Topical formulation comprising binimetinib

Abstract

The present invention relates to a topical composition comprising: - binimetinib or a pharmaceutically acceptable salt thereof; - water in an amount of at least 40% by weight relative to the total weight of the composition; and - a polar organic solvent in an amount less than or equal to 55% by weight relative to the total weight of the composition.

Description

Title of the invention: Topical formulation comprising binimetinib FIELD OF THE INVENTION

[0001] The invention relates to a topical formulation comprising binimetinib or a pharmaceutically acceptable salt thereof, water and a polar organic solvent. STATE OF THE ART

[0002] Binimetinib is a MEK inhibitor used particularly in the treatment of cancer (Tran & Cohen 2020) usually administered orally in the form of a tablet. For certain therapeutic indications, and in particular for skin diseases, however, topical application of the product is desirable.

[0003] Topical compositions are generally compositions comprising a large amount of water. It is known that binimetinib has almost zero solubility in water and is very poorly soluble in many conventional solvents. Therefore, it is not easy to solubilize binimetinib in a medium containing water without having recrystallization of the binimetinib during storage. Also, to overcome the drawback of crystallization, a large amount of solvent could be used. However, when used in topical application, a very large amount of solvent, in particular greater than 60% by weight relative to the total weight of the composition, can cause skin disorders such as, for example, skin irritations.

[0004] Thus, international application WO2020 / 106304 describes gelled topical formulations comprising a MEK inhibitor, which contain 70% to 99% by weight of an organic solvent and which are essentially free of water. These formulations contain a large amount of C2 to C6 alcohol, and in particular ethanol, which therefore makes them irritating to the skin.

[0005] There is therefore a need for new topical compositions based on binimetinib or a pharmaceutically acceptable salt thereof with improved skin tolerance. These compositions must be stable both physically (no recrystallization of binimetinib) and chemically (no degradation of binimetinib). These compositions should also have a texture that is pleasant for the consumer. Summary of the invention

[0006] The present invention therefore relates to compositions making it possible to solubilize an effective quantity of binimetinib or a pharmaceutically acceptable salt thereof, while keeping a sufficient quantity of water making it possible to provide textures light with good cosmeticity, i.e. ease of application and a pleasant feel. They also allow for better tolerance of the composition by patients in topical application compared to compositions with a significant amount of organic solvent.

[0007] The inventors have thus developed topical compositions based on at least 40% by weight, relative to the total weight of the composition, of water allowing good solubilization of the active ingredient, namely binimetinib or a pharmaceutically acceptable salt thereof, thanks to the presence of a polar organic solvent and good penetration of the active ingredient into the skin without however presenting major systemic passage.These compositions are physically stable (in particular from a macroscopic and microscopic point of view - absence of recrystallization of binimetinib or a pharmaceutically acceptable salt thereof at T0 and over time up to at least 1 month, in particular at least 2 months, preferably at least 3 months) and chemically stable (no degradation of binimetinib or a pharmaceutically acceptable salt thereof observed by dosage), and are well tolerated thanks to a limited presence of the polar organic solvent (less than 50% by weight relative to the total weight of the composition).

[0008] The present invention thus relates to a topical composition comprising:

[0009] - binimetinib or a pharmaceutically acceptable salt thereof,

[0010] - water in an amount of at least 40% by weight relative to the total weight of the composition, and

[0011] - a polar organic solvent in an amount less than or equal to 55% (in particular less than or equal to 52% or 51%) by weight relative to the total weight of the composition.

[0012] According to a preferred embodiment, the composition according to the invention is free of ethanol, more particularly of C2 to C6 and in particular C1 to C6 alkyl alcohol.

[0013] The composition according to the invention is advantageously free of chloroform.

[0014] According to another preferred embodiment, the composition according to the invention is free of chloroform and ethanol, and more particularly of C2 to C6 and in particular C1 to C6 alkyl alcohol.

[0015] According to another preferred embodiment, the composition according to the invention is free from solvents having a flash point below 23°C such as for example ethanol, acetone, diethyl ether, etc. This makes it possible to secure the industrial manufacture and distribution of the composition according to the invention.

[0016] According to another preferred embodiment, the composition according to the invention is free from chloroform and solvents having a flash point below 23°C such as for example ethanol, acetone, diethyl ether, etc. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0017] For the purposes of the present invention, the term "a" or "an", as in the expression "a polar organic solvent", means 1 or more.

[0018] By "topical composition" is meant that the composition according to the invention is formulated so that it can be administered by topical application to the skin or mucous membranes.

[0019] By "stable" is meant that the composition according to the invention is physically and / or chemically stable, for at least 1 month, in particular for at least 2 months, preferably for at least 3 months.

[0020] By "physically stable" is meant that the binimetinib or a pharmaceutically acceptable salt thereof is solubilized in the composition according to the invention, and is therefore not in a crystallized form. The solubilization of the binimetinib or the pharmaceutically acceptable salt thereof can be verified macroscopically with the naked eye and / or microscopically using an optical microscope, in particular at a magnification of 100 or 400, more particularly 400.

[0021] By "chemically stable" is meant that the binimetinib or a pharmaceutically acceptable salt thereof does not degrade in the composition. This means in particular that the amount of binimetinib or a pharmaceutically acceptable salt thereof in the composition does not decrease over time.

[0022] By "pharmaceutically acceptable" is meant that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for pharmaceutical use.

[0023] By “pharmaceutically acceptable salts” is meant in particular salts formed with a pharmaceutically acceptable acid (organic or inorganic) or base (organic or inorganic) as defined above. Examples of pharmaceutically acceptable acids that may be cited are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, trimethylacetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid, etc. Salts formed with pharmaceutically acceptable bases may be, for example, an ammonium salt; an alkali metal salt (e.g., a sodium or potassium salt); an alkali-earth metal salt (e.g., a calcium or magnesium salt); a zinc salt; a silver salt; an aluminum salt; a salt formed with an organic base such as dicyclohexylamine, N-methyl-D-glucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)methylamine(tromethamine); or a salt formed with an amino acid such as arginine, lysine, etc.

[0024] By "approximately" is meant in the present description that the value concerned may be 10% lower or higher, in particular 5%, in particular 1%, than the indicated value.

[0025] 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 with the ambient air a gaseous mixture which ignites on contact with a flame or a hot spot (also called a pilot flame), but insufficient for combustion to propagate by itself in the absence of the pilot flame. According to Regulation (EC) No. 1272 / 2008 on the classification, labeling and packaging of substances and mixtures, a substance having a PE of less than 23 °C belongs to category 1 "extremely flammable" or category 2 "highly flammable".

[0026] By “buffering agent” is meant any agent making it possible to keep the pH of the composition approximately constant.

[0027] By "fatty acid" is meant a carboxylic acid of formula R'CO2H where R1 represents a hydrocarbon chain, linear or branched, preferably linear, saturated or unsaturated (i.e. comprising one or more, in particular 1, 2 or 3, C=C double bonds), optionally substituted by an OH group. The fatty acid will advantageously comprise from 6 to 24, preferably from 8 to 22, and more preferably from 8 to 18 carbon atoms. It may be, for example, a stearic, oleic, lauric or caprylic acid. It may also be ricinoleic acid.

[0028] By "fatty alcohol" is meant an alcohol of formula R2OH where R2 represents a hydrocarbon chain, linear or branched, preferably linear, saturated or unsaturated (i.e. comprising one or more, in particular 1, 2 or 3, C=C double bonds). The fatty alcohol will advantageously comprise from 6 to 24, in particular from 8 to 22, in particular from 10 to 20, and preferably from 16 to 18 carbon atoms. It may be, for example, a cetyl or stearyl alcohol.

[0029] By “ethoxylated” is meant that the molecule comprises one or more ethoxyl units (-OCH2CH2-), in particular from 2 to 40, for example from 2 to 30.

[0030] By "emulsion" is meant a composition comprising a heterogeneous mixture of two immiscible liquid substances (generally an aqueous phase and an oily phase also called a fatty phase), one being dispersed in the form of droplets in the other which constitutes a continuous phase.

