosen in particular from C12-C15 alkyl benzoate, caprylic / capric triglycerides, dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2-ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isonanoate, butylene glycol dicaprylate / dicaprate, octyldodecanol, propylene glycol dicaprylate / dicaprate and the . dicaprylyl ether, in particular among caprylic / capric triglycerides, di-caprylyl carbonate, isopropyl palmitate, propylheptyl caprylate, phenethyl benzoate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2-ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isononoate, butylene glycol dicaprylate / dicaprate, octyldodecanol, propylene glycol dicaprylate / dicaprate, dicaprylyl ether and their combinations.

[0085] The liquid lipophilic emollient(s) are chosen in particular from C12-C15 alkyl benzoate, caprylic / capric triglycerides and dicaprylyl carbonate.

[0086] In a particular embodiment, the composition according to the invention does not comprise diisopropyl sebacate, diethylhexyl succinate, isopropyl myristate and / or dibutyl adipate. Typically, it does not include dicaprylyl carbonate, coco-caprylate, diisopropyl sebacate, diethylhexyl succinate, isopropyl palmitate, isopropyl myristate, propylheptyl caprylate, phenethyl benzoate, dibutyl adipate, diisopropyl adipate, glyceryl tri-2-ethylhexanoate, pentaerythrityl tetra-2-ethylhexanoate, cetyl 2-ethylhexanoate, isononyl isononoate, butylene glycol, dicaprylate / dicaprate, octyldodecanol, propylene glycol dicaprylate / dicaprate and / or dicaprylyl ether.

[0087] The composition may further comprise a water-miscible polyol at room temperature (approximately 25°C), in particular selected from polyols having from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having from 2 to 6 carbon atoms, such as glycerin; glycol derivatives such as propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol; glycol ethers such as 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.

[0088] The composition may also include one or more anionic, cationic and / or non-ionic emulsifiers selected from glucose derivatives such as cetearyl glucoside, arachidyl glucoside, lauryl glucoside, polyglyceryl-3 methylglucose distearate and methyl glucose sesquistearate; sucrose derivatives such as sucrose polystearate and sucrose palmitate; fatty acid glycerides such as glyceryl stearate, glyceryl oleate and glyceryl stearate citrate; glutamic acid derivatives such as sodium stearoyl glutamate; sulfosuccinic acid derivatives such as disodium cetearyl sulfosuccinate and sodium dioctyl sulfosuccinate; phosphoric acid derivatives such as potassium cetyl phosphate; polyglyceryl fatty acid esters such as polyglyceryl-3-diisostearate and polyglyceryl-2-dipolyhydroxystearate;sorbitol derivatives such as polysorbate, PEG-10 sorbitan laurate and sorbitan esters; fatty alcohol and fatty acid polyglycol ethers such as ceteareth-20, beheneth-25, the; steareth-2, trideceth-9, PEG-5 ethylhexanoate and PEG-100 stearate; sodium lauryl sulfate, sodium stearate, organomodified silicone / polysiloxane / polyalkyl / polyether oxyalkenyl copolymers and derivatives, and mixtures thereof.

[0089] The emulsifier(s) are chosen in particular from potassium cetyl phosphate, lauryl glucoside and glyceryl stearate citrate.

[0090] In a particular embodiment, the composition according to the invention does not comprise an ethoxylated emulsifier and / or one comprising a PEG chain. In particular, the composition does not comprise sorbitol derivatives such as a polysorbate 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.

[0091] The composition may also include one or more solid consistency agents selected from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyle stearate; polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; cellulose derivatives such as hydroxypropylcellulose; waxes such as beeswax, carnauba wax, microcrystalline wax, ceresin, and ozocerite; polyacrylates or homopolymers of acrylic acids or crosslinked polyacrylamides such as carbomers, acrylate copolymers, crosslinked acrylate / (C10-C30)alkylacrylate copolymers, acrylate / behenethyl-25 methacrylate copolymers; silicate derivatives such as magnesium silicates and their mixtures.

[0092] In a particular embodiment, the composition according to the invention comprises one or more consistency agents selected from fatty alcohols such as cetyl alcohol, cetearyl alcohol and stearyl alcohol; fatty acids such as stearic acid; fatty acid esters such as myristyle stearate; polysaccharides or derivatives such as xanthan gum, guar gum, agar gum, alginates, gellan gum and carrageenan; cellulose derivatives such as hydroxypropylcellulose, and mixtures thereof.

[0093] In a particular embodiment, the composition does not include a consistency agent selected from acrylates and their derivatives.

[0094] The composition may also include one or more water-resistant reactive agents selected from an N-vinylpyrrolidone (VP) and eicosene copolymer (INCI: VP / eicosen copolymer), a trimethylpentanediol, adipic acid and glycerol crosspolymer (INCI: trimethylpentanediol / adipic acid / glycerin crosspolymer), polyamide 3 (INCI), an acrylate and octylacrylamide copolymer (INCI: acrylates / octylacrylamide copolymer), and triacontanyl PVP (INCI).

[0095] Preferably, the composition for use according to the invention comprises VP / eicosene copolymer as a water-resistant agent.

[0096] The composition may also include one or more texturizing agents in powder form, in particular selected from ingredients in the starch family, such as rice, corn, and tapioca starches; talcs; cellulose derivatives such as microcrystalline cellulose, and mixtures thereof.

[0097] In a particular embodiment, the composition according to the invention does not include a texturizing agent selected from nylon derivatives and polymethyl methacrylate (PMMA).

[0098] The composition may also include colour pigments, in particular selected from CI77891, CI77491, CI77492 and CI77499 (INCI designations).

[0099] In a particular embodiment, the composition 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.

[0100] In another particular embodiment, the composition is devoid of ethanol and isopropanol.

[0101] In a particular embodiment, the composition 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.

[0102] By "volatile ingredients", for the purposes of the present invention, means non-alcoholic volatile organic or inorganic compounds such as volatile esters, silicones or alkanes, characterized by a flash point below 60°C.

[0103] For the purposes of this invention, "flash point" (FP) means the minimum temperature at which a combustible substance emits vapors in a concentration sufficient to form a gaseous mixture with the surrounding air that ignites upon contact with a flame or a hot spot, but insufficient for combustion to propagate spontaneously in the absence of the pilot flame. According to Regulation (EC) No 1272 / 2008 on the classification, labelling and packaging of substances and mixtures, a substance with an FP such that 23°C < FP < 60°C belongs to category 3 "low flammability".

[0104] Among volatile esters, isohexyl neopentanoate is a notable example. Among volatile silicones, cyclopentasiloxane is a notable example. Among volatile alkanes, isohexadecane is a notable example.

[0105] In another particular embodiment, the composition for use according to the invention is devoid of volatile ingredients within the meaning of the present invention.

[0106] The composition may also include alkalizing or acidifying agents, and more particularly acids and bases for adjusting the pH range of said composition. The bases may be mineral (sodium hydroxide, potassium hydroxide, ammonia, etc.) or organic, such as mono-, di-, or triethanolamine, an aminomethylpropanediol, N-methylglucamine, basic amino acids such as arginine and lysine, and mixtures thereof. The acids may be mineral (hydrochloric acid, etc.) or organic, such as lactic acid and citric acid.

[0107] The composition according to the invention may further comprise additional active agents selected in particular from among moisturizing agents, desquamating agents, barrier function improving agents, depigmenting agents, antioxidant agents, dermocontracting agents, anti-glycation agents, agents stimulating the synthesis of dermal and / or epidermal macromolecules and / or preventing their degradation, agents stimulating the proliferation of fibroblasts or keratinocytes and / or the differentiation of keratinocytes, NO synthase inhibitors, agents increasing the activity of the sebaceous gland, tightening agents, liporestructuring agents, slimming agents, agents promoting cutaneous microcirculation, soothing and / or irritating agents, sebo-regulators or antiseborrheic agents, astringent agents, healing agents, anti-inflammatory agents, anti-acne agents, and mixtures thereof.