[0031] By "oil-in-water emulsion" is meant a composition comprising an oily phase dispersed in the form of droplets in a continuous aqueous phase. The oily phase will therefore comprise an oil and the aqueous phase will therefore comprise water.

[0032] By "water-in-oil emulsion" is meant a composition comprising an aqueous phase dispersed in the form of droplets in a continuous oily phase. The oily phase will therefore comprise an oil and the aqueous phase will therefore comprise water.

[0033] By “oil” is meant a fatty substance which is in a liquid state at room temperature (approximately 25°C) and which does not mix with water.

[0034] By “micellar solution” is meant a solution comprising micelles.

[0035] By "micelle" is meant a spheroidal aggregate of molecules having a head hydrophilic polar chain directed towards the solvent of the solution (usually water) and a hydrophobic chain directed towards the interior of the aggregate.

[0036] All percentages are by weight relative to the total weight of the composition unless otherwise indicated. Composition

[0037] The composition according to the invention is a topical composition which may in particular be in the form of a solution, for example a micellar solution, a gel such as a foaming gel or mousse, a milk, an emulsion, etc.

[0038] The composition according to the invention will be more particularly stable, as defined above, for at least 1 month, in particular for at least 2 months, preferably for at least 3 months.

[0039] The composition according to the invention comprises binimetinib of the following structure:

[0040] or one of its pharmaceutically acceptable salts.

[0041] Binimetinib is also known as ARRY-162, MEK162, 5-((4-bromo-2-fluorophenyl)arnino)-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide and 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide.

[0042] Methods for preparing binimetinib or its pharmaceutically acceptable salts are described in particular in WO 03 / 077914 (example 18, compound 29111).

[0043] In one embodiment, binimetinib is in free base form. In another embodiment, binimetinib is in the form of a pharmaceutically acceptable salt of binimetinib. In one embodiment, binimetinib is introduced into the composition in crystalline form. Crystallized binimetinib and its methods of preparation are described in particular in WO 2014 / 063024.

[0044] The pharmaceutically acceptable salt of binimetinib may more particularly be a hydrochloride or a sulfate of binimetinib. Other examples of pharmaceutically acceptable salts of binimetinib are described in WO 03 / 077914.

[0045] The composition according to the invention advantageously comprises at least 0.01%, preferably from 0.01% to 5%, in particular from 0.03% to 3%, in particular from 0.05% to 2%, in particular from 0.05% to 1%, in particular from 0.05% to 0.5%, in particular from 0.05% to 0.1%, by weight of binimetinib or a pharmaceutically acceptable salt thereof relative to the total weight of the composition. In one embodiment, the composition according to the invention comprises approximately 0.05%, 0.1%, 0.15%, 0.3% or 1.5% by weight of binimetinib or a pharmaceutically acceptable salt thereof by weight relative to the total weight of the composition.

[0046] The polar organic solvent according to the invention advantageously makes it possible to solubilize at room temperature (in particular at 20-25°C, more particularly at approximately 20°C) at least 1 mg, in particular at least 2 mg, in particular at least 3 mg, in particular at least 4 mg, in particular at least 5 mg, in particular at least 6 mg, in particular at least 7 mg, in particular at least 8 mg, in particular at least 9 mg, at least 10 mg, including at least 12 mg, including at least 15 mg of binimetinib per mL of polar organic solvent and for example at most 25 mg of binimetinib per mL of polar organic solvent, in particular from 2 mg to 25 mg, in particular from 5 mg to 25 mg, in particular from 10 mg to 25 mg, in particular from 12 mg to 25 mg, in particular from 15 mg to 25 mg of binimetinib per mL of said polar organic solvent. The solubilization of binimetinib can be verified macroscopically with the naked eye and / or microscopically using an optical microscope (in particular at a magnification of 100 or 400, more particularly 400), i.e. the absence of crystals or precipitate is observed.

[0047] The polar organic solvent is in particular selected from the group consisting of acetonitrile, polyethylene glycol 400 (also called Macrogol 400 or PEG 400), diethylene glycol monoethyl ether (also called 2-(2-ethoxy-ethoxy)ethanol), dimethylisosorbide, propylene glycol, polysorbates (eg polysorbate 80), ethoxylated fatty alcohols, ethoxylated fatty acids, fatty acids ethoxylated and etherified by an alkyl or alkenyl group (for example C12 to C22, preferably C14 to C18), fatty acids ethoxylated and esterified by a CO-alkyl or CO-alkenyl group (for example with a C12 to C22, preferably C14 to C18 alkyl or alkenyl), fatty acid esters and propylene glycol, ethoxylated esters of fatty acids (preferably C8 to C18) and glycerol, polyglycerol, propylene glycol, polyethylene glycol or sorbitan, and mixtures thereof.The polar organic solvent may be chosen in particular from polyethylene glycol 400 (also known as Macrogol 400), diethylene glycol monoethyl ether, polypropylene glycol, polysorbate 80, PEG-35 castor oil, propylene glycol monolaurate, propylene glycol monocaprylate, and mixtures thereof. Preferably, the polar organic solvent may be selected from polyethylene glycol 400 (also known as Macrogol 400), diethylene glycol monoethyl ether, polypropylene glycol, polysorbate 80, and mixtures thereof.

[0048] Preferably, the polar organic solvent comprises a main polar organic solvent and optionally a co-solvent,

[0049] the main polar organic solvent being a polar organic solvent making it possible to solubilize at room temperature (in particular at 20-25°C, more particularly at approximately 20°C) at least 10 mg, in particular at least 12 mg, in particular at least 15 mg of binimetinib per mL of main polar organic solvent and for example at most 25 mg of binimetinib per mL of polar organic solvent, in particular from 10 mg to 25 mg, in particular from 12 mg to 25 mg, in particular from 15 mg to 25 mg, in particular from 20 mg to 25 mg of binimetinib per mL of said main polar organic solvent,

[0050] the co-solvent being a polar organic solvent making it possible to solubilize at room temperature (in particular at 20-25°C, more particularly at approximately 20°C) from 1 mg to less than 10 mg, in particular from 2 mg to less than 10 mg, in particular from 3 mg to less than 10 mg of binimetinib per mL of co-solvent.

[0051] The main polar organic solvent according to the invention is in particular selected from the group consisting of acetonitrile, polyethylene glycol 400 (also called Macrogol 400 or PEG 400), diethylene glycol monoethyl ether (also called 2-(2-ethoxy-ethoxy)ethanol), dimethylisosorbide and mixtures thereof.

[0052] In one embodiment, the main polar organic solvent according to the invention consists of polyethylene glycol 400 (also known as Macrogol 400) and / or diethylene glycol monoethyl ether, preferably consists of diethylene glycol monoethyl ether.

[0053] The co-solvent may in particular be chosen from the group consisting of propylene glycol, polysorbates (e.g. polysorbate 80), ethoxylated fatty acids (e.g. PEG-35 castor oil), esters (mono or di-esters) of fatty acid and propylene glycol, ethoxylated esters of fatty acid (preferably C8 to C18) and glycerol, polyglycerol, propylene glycol, polyethylene glycol or sorbitan, and mixtures thereof.

[0054] Thus, the co-solvent may be an amphiphilic molecule (amphiphilic co-solvent) also having surfactant properties, in particular when the co-solvent is chosen from the group consisting of polysorbates (e.g. polysorbate 80), ethoxylated fatty acids (e.g. PEG-35 castor oil), esters (mono or di-esters) of fatty acid and propylene glycol, non-ethoxylated esters of fatty acids (preferably C8 to C18) and glycerol, polyglycerol, propylene glycol, polyethylene glycol or sorbitan, and mixtures thereof.

[0055] The co-solvent may be chosen in particular from the group consisting of propylene glycol, polysorbates (e.g. polysorbate 80), ethoxylated fatty acids (e.g. PEG-35 castor oil), esters (mono or di-esters) of fatty acid and propylene glycol, and mixtures thereof. The co-solvent may be chosen in particular from propylene glycol, polysorbate 80, PEG-35 castor oil, propylene glycol monolaurate, propylene glycol monocaprylate, and mixtures thereof. In particular, the co-solvent will be propylene glycol, optionally in a mixture with polysorbate 80.

[0056] Preferably, the primary polar organic solvent is polyethylene glycol 400, diethylene glycol monoethyl ether, or a mixture thereof; and the co-solvent is propylene glycol, polysorbate 80, or a mixture thereof.

[0057] The quantity of the polar organic solvent in the topical composition according to the invention is less than or equal to 55%, in particular less than or equal to 52%, in particular less than or equal to 51%, in particular less than or equal to 50%, in particular less than or equal to 40%, in particular less than or equal to 35% by weight relative to the total weight of the composition.

[0058] The amount of the polar organic solvent in the topical composition according to the invention is more particularly from 3% to 55%, in particular from 3% to 52%, in particular from 3% to 51%, in particular from 8% to 51%, in particular from 8% to 40%, in particular from 8% to 35%, in particular from 10% to 33%, in particular from 20% to 32% by weight relative to the total weight of the composition. The amount of the polar organic solvent may vary depending on the type of topical composition desired as indicated in the remainder of this application.

[0059] The amount of the main polar organic solvent in the topical composition according to the invention is more particularly from 3% to 55%, in particular from 3% to 52%, in particular from 3% to 51%, in particular from 8% to 51%, in particular from 8% to 40%, in particular from 8% to 35%, in particular from 10% to 33%, in particular from 20% to 32% by weight relative to the total weight of the composition. The amount of the main polar organic solvent may vary depending on the type of topical composition desired as indicated in the remainder of this application.

[0060] The amount of co-solvent in the topical composition according to the invention is more particularly from 0% to 25%, in particular from 0% to 20% or from 3% to 20%, in particular from 0% to 15% or from 5% to 15%, in particular from 0% to 12% or from 7% to 12% by weight relative to the total weight of the composition. The amount of co-solvent may vary depending on the type of topical composition desired as indicated in the remainder of this application.

[0061] The mass ratio of co-solvent to main polar organic solvent is advantageously at most 0.8, in particular at most 0.7, in particular at most 0.6, more particularly at most 0.5. This ratio can also be 0 (when there is no co-solvent).

[0062] It should be noted that the polar organic solvent, and in particular the main polar organic solvent and / or the co-solvent, may have properties other than those of solubilizing binimetinib in the composition, in particular surfactant or other properties, which a person skilled in the art will be able to determine.

[0063] The composition according to the invention comprises water.

[0064] In one embodiment, the amount of water in the topical composition according to the invention is greater than or equal to 40% or 45%, preferably is from 40% to 80%, in particular from 45% to 75%, more particularly from 45% to 70%, by weight relative to the total weight of the composition.

[0065] A high concentration (of at least 40%) of water makes it possible to have a topical composition better tolerated by the skin of patients because it is less irritating than a composition having a high concentration of solvent.

[0066] According to a particular embodiment, the composition according to the invention contains: • 8% to 52%, in particular 8% to 51%, 8% to 40%, in particular 8% to 35%, in particular 10% to 33%, in particular 20% to 32%, by weight of the at least one polar organic solvent relative to the total weight of the composition; and • 40% to 80%, in particular 45% to 75%, more particularly 45% to 70%, in weight of water, relative to the total weight of the composition.

[0067] The composition according to the invention may also comprise a surfactant, a preservative, a buffering agent, a gelling agent, a consistency agent other than a gelling agent, a stabilizing agent, an oil or a mixture thereof.

[0068] The composition according to the invention can thus comprise a surfactant, also referred to without distinction as emulsifier in the present application.

[0069] The surfactant may be an amphiphilic co-solvent (surfactant C), another surfactant (surfactant T) or a mixture thereof.

[0070] The surfactant may in particular be chosen from the group consisting of polysorbates (such as polysorbate 80), ethoxylated fatty alcohols (such as macrogol cetostearyl ethers (in particular macrogol cetostearyl ether 6 or 25)), ethoxylated fatty acids, fatty acids ethoxylated and etherified by an alkyl or alkenyl group (for example C12 to C22, preferably C14 to C18), fatty acids ethoxylated and esterified by a CO-alkyl or CO-alkenyl group (for example with a C12 to C22, preferably C14 to C18, alkyl or alkenyl), esters (mono or di-esters) of fatty acid and propylene glycol, ethoxylated esters of fatty acids and glycerol, propylene glycol, polyethylene glycol, or sorbitan (e.g. a mixture of glycerides (mono-, di- and triglycerides) of caprylic esters of polyethylene glycol), fatty alcohol sulfates e.g. sodium or potassium (e.g.sodium lauryl sulfate), ethers (especially alkyl, preferably C1 to C6) of fatty alcohol, copolymers of ethylene oxide and propylene oxide (Poloxamer® or Pluronic® type), glucoside derivatives such as alkylglucosides and alkylpolyglucosides, having C8 to C22 alkyl hydrocarbon chains with numbers of glucose units from 1 to 7, for example, octylglucoside, decylglucoside, lauryglucoside, myristylglucoside, palmitylglucoside, stearylglucoside, oleylglucosides, behenylglucosides (in particular glucoside derivatives having C10 to C14 alkyl hydrocarbon chains with a number of glucose units from 1 to 3 such as decylglucoside (Oramix™ NS 10, Seppic), and mixtures thereof. .

[0071] Surfactant C (amphiphilic co-solvent) may more particularly be chosen from the group consisting of polysorbates such as polysorbate 80, ethoxylated fatty acids, esters (mono or diesters) of fatty acid and propylene glycol, ethoxylated esters of fatty acids and glycerol, propylene glycol, polyethylene glycol, or sorbitan (for example a mixture of glycerides (mono-, di- and tri-glycerides) of caprylic esters of polyethylene glycol), and mixtures thereof. It may be chosen in particular from the group consisting of polysorbates (eg polysorbate 80), ethoxylated fatty acids, esters (mono or diesters) of fatty acid and propylene glycol, and mixtures thereof. It may be chosen in particular from polysorbate 80, PEG-35 castor oil, propylene glycol monolaurate, propylene glycol monocaprylate, and mixtures thereof. In particular, it will be polysorbate 80.

[0072] The surfactant T may more particularly be chosen from the group consisting of ethoxylated fatty alcohols (such as macrogol cetostearyl ethers (in particular macrogol cetostearyl ether 6 or 25)), fatty acids ethoxylated and etherified by a alkyl or alkenyl group (e.g. C12 to C22, preferably C14 to C18), fatty acids ethoxylated and esterified with a CO-alkyl or CO-alkenyl group (e.g. with a C12 to C22, preferably C14 to C18 alkyl or alkenyl), fatty alcohol sulfates e.g. sodium or potassium (e.g.sodium lauryl sulfate), ethers (especially alkyl, preferably C1 to C6) of fatty alcohol, copolymers of ethylene oxide and propylene oxide (Poloxamer® or Pluronic® type), glucoside derivatives such as alkylglucosides and alkylpolyglucosides, having C8 to C22 alkyl hydrocarbon chains with numbers of glucose units from 1 to 7, for example, octylglucoside, decylglucoside, lauryglucoside, myristylglucoside, palmitylglucoside, stearylglucoside, oleylglucosides, behenylglucosides (in particular glucoside derivatives having C10 to C14 alkyl hydrocarbon chains with a number of glucose units from 1 to 3 such as decylglucoside (Oramix™ NS 10, Seppic), and mixtures thereof. may in particular be a macrogol cetostearyl ether (notably macrogol cetostearyl ether 6 or 25).

[0073] In one embodiment, the surfactant is selected from the group consisting of ethoxylated fatty alcohols (such as macrogol cetostearyl ethers (in particular macrogol cetostearyl ether 6 or 25)), polysorbates (in particular polysorbate 80) and mixtures thereof. In another embodiment, the surfactant is selected from the group consisting of macrogol cetostearyl ethers (in particular macrogol cetostearyl ether 6 or 25) and mixtures thereof. In another embodiment, the surfactant is a polysorbate and more particularly polysorbate 80.