[0108] In a particular embodiment, the composition according to the invention is devoid of silicone.

[0109] In a preferred embodiment, the composition according to the invention comprises one or more antioxidant agents, typically chosen from vitamin E (i.e. tocopherols and tocotrienols) and its derivatives.

[0110] The terms "tocopherols" or "tocotrienols" refer to the compounds α-, γ-, γ-, and β-tocopherol or tocotrienol. The term "tocopherol" commonly refers to α-tocopherol. Among the tocopherol derivatives, one may notably mention ester derivatives, such as tocopheryl acetate, and glycosylated derivatives, such as tocopheryl glucoside (INCI: tocopheryl glucoside).

[0111] In a preferred embodiment, the composition for use according to the invention comprises one or more antioxidants selected from tocopherol and its derivatives, in particular from tocopherol, tocopherol glycoside and mixtures thereof, in an amount typically between 0.01% and 1% by weight relative to the total weight of the composition. Applications

[0112] The present invention relates to the 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or a composition comprising it as defined above for its use in the prevention and / or treatment of a pre-cancerous or cancerous skin lesion, preferably pre-cancerous.

[0113] The pre-cancerous skin lesion will more specifically be an actinic keratosis.

[0114] Preferably, the cancerous skin lesion is not a melanoma. The cancerous skin lesion may be a skin cancer due to a defect in DNA repair of skin cells, the defect in DNA repair being due in particular to exposure of the skin to high-energy visible blue light, especially from the sun, and therefore may in particular be due to exposure to solar radiation. Preferably, the cancerous skin lesion is a carcinoma, for example, a squamous cell carcinoma.

[0115] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or the composition according to the invention may be administered more particularly to a patient with sensitive or hypersensitive skin and / or reactive to the sun and / or prone to actinic keratosis.

[0116] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or the composition according to the invention may be administered topically, more particularly by application to the skin, the skin being more particularly sensitive or hypersensitive and / or reactive to the sun and / or prone to actinic keratosis.

[0117] Treatment based on 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or a composition comprising it as defined above can be combined, preferably sequentially, with photodynamic therapy (PDT), particularly in the case of a pre-cancerous skin lesion, and more particularly of actinic keratosis.

[0118] For the purposes of this invention, "photodynamic therapy," also called "photodynamic therapy" or "PDT" for short, refers to a technique for treating a pre-cancerous or cancerous skin lesion using a photosensitizing chemical substance administered, preferably by topical application to the lesion, in combination with exposure to light. The photosensitizing chemical substance is then activated by the light to become cytotoxic. This treatment technique therefore has the advantage of being local and non-invasive. Preferably, the photosensitizing chemical substance is methyl aminolevulinate (MAL).

[0119] The present invention also relates to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or a composition comprising it as defined above for its use in the repair of DNA in skin cells and / or in the prevention and / or reduction of a re- deficiency Repair of DNA damage to skin cells.

[0120] For example, DNA may exhibit lesions requiring repair following exposure to radiation, i.e., photoinduced damage, the radiation having caused said lesions. The radiation may be UV radiation, particularly UVB and / or UVA, notably from the sun. This UV radiation may have been combined with high-energy visible blue light, notably from the sun, which prevented the DNA from repairing itself. Thus, DNA may exhibit lesions requiring repair following exposure to sunlight.

[0121] In particular, DNA may have lesions to be repaired at the level of bi-pyrimidine sequences TT, TC, CT and CC, in particular in the form of cyclobutane dimers of pyrimidines (CPD) or of pyrimidines 6-4,pyrimidone (6-4PP) and their Dewar valence isomers.

[0122] The deficiency in repairing DNA damage in skin cells may in particular be due to exposure of skin cells, and therefore of the skin, to high energy visible blue light, in particular from the sun, and therefore in particular may be due to exposure to solar radiation.