[0074] In one embodiment, the amount of surfactant included in the composition according to the invention is from 0% to 15%, in particular from 0% to 5% by weight relative to the total weight of the composition. This amount of surfactant includes the amount of surfactant C (amphiphilic co-solvent) and surfactant T. Thus, a person skilled in the art will know how to adapt the amount of surfactant T depending on the presence or absence of amphiphilic co-solvent (surfactant C).

[0075] In order to protect the composition according to the present invention from the risks of microbial contamination, a preservative may be added. Suitable preservatives for implementing the composition according to the invention may be chosen from conventional preservatives for topical medicinal products such as boric acid, benzoic acid, lactic acid, sorbic acid and their pharmaceutically acceptable salts, benzyl alcohol, 2-phenoxyethanol, p-chloro-m-cresol, alkyl esters, preferably C1-C6, of parahydroxybenzoic acid, also called parabens (e.g. methylparaben, ethylparaben, propylparaben, butylparaben), and imidazolidinyl urea and its derivatives. (eg dimethylol dimethyl hydantoin also called DMDM ​​hydantoin or diazolidinyl urea), chlorphenesin, or mixtures thereof.

[0076] Advantageously, the preservatives are chosen from the group consisting of esters of parahydroxybenzoic acid (in particular propyl parahydroxybenzoate and / or methyl parahydroxybenzoate, i.e. propylparaben and / or methylparaben), alcohols (in particular 2-phenoxyethanol) and mixtures thereof. Preferably, the preservatives are chosen from the group consisting of esters of parahydroxybenzoic acid (in particular propyl parahydroxybenzoate and / or methyl parahydroxybenzoate), 2-phenoxyethanol and mixtures thereof.

[0077] The amount of preservative included in the composition according to the invention is advantageously less than or equal to 1.5%, in particular less than or equal to 1.25%, in particular less than or equal to 1.0% by weight relative to the total weight of the composition. The amount of preservative will be in particular from 0% to 1.5%, in particular from 0.05% to 1.25%, in particular from 0.1% to 1% by weight relative to the total weight of the composition.

[0078] The composition according to the invention may comprise a buffering agent in order to maintain the pH of the composition approximately constant. The buffering agent may in particular be chosen from the group consisting of hydrated monosodium phosphate, disodium hydrogen phosphate dihydrate, sodium citrate, citric acid and mixtures thereof.

[0079] The amount of buffering agent will be in particular from 0% to 1%, in particular from 0.005% to 0.5%, in particular from 0.04% to 0.1% by weight relative to the total weight of the composition. The pH of the composition according to the invention will advantageously be from 5 to 8, for example from 5 to 6, from 6 to 7 or from 7 to 8.

[0080] The composition according to the invention may also comprise a gelling agent to give the composition the consistency of a gel. The gelling agent is in particular chosen from the group consisting of gelling agents extracted from plants (in particular pectins, alginates, carrageenans, agar-agar, starches), xanthan gum, gelling agents derived from celluloses and more particularly cellulose ethers (in particular carboxymethylcellulose (in particular sodium), methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), carbomers (acrylic acid polymers), poloxamers, and mixtures thereof.

[0081] The amount of gelling agent included in the composition according to the invention is advantageously from 0% to 5%, in particular from 0.5% to 3%, for example from 1% to 2% by weight relative to the total weight of the composition.

[0082] The composition according to the invention may also comprise a consistency agent (other than a gelling agent), the consistency agent making it possible to improve the consistency or texture of the composition. The consistency agent is in particular selected from the group consisting of fatty alcohols such as cetyl, stearyl or cetostearyl alcohol, high molecular weight macrogol (average molecular weight greater than 1000 g / mol) (e.g. PEG1000 to PEG 20000), fatty acids, vegetable, mineral or synthetic waxes (e.g. beeswax, cetyl palmitate, microcrystalline waxes), butters such as shea or cocoa butter, and mixtures thereof.

[0083] The amount of consistency agent included in the composition according to the invention is advantageously from 0% to 15%, in particular from 1% to 10%, in particular from 5% to 8% by weight relative to the total weight of the composition.

[0084] The composition according to the invention may also comprise a stabilizing agent in order to help maintain the physical structure of the composition over time. In a particular embodiment of the invention, the stabilizing agent is in particular Sepineo™ P600 (mixture of Acrylamide, Sodium Acryloyldimethyl Taurate Copolymer, Isohexadecane and Polysorbate 80).

[0085] The amount of stabilizing agent included in the composition according to the invention will be in particular from 0% to 5%, in particular from 0.01% to 2%, in particular from 0.1% to 1% by weight relative to the total weight of the composition.

[0086] The composition according to the invention may further comprise a colorant, a moisturizing, soothing, healing, exfoliating, or antioxidant active agent or a mixture thereof and / or any other additive or adjuvant not detrimental to the stability and effectiveness of the compositions according to the invention.

[0087] The composition according to the invention may also comprise an oil. An oil is more particularly a fatty substance that is liquid at room temperature, in particular at 20°C. The oil according to the invention may in particular be chosen from the group consisting of triglycerides, monoglycerides, diglycerides, esters (in particular alkyl, in particular C1 to C25) of fatty acids, natural oils (e.g. vegetable or mineral) hydrogenated or not (e.g. paraffin (in particular liquid paraffin), polybutenes, polyisobutenes), synthetic oils (e.g. hydrocarbon oils, aliphatic, in particular cyclic, linear or branched (saturated or not); perfluorinated or fluorinated oils), volatile or non-volatile silicones, organomodified or not, and mixtures thereof. For example, it may be liquid paraffin, octyldodecyl myristate, isopropyl myristate, glycerol tricaprylate, caprylic-capric triglyceride, and mixtures thereof.

[0088] In one embodiment, the oil according to the invention will in particular be included in the group consisting of liquid paraffin.

[0089] The quantity of oil in a composition according to the invention will in particular be from 5% to 25%, in particular from 10% to 20% by weight relative to the total weight of the composition.

[0090] The composition according to the invention may more particularly be in the form of an emulsion, a gel, or a solution, preferably micellar. Emulsion

[0091] In one embodiment, the composition according to the invention is in the form of an emulsion, and more particularly an oil-in-water or water-in-oil emulsion.

[0092] In one embodiment, the composition in emulsion form according to the invention is an oil-in-water emulsion.

[0093] In one embodiment, the amount of the polar organic solvent in the topical composition in emulsion form according to the invention is from 3% to 40%, in particular from 5% to 35%, in particular from 10% to 33%, in particular from 20% to 32%. The composition may comprise in particular from 3% to 40%, in particular from 5% to 35%, in particular from 10% to 33%, in particular from 20% to 32% of a main polar organic solvent and optionally from 0% to 10%, in particular from 5% to 8% of a co-solvent.

[0094] In this embodiment, the mass ratio of co-solvent to main polar organic solvent is advantageously at most 0.8, in particular at most 0.7, in particular at most 0.6, more particularly at most 0.5. This ratio can also be 0 (when there is no co-solvent).

[0095] The emulsion according to the invention will advantageously comprise an oil and a surfactant. The surfactant may be an amphiphilic co-solvent (surfactant C) and / or another surfactant (surfactant T).

[0096] An oil will more particularly be a fatty substance that is liquid at room temperature, in particular at 20°C. The oil according to the invention may in particular be chosen from the group consisting of triglycerides, monoglycerides, diglycerides, esters (in particular alkyl, in particular C1 to C25) of fatty acids, natural oils (e.g. vegetable or mineral) hydrogenated or not (e.g. paraffin (in particular liquid paraffin), polybutenes, polyisobutenes), synthetic (e.g. hydrocarbon oils, aliphatic, in particular cyclic, linear or branched (saturated or not); perfluorinated or fluorinated oils), volatile or non-volatile silicones, organomodified or not, and mixtures thereof. For example, it may be liquid paraffin, octyldodecyl myristate, isopropyl myristate, glycerol tricaprylate, caprylic-capric triglyceride, and mixtures thereof.

[0097] In one embodiment, the oil according to the invention will in particular be included in the group consisting of liquid paraffin.

[0098] The quantity of oil in an emulsion according to the invention will be in particular from 5% to 25%, in particular from 10% to 20% by weight relative to the total weight of the composition.

[0099] The quantity of water in an emulsion, preferably oil in water, according to the invention is greater than or equal to 40%, preferably greater than or equal to 45% and more preferably from 45% to 80%, in particular from 45% to 75%, in particular from 45% to 70% by weight relative to the total weight of the composition.

[0100] The surfactant may be as defined above. The amount of surfactant present in an emulsion, preferably oil in water, according to the present invention is in particular from 0% to 5%, in particular from 0.5% to 5%, in particular from 1% to 4% by weight relative to the total weight of the composition.

[0101] In one embodiment, the composition in emulsion form according to the invention comprises: - Binimetinib or a pharmaceutically acceptable salt thereof, - A polar organic solvent, in particular a main polar organic solvent and possibly a co-solvent, - A surfactant, which may be an amphiphilic co-solvent (surfactant C) and / or another surfactant (surfactant T), - An oil, and - Water.

[0102] In one embodiment according to the invention, the composition in emulsion form according to the invention comprises: - 0.01% to 5% binimetinib or a pharmaceutically acceptable salt of this one, - 3% to 40% of a polar organic solvent, in particular 3% to 40% of a main polar organic solvent and 0% to 15% of a co-solvent, - 0.5% to 5% of a surfactant, - 5% to 25% of an oil, and - At least 40% water,

[0103] the percentages being given by weight relative to the total weight of the composition.

[0104] In another embodiment according to the invention, the composition in the form of an emulsion according to the invention comprises: - 0.05% to 2% binimetinib or a pharmaceutically acceptable salt of this one, - 10% to 35% of a polar organic solvent, in particular 10% to 35% of a main polar organic solvent and 0% to 10% or 5% to 10% of a cosolvent, - 1% to 4% of a surfactant, - 10% to 20% of an oil, and - At least 40% water,

[0105] the percentages being given by weight relative to the total weight of the composition.

[0106] In one embodiment according to the invention, the composition in the form of an emulsion according to the invention comprises: - 0.05% to 0.1% binimetinib or a pharmaceutically acceptable salt of this one, - 5% to 32% of a polar organic solvent, in particular 10% to 32% of a main polar organic solvent and 0% to 10% or 5% to 10% of a cosolvent, - 1.5% to 3.5% of a surfactant, - 10% to 20% of an oil, and - At least 40% water,

[0107] the percentages being given by weight relative to the total weight of the composition

[0108] The composition according to the invention in the form of an emulsion according to the invention may further comprise at least one ingredient chosen from a preservative, a buffering agent, a consistency agent (preferably other than a gelling agent), a stabilizing agent and their mixtures

[0109] The composition according to the invention in the form of an emulsion according to the invention may comprise a preservative, in particular as defined above. The amount of preservative will be in particular from 0% to 1.5%, in particular from 0.05% to 1.25%, in particular from 0.1% to 1% by weight relative to the total weight of the composition.

[0110] The composition according to the invention in the form of an emulsion according to the invention may comprise a buffering agent, in particular as defined above. The amount of buffering agent will be in particular from 0% to 1%, in particular from 0.005% to 0.5%, in particular from 0.04% to 0.1% by weight relative to the total weight of the composition. The pH of the composition according to the invention will advantageously be from 5 to 8, for example from 5 to 6, from 6 to 7 or from 7 to 8.

[0111] The composition according to the invention in the form of an emulsion according to the invention may comprise a consistency agent, in particular as defined above. The consistency agent according to the invention is in particular chosen from the group comprising fatty alcohols including cetostearyl alcohols, synthetic or natural waxes (beeswax, cetyl palmitate, microcrystalline waxes). The quantity of consistency agent will in particular be from 0% to 15%, in particular from 1% to 10%, in particular from 5% to 8% by weight relative to the total weight of the composition.

[0112] The composition according to the invention may also comprise a stabilizing agent. In a particular embodiment of the invention, the stabilizing agent is in particular Sepineo™ P600 (mixture of Acrylamide, Sodium Acryloyldimethyl Taurate Copolymer, Isohexadecane and Polysorbate 80).

[0113] The composition according to the invention in the form of an emulsion according to the invention may comprise a stabilizing agent, in particular as defined above. The amount of stabilizing agent will be in particular from 0% to 5%, in particular from 0.01% to 2%, in particular from 0.1% to 1% by weight relative to the total weight of the composition. Freeze

[0114] In one embodiment, the composition according to the invention is in the form of a gel, also called an aqueous gel due to the high water content.

[0115] In one embodiment, the amount of the polar organic solvent in the topical composition in gel form according to the invention is from 5% to 50%, in particular from 10% to 45%, in particular from 20% to 45%, in particular from 25% to 42%. The composition may comprise in particular from 5% to 50%, in particular from 10% to 45%, in particular from 20% to 45%, in particular from 25% to 42% of a main polar organic solvent and optionally from 0% to 15%, in particular from 5% to 15% of a co-solvent. Preferably, the co-solvent, when present, is propylene glycol.

[0116] In this embodiment, the co-solvent / main polar organic solvent mass ratio is advantageously at most 0.8, in particular at most 0.7, in particular at most 0.6, more particularly at most 0.5. This ratio can also be 0 (when there is no co-solvent).

[0117] The quantity of water included in the composition in the form of gel according to the invention will be in particular from 40% to 80%, in particular from 40% to 70%, in particular from 50% to 60% by weight relative to the total weight of the composition.

[0118] The composition according to the invention in the form of a gel according to the invention will advantageously comprise a gelling agent.

[0119] The gelling agent may be as defined above and in particular chosen from poloxamers, starches, cellulose ethers (e.g. sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), carbomers and mixtures thereof. In one embodiment, the gelling agent is a cellulose ether, in particular hydroxyethylcellulose.

[0120] The amount of gelling agent included in the composition in gel form will be in particular from 0.2% to 5%, in particular from 0.5% to 2%, in particular from 1% to 1.8%, in particular approximately 1.5%.

[0121] In one embodiment, the composition in gel form according to the invention comprises: - Binimetinib or a pharmaceutically acceptable salt thereof, - A polar organic solvent, including a main polar organic solvent and optionally a co-solvent, - A gelling agent - At least 40% water.

[0122] In one embodiment according to the invention, the composition in gel form according to the invention comprises: - 0.01% to 2% binimetinib or a pharmaceutically acceptable salt of this one, - 5% to 50% of a polar organic solvent, in particular 5% to 50% of a main polar organic solvent and 0% to 15% of a co-solvent, - 0.5% to 2% of a gelling agent, and - At least 40% water,

[0123] the percentages being given by weight relative to the total weight of the composition.

[0124] In one embodiment according to the invention, the composition in gel form according to the invention comprises: - 0.05% to 0.5% binimetinib or a pharmaceutically acceptable salt of this one, - 20% to 35% of a polar organic solvent, in particular 20% to 35% of a main polar organic solvent and 0% to 15% or 5% to 15% of a cosolvent, - 0.5% to 2% of a gelling agent, and - At least 40% water,

[0125] the percentages being given by weight relative to the total weight of the composition.

[0126] In one embodiment according to the invention, the composition in gel form according to the invention comprises: - 0.05% to 0.25% binimetinib or a pharmaceutically acceptable salt of this one, - 25% to 32% of a polar organic solvent, in particular 25% to 32% of a main polar organic solvent and 0% to 12% or 7% to 12% of a cosolvent, - 1% to 1.8% of a gelling agent, and - At least 40% water,

[0127] the percentages being given by weight relative to the total weight of the composition

[0128] The composition according to the invention in gel form may further comprise a preservative.

[0129] The composition according to the invention in the form of a gel according to the invention may comprise a preservative, in particular as defined above. The amount of preservative will be in particular from 0% to 1.5%, in particular from 0.05% to 1.25%, in particular from 0.1% to 1% by weight relative to the total weight of the composition. Solution

[0130] In one embodiment, the composition according to the invention is in the form of a solution, in particular a micellar solution.