[0123] The skin may be more particularly sensitive or hypersensitive and / or reactive to the sun and / or prone to actinic keratosis.

[0124] 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine or the composition according to the invention may be administered topically, more particularly by application to the skin, the skin being more particularly sensitive or hypersensitive and / or reactive to sunlight and / or prone to actinic keratosis. EXAMPLES

[0125] Example 1: Effects of HEV blue light on DNA damage

[0126] Visible light, which corresponds to radiation whose wavelengths are High-energy visible (HEV) light (400-450 nm), which represents approximately 50% of all solar radiation reaching Earth, has recently been identified as a contributing factor to photodamage of the skin, in addition to UV rays. Specifically, high-energy visible (HEV) light (400-450 nm), belonging to the blue light wavelength band (400-500 nm), can penetrate from the epidermis to the upper dermis of the skin, where it can have a significant impact on skin cells. Blue light has been shown to induce pigmentary disorders and, although clinical data are limited, may also contribute to signs of photoaging.

[0127] Activation of biological pathways can affect cellular macromolecules (DNA, proteins, and lipids), leading to structural damage and altered biological function. Although conflicting results have been obtained due to differences in light sources and exposure between studies, it has been demonstrated HEV / blue light radiation leads to increased melanin production and transfer, promoting cell differentiation, inhibiting cell growth, and potentially even inducing cell death by apoptosis. These cellular effects can then manifest on the skin as erythema, pigmentary changes, wrinkles, and, in some cases, photodermatosis.

[0128] Although blue light has been shown to have harmful effects on the skin, it can also have beneficial effects such as anti-proliferative and anti-inflammatory properties. Blue light phototherapy has been investigated as a potential treatment for psoriasis and Alzheimer's disease. The overall physiological effect of blue light on the skin therefore depends on the underlying condition of the skin, as well as the duration, dose, and irradiance of the exposure.

[0129] Therefore, the objective of this study is to evaluate the effect of HEV radiation on the DNA damage repair process following UVB exposure. Secondly, the protective effect of a formulation comprising phenylene bis-diphenyltriazine is evaluated.

[0130] In this study, the model used is a follicular model of human epidermis reconstructed in vitro.

[0131] Epidermis was reconstructed from keratinocytes derived from the outer epithelial sheath of human hair follicles obtained from healthy volunteers who had given their informed consent. The 3D reconstruction method described by Guiraud et al. 2014 was used. Cells from the outer epithelial sheath of human hair follicles are a readily available and non-invasive source of keratinocytes for epidermal reconstruction.

[0132] Briefly, cells (keratinocytes) were isolated from the outer epithelial sheath of hair follicles, then cultured before being seeded onto culture inserts immersed in culture medium. The culture inserts were then placed at the air / liquid interface in an incubator at 37°C in a humidified atmosphere with 5% CO2 to induce epidermal differentiation and the formation of the stratum corneum. At 16 days (D16), a reconstructed epidermis with a surface area of ​​1.12 cm² was formed. The culture medium was renewed every 24 hours. Method :

[0133] Three different formulations are investigated in this model. Each is applied at a dose of 2 mg / cm² to the surface of a polymethyl methacrylate (PMMA) plate. This plastic is naturally transparent and has greater light transmission than glass. The PMMA plate is then deposited onto the reconstructed epidermis model obtained according to Guiraud et al. 2014 just before exposure to HEV blue light stress (60 J / cm²). After HEV blue light stress, the PMMA plate is removed and the reconstructed epidermis is exposed to UVB at a dose of (50mJ / cm2). DNA damage is then analyzed immediately at the end of UVB irradiation (TO) or after 48h of re-culturing (T48h).