[0131] In one embodiment, the amount of the polar organic solvent in the topical composition in solution form according to the invention is from 5% to 55%, in particular from 10% to 52%, in particular from 20% to 51%, in particular from 25% to 51%. The composition may comprise in particular from 5% to 55%, in particular from 10% to 52%, in particular from 20% to 51%, in particular from 25% to 51% of a main polar organic solvent and optionally from 0% to 25%, in particular from 5% to 25%, in particular from 10% to 25%, in particular from 15% to 20% of a co-solvent. In this embodiment, the mass ratio of co-solvent / main polar organic solvent is advantageously at most 0.8, in particular at most 0.7, in particular at most 0.6, more particularly at most 0.5. This ratio may also be 0 (when there is no co-solvent).

[0132] In one embodiment, the primary polar organic solvent will be diethylene glycol monoethyl ether.

[0133] The quantity of water in a solution, preferably micellar, according to the invention will be in particular from 40% to 80%, in particular from 45% to 70% by weight relative to the total weight of the composition.

[0134] The composition in the form of a micellar solution will comprise at least one surfactant. Surfactants being molecules having a hydrophilic polar head and a hydrophobic chain, they allow the formation of micelles. The surfactant may be an amphiphilic co-solvent (surfactant C) and / or another surfactant (surfactant T).

[0135] The surfactant is in particular chosen from the group consisting of a polysorbate (eg polysorbate 80), fatty alcohol sulfates, for example sodium or potassium (by sodium lauryl sulfate), ethers (in particular alkyl, preferably C1 to C6) of fatty alcohol, ethoxylated fatty alcohols (such as macrogol cetostearyl ethers (in particular macrogol cetostearyl ether 6 or 25)), and mixtures thereof. Preferably, it is a polysorbate such as polysorbate 80.

[0136] The amount of surfactant included in the composition in the form of a micellar solution according to the invention will be in particular from 2% to 30%, in particular from 5% to 25%, in particular from 10% to 20%, in particular approximately 15% by weight relative to the total weight of the composition.

[0137] In one embodiment, the composition in the form of a micellar solution according to the invention comprises: - Binimetinib or a pharmaceutically acceptable salt thereof, - A polar organic solvent, in particular a main polar organic solvent and possibly a co-solvent, - A surfactant, which may be an amphiphilic co-solvent (surfactant C) and / or another surfactant (surfactant T), and - At least 40% water.

[0138] In one embodiment according to the invention, the composition in the form of a micellar solution according to the invention comprises: 0.01% to 2% binimetinib or a pharmaceutically acceptable salt thereof, 5% to 55% of a polar organic solvent, including 5% to 55% of a main polar organic solvent and 0% to 25% of a co-solvent, 2% to 30% of a surfactant, and At least 40% water,

[0139] the percentages being given by weight relative to the total weight of the composition.

[0140] In one embodiment according to the invention, the composition in the form of a micellar solution according to the invention comprises: 0.05% to 0.5% binimetinib or a pharmaceutically acceptable salt thereof, 10% to 52% of a polar organic solvent, including 10% to 52% of a main polar organic solvent and 0% to 25% or 5% to 25% of a cosolvent, 5% to 25% of a surfactant, and At least 40% water,

[0141] the percentages being given by weight relative to the total weight of the composition.

[0142] In one embodiment according to the invention, the composition in the form of a micellar solution according to the invention comprises: 0.05% to 0.5% binimetinib or a pharmaceutically acceptable salt thereof, 20% to 51% of a polar organic solvent, including 20% ​​to 51% of a main polar organic solvent and 0% to 22% or 15% to 22% of a cosolvent, 10% to 20% of a surfactant, and At least 40% water,

[0143] the percentages being given by weight relative to the total weight of the composition.

[0144] The composition according to the invention in the form of a solution, preferably micellar, may further comprise a preservative.

[0145] The composition according to the invention in the form of a solution, preferably micellar, according to the invention may further comprise a preservative, in particular as defined above. The amount of preservative will in particular be from 0% to 1.5%, in particular from 0.05% to 1.25%, in particular from 0.1% to 1% by weight relative to the total weight of the composition. Applications

[0146] The present invention further relates to a composition according to the invention, for its use as a medicament, more particularly in the treatment of a skin tumor and more particularly in the treatment of skin cancer.

[0147] The present invention also relates to the use of a composition according to the invention, as a medicament, more particularly in the treatment of skin cancer.

[0148] The present invention also relates to the use of a composition according to the invention for the preparation of a medicament intended for the treatment of skin cancer.

[0149] The present invention also relates to a method of treating skin cancer comprising the topical administration of an effective amount of a composition according to the invention to a person in need thereof.

[0150] The cancer can be, for example, a melanoma. EXAMPLES

[0151] Example 1: S olubility of binimetinib and compositions according to the invention 1.1. Solubility data of binimetinib

[0152] The solubility of binimetinib in saturated solution in different solvents was evaluated by UV-HPLC (high performance liquid chromatography coupled with UV detection). The results obtained are presented in Table 1 below. With respect to its capacity to solubilize binimetinib, the solvent is then classified as a “solvent” if it allows solubilizing at least 10 mg / mL of binimetinib, “co-solvent” if it allows solubilizing from 1 mg to less than 10 mg / mL of binimetinib, and “non-solvent” if it allows solubilizing less than 1 mg / mL of binimetinib.

[0153] [Tables 1] Solvent Binimetinib concentration in saturated solution after filtration (mg / mL) Classification PEG 400 15.9 Solvent Diethylene glycol monoethyl ether 10.7 Solvent PEG-3 castor oil 5 7.2 Co-solvent Propylene glycol 3.7 Co-solvent Water <0.1 Non-solvent Medium-chain triglycerides <0.1 Non-solvent

[0154] The solubility results in Table 1 show that binimetinib is practically insoluble in water and the tested oil (medium chain triglycerides). Binimetinib is fairly soluble in PEG 400, and diethylene glycol monoethyl ether. 1.2. Characterization of compositions

[0155] The compositions according to the invention described in the examples of the application are characterized by different criteria detailed below. 1.2.1. Macroscopic appearance

[0156] This visual observation makes it possible to check the homogeneity of the formula. The presence or absence of phase shift is observed. 1.2.2. Microscopic appearance

[0157] Microscopic observation is carried out using an optical microscope (Olympus BX40 x10 and x40 objective), and makes it possible to verify the absence or presence of binimetinib crystals.

[0158] 1.2.3. _ Dosage of the titer of b inimetinib in the compositions

[0159] The dosage of binimetinib in the compositions is carried out by UHPLC-DAD (ultra-high performance liquid chromatography coupled with diode array detection).

[0160] The dosage results are expressed as a percentage relative to the amount of binimetinib at T0. 1.3. Compositions according to the invention 1.3.1. Oil-in-water emulsions

[0161] Different oil-in-water emulsions according to the invention are obtained by the manufacturing process below: • Step 1: Preparation of the aqueous phase and the fatty phase

[0162] In a main beaker Bl, introduce the purified water and the water-soluble components (buffers, preservatives) and heat to 70°C-80°C. Add, if present in the composition, the Sepineo™ P600 while stirring.

[0163] In parallel, heat the fatty phase to 70°C-80°C in a beaker B2 containing the oil, surfactants and consistency agents. • Step 2: Emulsification

[0164] Add the fatty phase from beaker B2 to the main beaker Bl with shear stirring for 10 minutes. • Step 3: Solubilization and introduction of binimetinib

[0165] In a beaker B3, solubilize the binimetinib in the solvent and the co-solvent if present by heating to 70°C with magnetic stirring. Once the binimetinib is solubilized, add the solution from beaker B3 to the main beaker BL. Emulsify at 70°C with shear stirring. • Step 4: Cooling

[0166] Cool to 30°C.

[0167] Table 2 summarizes the qualitative and quantitative compositions of five oil-in-water emulsions (Comp. 1 to Comp. 5) produced.