[0134] The three formulations tested are as follows: • Formulation A comprising 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine as the sole sunscreen and whose composition is given in Table 1; • Formulation B comprising BEMT, DHHB and BEMT as sunscreens, in addition to 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine (4-filter photoprotective system), the composition of which is given in Table 2; • Formulation C corresponding to a commercial sun composition not including 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine as a sun filter and whose list of ingredients (INCI names) is given below in order of predominance, the sun filters being identified by an asterisk: AQUA • DIISOPROPYL SEBACATE • ALCOHOL DENAT.• ETHYLHEXYL SALICYLATE* • ETHYLHEXYL TRIAZONE* • BIS-ETHYLHEXYLOXYPHENOL METHOXYPHENYL TRIAZINE* • DIL SOPROPYL ADIPATE • PEG-8 • DIPROPYLENE GLYCOL • C12-22 ALKYL ACRYLATE / HYDROXYETHYLACRYLATE COPOLYMER • GLYCERIN • DROMETRIZOLE TRISILOXANE* • ALUMINUM STARCH OCTENYLSUCCINATE • BUTYL METHOXYDIBEN-ZOYLMETHANE* • METHOXYPROPYLAMINO CYCLOHEXE-NYLIDENE ETHOXYETHYLCYANOACETATE* • SILICA • TO-COPHEROL • DIETHYLAMINO HYDROXYBENZOYL HEXYL BENZOATE* • ACRYLATES COPOLYMER • ACRYLATES / C10-30 ALKYL ACRYLATE CROSSPOLYMER • CAPRYLYL GLYCOL • HY-DROXYACETOPHENONE • PENTAERYTHRITYL TETRA-DLT-BUTYL HYDROXYHYDROCINNAMATE • SODIUM POLYACRYLATE • TE-REPHTHALYLIDENE DICAMPHOR SULFONIC ACID* • TRIETHA-NOLAMINE • TRISODIUM ETHYLENEDIAMINE DISUCCINATE. .

[0135] [Tableaux 1] Ingredients of Formulation A % (w / w) 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine 5 Glycerin 5 Demineralized Water Qs. 100 Xanthan Gum 0.2 C12-C15 Alkyl Benzoate 12.0 Dicaprylyl Carbonate 9.0 Caprylic / Capric Triglycerides 9.0 Preservatives Qs. Stearyl Alcohol 1.0 Glyceryl Monostearate 0.5 Glyceryl Behenate 0.4 PEG-100 Stearate 0.5 VP / Eicosene Copolymer 1.0 Polyacrylate 0.2 Potassium Cetyl Phosphate 2.0

[0136] [Tables2] Ingredients of Formulation B % (w / w) 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine 3-3,5 Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine 2,5-3 Diethylamino hydroxybenzoyl hexyl benzoate 5-6 Ethyl Hexyl Triazone 3,5-4 Glycerin 5.0 Demineralized Water q.s. 100 Xanthan Gum 0.2 C12-C15 Alkyl Benzoate 12.0 Dicaprylyl Carbonate 9.0 Caprylic / Capric Triglycerides 9.0 Preservatives q.s. Stearyl Alcohol 1.0 Glyceryl Monostearate 0.5 Glyceryl Behenate 0.4 PEG-100 Stearate 0.5 VP / Eicosene Copolymer 1.0 Polyacrylate 0.2 Potassium cetyl phosphate 2.0

[0137] Reconstructed epidermis onto which PMMA plates coated with the formulations to be tested are applied is irradiated by simulated HEV stress using a blue LED lamp (Kessil PR160). The wavelength is 427 ± 30 nm (HEV spectrum 400–450 nm), and a dose of 60 J / cm² was applied to the reconstructed epidermis for an average duration of 39 minutes. The power of the LED lamp is approximately 176 mW / cm². After this blue HEV stress, the PMMA plate is then removed.

[0138] The reconstructed epidermis is then exposed to specific UVB stress using a Biosun RMX irradiator (Vilber Lourmat, Germany) equipped with a monochromatic illumination lamp at 312 nm. The lamp power is approximately 3 mW / cm². The skin models are exposed to a single dose of 50 mJ / cm².