[0168] [Tables2] Components Function Comp. 1 %w / w Comp. 2 %w / w Comp. 3 %w / w Comp. 4 %w / w Comp. 5%w / w Binimetinib Active 0.1 0.05 0.1 0.1 0.1 Macrogol cetostearyl ether 6 Surfactant 1.5 1.5 1.5 1.5 / Macrogol cetostearyl ether 25 Surfactant 1.5 1.5 1.5 1.5 1.5 Macrogol cetostearyl ether 6 + stearyl alcohol (Emulgade(r) B25) Surfactant / / / / 1.5 Liquid paraffin Oil 12 12 12 17 12 Cetostearyl alcohol Consisting agent 7 7 7 / 7 Purified water Water Qs Qs Qs Qs Qs 2-Phenoxyethanol Preservative 0.7 0.7 0.7 / 0.7 Methylparaben Preservative 0.15 0.15 0.15 0.15 0.15 Propylparaben Preservative 0.03 0.03 0.03 0.03 0.03 Diethylene glycol monoethyl ether Solvent 23.1 10 / 23.1 10 PEG 400 Solvent / / 30 / / Propylene glycol Co-solvent 7.7 / / 7.7 / Sepineo™ P600* Stabilizer / / / 0.25 / Monosodium phosphate dihydrate Buffer / / / 0.07 / Isodium hydrogen phosphate dihydrate Buffer / / / 0.01 /

[0169] * Copolymer of acrylamide and sodium acryloyldimethyltaurate / Isohexadecane & Polysorbate 80

[0170] The compositions thus obtained are immediately characterized (T0) as described in point 1.2. The characteristics obtained are summarized in Table 3 below.

[0171] [Tables3] Physical characterization Comp. 1 Comp. 2 Comp. 3 Comp. 4 Comp. 5 Macroscopic appearance He white cream He white cream He white cream He white cream He white cream Microscopic appearance Solubilized Binimetinib Solubilized Binimetinib Solubilized Binimetinib Solubilized Binimetinib Solubilized Binimetinib

[0172] Compositions having the desired appearance are therefore obtained and in which the binimetinib is well solubilized.

[0173] The physical and chemical stability of the compositions after storage for one month (T1M) and 3 months (T3M) at a temperature of 5°C, 25°C or 40°C was then verified. Table 4 summarizes the evolution of the macroscopic appearance of the emulsions obtained and Table 5 summarizes the evolution of the microscopic appearance of the emulsions obtained.

[0174] [Tables4] Time Temperature Storage Comp. 1 Comp. 2 Comp. 3 Comp. 4 Comp. 5 T1M 5°C White cream White cream White cream White cream White cream 25°C White cream White cream White cream White cream White cream 40°C White cream White cream White cream White cream White cream T3M 25°C White cream White cream White cream / White cream 40°C White cream White cream White cream / White cream

[0175] The compositions according to the invention retain macroscopically the same appearance at 1 or 3 months after their preparation and whatever the storage temperature.

[0176] [Tables5] Time Temperature storage Comp. 1 Comp. 2 Comp. 3 Comp. 4 Comp. 5 T1M 5°C Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib T3M 25°C Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib / Soluble Binimetinib 40°C Soluble Binimetinib Soluble Binimetinib Soluble Binimetinib / Soluble Binimetinib

[0177] The compositions according to the invention retain the same microscopic characteristics (in particular absence of recrystallization of binimetinib) 1 or 3 months after their preparation and whatever the storage temperature.

[0178] Binimetinib was also assayed in the oil-in-water emulsion of composition 5, after 1, 3 and 6 months (T1M, T3M, T6M) at a temperature of 25°C or 40°C. Table 6 represents the evolution of this dosage represented as a percentage of binimetinib compared to the dosage at T0.

[0179] [Tableauxô] Time Storage temperature Comp. 5 T1M 25°C 100% 40°C 100% T3M 25°C 100% 40°C 100% T6M 25°C 100%

[0180] The results obtained allow us to conclude that binimetinib does not degrade in the composition of example 5, even after 1, 3 or 6 months and whatever the storage temperature.

[0181] The present invention surprisingly shows that it is possible, thanks to the presence of certain solvents, to obtain oil-in-water emulsions with a high concentration of binimetinib (0.05% w / w or 0.1% w / w of active ingredient), said emulsions being macroscopically and microscopically stable for at least 3 months, regardless of the storage temperature (tested up to 40°C). The binimetinib contained in these emulsions remains well solubilized throughout the study and does not undergo degradation. The emulsions according to the invention therefore have all the characteristics desired for a pharmaceutically acceptable product. 1.3.2. Aqueous gels

[0182] An aqueous gel according to the invention is obtained by the manufacturing process below at room temperature: • Step 1: Solubilization of parabens

[0183] In a first beaker B1, introduce the 2-phenoxyethanol and the parabens, and solubilize the parabens under magnetic stirring at room temperature. • Step 2: Solubilization of Binimetinib

[0184] In a second beaker B2, introduce the diethylene glycol monoethyl ether, the propylene glycol and the contents of beaker B1 and stir until a clear mixture is obtained. Then add the Binimetinib and stir until completely dissolved. • Step 3: Gelation

[0185] In a third beaker B3, introduce the water and the hydroxyethylcellulose. Disperse the cellulose while stirring with a deflocculating paddle until a clear gel is obtained. Then add the contents of beaker B2 to beaker B3 while stirring with a deflocculating paddle until a clear gel is obtained.

[0186] Table 7 describes the qualitative and quantitative composition of an aqueous gel according to the invention (Comp. 6).

[0187] [Tables7] Components Function Comp. 6 %w / w Binimetinib Active 0.15 Hydroxyethylcellulose (Natrosol® 250M) Gelling agent 1.5 Propylene glycol Co-solvent 10 Diethylene glycol monoethyl ether Solvent 30 2-Phenoxyethanol Preservative 0.5 Methylparaben Preservative 0.1 Propylparaben Preservative 0.02 Purified water Water Qs

[0188] The composition thus obtained is immediately characterized (T0) as described in point 1.2. The characteristics obtained are summarized in Table 8.

[0189] [Tables8] Physical characterization Comp. 6 Macroscopic appearance Clear gel Microscopic appearance Solubilized binimetinib Binimetinib dosage (%w / w relative to theoretical amount) 100%

[0190] Composition 6 has the desired appearance (clear gel) and allows good solubilization of binimetinib (absence of binimetinib crystals in the gel).

[0191] The physical and chemical stability of the composition after storage for one month (T1M) at a temperature of 25°C or 40°C was then verified. Table 9 summarizes the evolution of the macroscopic appearance of the gel of composition 6 and Table 10 summarizes the evolution of the microscopic appearance of composition 6.

[0192] [Tables9] Time Storage temperature Comp. 6 T1M 25°C Clear gel 40°C Clear gel

[0193] The gel of composition 6 retains macroscopically the same appearance after 1 month of storage following its preparation and this whatever the storage temperature.

[0194] [TableauxlO] Time Temperature Storage Comp. 6 T1M 25°C Binimetinib solubilized 40°C Binimetinib solubilized

[0195] The gel of Comp. 6 according to the invention retains the same microscopic characteristics (in particular absence of recrystallization of binimetinib) after 1 month of storage following its preparation and whatever the storage temperature.

[0196] Binimetinib was also dosed in composition 6, after 1 month (T1M) at a temperature of 25°C or 40°C. Table 11 represents the evolution of the dosage of Binimetinib in composition 6 after 1 month compared to the dosage at T0.

[0197] [Tableauxll] Time Storage temperature Comp. 6 T1M 25°C 100% 40°C 100%

[0198] The results obtained allow us to conclude that binimetinib does not degrade in composition 6 after 1 month of storage, whatever the temperature.