[0139] The reconstructed epidermis is then harvested immediately after UVB stress for half of it (T0) and 48 hours after this UVB stress for the second half (T48h), and all are frozen at -80°C for LC / MS analysis (liquid chromatography coupled with mass spectrometry).

[0140] All experimental conditions were carried out with n=3 technical replicates and 1 donor (N=1, n=3), except for the UVB (UVB stress only) and HEV + UVB (HEV blue light stress then UVB stress) controls carried out with 3 donors (N=3, n=3).

[0141] DNA is extracted using an approach that combines tissue grinding in a Qiagen TissueLyser system based on the use of metal beads in a buffer, followed by epidermal destructuring with suitable buffers and proteinase K according to the supplier's recommendations. The DNA is then isolated on a column using the DNAeasy Blood and Tissue kit (Qiagen). The DNA is obtained in aqueous solution and hydrolyzed into monomers by successive incubation with two enzyme cocktails (endonucleases, exonucleases, phosphodiesterases).

[0142] The hydrolyzed samples are then injected into a reversed-phase HPLC (high-performance liquid chromatography) system. At the column outlet, the eluent passes through a UV detector, which quantifies the normal bases of DNA. The flow is then directed to the inlet of an electrospray mass spectrometer with a triple quadrupole analyzer (MS / MS). Detection is performed in multiple reaction monitoring (MRM) mode, which sensitively and specifically tracks the production of characteristic fragments of targeted analytes. In the DNA of reconstructed epidermis, UV-produced pyrimidine dimers will be sought, namely cyclobutane pyrimidine dimers (CPD), pyrimidine (6-4)pyrimidone (6-4PP) photoproducts and their Dewar valence isomers (Dewar), for each of the bipyrimidic dinucleotides (TT, TC, CT).The precise quantity of each analyte detected by MS / MS is determined by isotopic dilution using TpT [M+12] photoproducts. The amount of DNA analyzed is determined simultaneously by measuring the normal nucleosides 2'-deoxyguanosine and thymidine with a UV detector and quantified by external calibration.

[0143] The raw data will then be processed to express the results as the number of photoproducts per million normal bases. This approach eliminates the inevitable variations in the amount of DNA extracted from one sample to another. Results

[0144] The results concerning the levels of photoproducts observed for the UFV and HEV + UVB controls are presented in Table 3 below. The level of photoproducts is expressed as dimers per million normal bases. The data are means ± esm (standard error of the mean).

[0145] [Tables3] Quantified Photoproducts UVB Control HEV + UVB Control T0 T48h T0 T48h TT CPD 76.9 + 4.9 46.5 + 3.6 79.2 + 3.6 69.7 + 3.5 TC CPD 38.7 + 2.7 23.4 + 1.6 41.9 + 2.2 34.9 + 2.1 CT CPD 12.8 + 1.1 4.4 + 0.4 13.8 + 1.6 9.0 + 1.2

[0146] Table 4 presents a one-way statistical analysis (ANOVA) followed by Tuckey's multiple comparison test.

[0147] [Tables4] Quantified photoproducts Impact of HEV blue light Evidence of DNA repair AT0 T0 compared to T48h UVB control vs HEV + UVB control UVB control HEV + UVB control TT CPD NS P<0.001 NS TC CPD NS P<0.001 NS CT CPD NS P<0.001 NS

[0148] Exposure to UVB alone induces a substantial and significant increase in DNA photoproducts immediately after irradiation. The rate of TT CPD lesions is higher than that of TC CPD and CT CPD. After 48 hours, the inventors observed a significant decrease (***p<0.001) in photoproducts, which is explained by the fact that DNA lesions had been repaired.

[0149] When irradiation with HEV blue light is performed before UVB exposure, the induction of DNA photoproducts is not significantly different from exposure to UVB alone at T0. Exposure to HEV blue light does not cause DNA damage. However, after 48 hours, the photoproducts are found in quantities equivalent to T0. Under these conditions, there was no DNA repair. These results demonstrate the negative impact of HEV blue light exposure on the DNA repair process.

[0150] Similar results are found when analyzing the TT CPD, TC CPD or CT CPD photoproducts.

[0151] The results of the tests carried out with formulations A, B, or C on the efficiency of DNA repair are summarized in Table 5 below. The efficiency of DNA repair is calculated under the different conditions. The statistical analysis is carried out by comparing the data of each condition at T48h with the conditions of the UVB control at TO.

[0152] [Tables5] Photoproducts tested: TT CPD TC CPD CT CPD UVB Control 39.5% ± 4.6 39.7% ± 4.1 65.9% ± 3.5 HEV + UVB Control 14.8% ± 5.5 16.6% ± 5.0 35.0% ± 8.6 Formulation A 30.0% ± 5.3* 34.1% ± 4.9* 58.8% ± 4.4* Formulation B 38.4% ± 5.4*** 35.0% ± 7.9* 45.9% ± 7.9* Formulation C -1.0% ± 9.6 1.8% ± 8.03 -0.5% ± 14.5

[0153] *p<0.05 ; ***p<0.001

[0154] Formulation A containing the 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine at 5% effectively protects against the effects of HEV blue light, as 30% DNA repair is observed for the TT CPD photoproduct.

[0155] Formulation B containing a 4-filter photoprotective system including 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine also effectively protects against the effects of HEV blue light, DNA repair of 39% is observed for the TT CPD photoproduct.

[0156] On the other hand, Formulation C not containing 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine has no significant effect on the deleterious effects of HEV blue light.

[0157] Similar results are observed for the TC CPD and CT CPD photoproducts.

[0158] The inventors therefore demonstrate that only formulations containing 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine make it possible to protect against damage due to HEV blue light and to protect DNA damage repair enzymes.

[0159] It is important to remember that these DNA lesions are responsible for the transformation of keratinocytes in an "atypical" manner, leading to a proliferation of keratinocytes which results in actinic keratosis.

[0160] The inventors therefore demonstrate that formulations containing 5,6,5',6'-tetraphenyl-3,3'-(l,4-phenylene)-bis[l,2,4]triazine are capable of preventing and limiting the formation of pre-cancerous skin lesions of the actinic keratosis type. Example 2: Clinical study on healthy volunteers

[0161] 2.1. Study without application of composition according to the invention

[0162] This study is conducted on 3 healthy volunteers. Each volunteer is exposed to lo- support in 2 distinct areas on the back, namely: - A zone A exposed only to UVB radiation according to the UVB radiation stress conditions of the protocol below; - A zone B exposed to HEV blue light and UVB radiation according to the protocol below. Protocol

[0163] Patients are exposed to stress sequences with HEV blue light (60 J / cm² for each sequence), twice a day (the sequences being spaced approximately 4 hours apart) for 3 consecutive days, in order to mimic real-life exposure conditions. Approximately 30 minutes after the 6th sequence, stress with UVB radiation is administered (150 mJ / cm²).

[0164] Biopsies with a diameter of approximately 4 mm were taken from areas A and B. They were collected only after 48 hours to evaluate the potential effect of HEV blue light on DNA repair. To limit the number of biopsies, no samples were taken at T0. Results

[0165] The photoproduct levels (expressed as photoproduct per million normal bases) in the biopsies of the 3 donors are reported in Table 6 below.

[0166] [Tableauxô] Samples TT CPD TC CPD CT CPD Patient 1, zone A 8.16 1.30 0.65 Patient 1, zone B 11.33 5.74 0.77 Patient 2, zone A 6.49 4.02 0.32 Patient 2, zone B 7.69 3.06 0.12 Patient 3, zone A 4.04 2.37 0.00 Patient 3, zone B 5.34 2.53 0.00

[0167] Analyses show that a satisfactory amount of DNA was obtained, on average 5pg per biopsy.

[0168] Table 7 below presents the average values ​​on the 3 patients in TT CPD following UVB stress, preceded or not by HEV blue light stress.

[0169] [Tables?] Condition / Parameter TT CPD UVB Stress 6.23 ±1.2 per million normal bases (B) HEV Stress + UVB Stress 8.12 ± 1.7 per million normal bases (HB) Ratio (HB-B) / Bxl00 30%

[0170] The averaged values ​​above clearly demonstrate a higher residual CPD TT rate when the skin is pre-exposed to HEV blue light (zone B) before exposure to UVB radiation. This difference in the CPD rate observed at 48 hours between the two zones reveals that there was approximately 30% greater DNA damage repair in the absence of HEV blue light exposure.

[0171] 2.2. Study with application of composition according to the invention

[0172] This study is conducted on healthy volunteers with phototype III or IV skin. Each volunteer is exposed locally to 4 distinct areas on the back, namely: • Zone A exposed only to HEV blue light; • Zone B exposed only to UVB radiation according to the conditions stress from UVB radiation as per the protocol in section 2.1 above; • A zone C exposed to HEV blue light and UVB radiation according to the protocol in section 2.1 above; • A zone D exposed to HEV blue light and UVB radiation according to the protocol in section 2.1 above, the exposure to HEV blue light being carried out after application of formulation B to zone C (see table 2).

[0173] Measurements of pigmentation and erythema are carried out at 20h and 48h after the end of exposure to UVB radiation.

[0174] Biopsies with a diameter of approximately 4 mm were taken from areas A and B. They were collected only 48 hours after the end of exposure to UVB radiation to evaluate the potential effect of HEV blue light on DNA repair. To limit the number of biopsies, no samples were taken at T0. Bibliographical references

[0175] • Dréno et al. 2014, J Eur Acad Dermatol Venereol, 28, 1141-1149. • Guiraud et al. 2014, Int J Cosmet Sci, 36, 485-493. • Marzouki et al. 2017, Life Sci, 188, 10-16. • Wemer et al. 2013, Br J Dermatol, 169, 502-518

Claims

Claims

1. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for use in the prevention and / or treatment of a pre-cancerous skin lesion or a cancerous skin lesion.

2. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for use according to claim 1, characterized in that the pre-cancerous skin lesion is an actinic keratosis and the pre-cancerous skin lesion is a carcinoma, in particular a squamous cell carcinoma.

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 for use in the prevention and / or treatment of a pre-cancerous skin lesion or a cancerous skin lesion.

4. Composition for use according to claim 3, characterized in that the pre-cancerous skin lesion is an actinic keratosis and the pre-cancerous skin lesion is a carcinoma, in particular a squamous cell carcinoma.

5. Composition for use according to claim 3 or 4, characterized in that it comprises a photoprotective system consisting of: (a) 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine, (b) 2,4-bis[4-(2-ethylhexyloxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, (c) hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, and (d) ethylhexyl triazone or diethylhexyl butamido triazone, the photoprotective system representing between 4% and 25% by weight relative to the total weight of the composition, said composition not comprising any sunscreen other than those constituting said photoprotective system.

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

7. Composition for 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 use according to any one of claims 3 to 7, characterized in that the 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 use according to any one of claims 3 to 9, characterized in that the sunscreen (d) is ethylhexyl triazone.

11. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for use in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in repair of DNA damage in skin cells.

12. 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 use in the repair of DNA damage in skin cells and / or in the prevention and / or reduction of a deficiency in the repair of DNA damage in skin cells.

13. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for its use according to claim 11 or composition for its use according to claim 12, characterized in that the DNA lesions are photoinduced, in particular by UV radiation.

14. 5,6,5',6'-tetraphenyl-3,3'-(1,4-phenylene)-bis[1,2,4]triazine for use according to claim 11 or 13 or composition for use according to claim 12 or 13, characterized in that the DNA damage repair deficit is due to exposure of skin cells to high energy visible blue light.