[0199] The present invention surprisingly shows that it is possible, thanks to the presence of certain solvents, to obtain a gel with a high dose of binimetinib (0.15% w / w of active ingredient), said gel being stable macroscopically and microscopically for at least 1 month and this whatever the storage temperature (tested up to 40°C). The binimetinib contained in this gel remains well solubilized throughout the study and does not undergo degradation. The gels according to the invention therefore have all the characteristics desired for a pharmaceutically acceptable product. 1.3.3. Micellar solution

[0200] A micellar solution according to the invention is obtained by the manufacturing process below: • Step 1: Solubilization of parabens

[0201] In a first beaker B1, introduce the 2-phenoxyethanol and the parabens, and solubilize the parabens under magnetic stirring at room temperature. • Step 2: Solubilization of Binimetinib

[0202] In a second beaker B2, introduce the diethylene glycol monoethyl ether, propylene glycol, polysorbate 80 and the contents of beaker B1 and stir until a clear mixture is obtained. Then add the Binimetinib and stir until completely dissolved. • Step 3: Adding water and adjusting the pH

[0203] Then add the purified water and stir until a clear solution is obtained in beaker B2. Then adjust the pH between 5.0 and 6.5 with a 0.1N hydrochloric acid solution.

[0204] Table 12 describes the qualitative and quantitative composition of a micellar solution according to the invention (Comp. 7).

[0205] [Tablesl2] Components Function Comp. 7 %w / w Binimetinib Active 0.3 Propylene glycol Co-solvent 5 Polysorbate 80 Amphiphilic co-solvent / Surfactant 15 Diethylene glycol monoethyl ether Solvent 30 2-Phenoxyethanol Preservative 0.7 Methylparaben Preservative 0.1 Propylparaben Preservative 0.02 Purified water Water Qs

[0206] Composition 7 thus obtained is immediately characterized (T0) as described in point 1.2. The characteristics obtained are summarized in Table 13.

[0207] [Tables 13] Physical characterization Comp. 7 Macroscopic appearance Clear solution Microscopic appearance Solubilized binimetinib Binimetinib dosage (%w / w relative to the theoretical quantity) 100%

[0208] Composition 7 has the desired appearance (transparent solution) and allows good solubilization of binimetinib (absence of binimetinib crystals in the micellar solution).

[0209] The physical and chemical stability of composition 7 after storage for one month (T1M) or 2.5 months (T2.5M) at a temperature of 25°C or 40°C was then verified. Table 14 summarizes the evolution of the macroscopic appearance of the micellar solution of composition 7 and Table 15 summarizes the evolution of the microscopic appearance of composition 7.

[0210] [Tablesl4] Time Storage temperature Comp. 7 T1M 25°C Clear solution 40°C Clear solution T2.5M 25°C Clear solution 40°C Clear solution

[0211] Composition 7 retains macroscopically the same appearance after 1 or 2.5 months of storage following its preparation and whatever the storage temperature.

[0212] [Tablesl5] Time Temperature Storage Comp. 7 T1M 25°C Binimetinib solubilized 40°C Binimetinib solubilized T2.5M 25°C Binimetinib solubilized 40°C Binimetinib solubilized

[0213] The micellar solution of composition 7 according to the invention retains the same microscopic characteristics (in particular absence of recrystallization of binimetinib) after 1 or 2.5 months of storage following its preparation and whatever the storage temperature.

[0214] Binimetinib was also dosed in composition 7, after 1 or 2.5 months (T1M) at a temperature of 25°C or 40°C. Table 16 represents the evolution of the dosage of Binimetinib in composition 7 after 1 or 2.5 months of storage at 25 or 40°C compared to the dosage at T0.

[0215] [Tables 16] Time Storage temperature Comp. 7 T1M 25°C 100% 40°C 100% T2.5M 25°C 100% 40°C 100%

[0216] The results obtained allow us to conclude that binimetinib does not degrade in the micellar solution of composition 7 after 1 or 2.5 months of storage, whatever the temperature.

[0217] The present invention surprisingly shows that it is possible, thanks to the presence of certain solvents, to obtain a micellar solution with a high dose of binimetinib (0.3% w / w of active ingredient), said micellar solution being stable macroscopically and microscopically for at least 2.5 months and this regardless of the storage temperature (tested up to 40°C). The binimetinib contained in this micellar solution remains well solubilized throughout the study and does not undergo degradation. The micellar solutions according to the invention therefore have all the characteristics desired for a pharmaceutically acceptable product.

[0218] Example!: Evaluation of the penetration and distribution of binim e tinib in the different layers of human skin

[0219] Three compositions according to the invention were selected in order to evaluate the distribution of binimetinib in the different layers of skin after application to human skin.

[0220] The compositions selected are composition 5 (oil-in-water emulsion as described in example 1.3.1), composition 6 (aqueous gel as described in example 1.3.2), and composition 7 (micellar solution as described in example 1.3.3). 2.1. Materials and methods 2.1.1. Skin samples

[0221] Non-dermatometal human skin samples (explants) from abdominoplasty with a thickness of less than 1500 μm were used. Three different donors were used for each group.

[0222] 2.1.2. Measurement of the integrity of the skin sample

[0223] The integrity of skin samples is assessed by measuring TEWL (Transepidermal Water Loss values) prior to application of the formulation. The skin must have a TEWL less than or equal to 20 g / m2xh. 2.1.3. Diffusion cells

[0224] Franz cells with a surface area of ​​1.76 cm2 and a volume of approximately 7 ml of receptor liquid were used as diffusion cells.

[0225] Approximately one hour before the start of the experiments, the explants were thawed at 4°C and then at room temperature. The skin samples were placed on the receiver compartment containing the receiver liquid. The donor compartment was then placed on the skin samples. The receiver compartment of each cell was filled with an aqueous solution of 0.9% NaCl / 0.25% Tween 20 as the receiver liquid to prevent the formation of bubbles. After checking for the absence of air bubbles, a clamp was placed to connect the two compartments. The cells were then placed on a magnetic stirrer in a water bath at a temperature of approximately 35-36°C, which allowed the skin temperature to be maintained at 32±1°C. The donor chamber was left open in a non-occlusive state. 2.1.4. Application to the skin

[0226] The compositions according to the invention tested were applied homogeneously (without massage) to each skin sample at a dose of 10 pL / cm2 using a pipette or a spatula depending on the viscosity. 2.1.5. Sampling of the receiving liquid

[0227] The receiving fluid was completely removed at each defined time after application and the skin samples were analyzed the following day.

[0228] 2.1.6. Separation of the different layers of the skin

[0229] At the end of the skin exposure to the tested composition (4h, 10h or 24h), the excess composition remaining on the skin was removed (donor liquid). Then, the recovery of the stratum corneum was done using D-squame® strips applied successively to the skin sample. Pressure with a device (from Monaderm) equivalent to a weight of approximately 150 g / cm2 was made on the strips for approximately 5 seconds before their removal. The first two strips were grouped with the donor liquid from each skin. Then, the stratum corneum was collected using 20 strips which were analyzed in groups of 3 or 5.

[0230] The epidermis and dermis were separated using a hair dryer and analyzed separately. [0231 ] 2.1.7. Determination of the penetration and distribution of binimetinib in the layers of the skin

[0232] Binimetinib was measured in the samples using an LC-MS / MS (liquid chromatography with tandem mass spectrometry) method. Binimetinib quantification was performed using a calibration curve. Quality controls using binimetinib solutions prepared at different concentrations were performed during the dosing sequence in the different samples.

[0233] Binimetinib penetration was calculated for each cell and the distribution of binimetinib in the layers of human skin was estimated as a percentage of the dose and as the amount of binimetinib recovered in the stratum corneum, epidermis, dermis and receptor fluid.

[0234] - The recovery rate corresponds to the ratio, expressed as a percentage, between the sum binimetinib levels in donor fluid, D-squame® strips, epidermis, dermis and recipient fluid and the initial binimetinib level in the tested composition.

[0235] - Penetration corresponds to the ratio, expressed in percent, between the sum of the binimetinib contents of the receptor fluid, D-squame® strips (except strips 1 and 2), epidermis and dermis and the initial binimetinib content in the tested composition.

[0236] - The distribution was calculated in each layer of skin: stratum corneum (corresponding to D-squame® bands 3 to 20), epidermis, dermis and receptor fluid. 2.2. Results

[0237] All human explants exhibited good integrity since transepidermal water loss (TEWL) values ​​were always less than 20 g / m2xh. The skin surface temperature in the diffusion cell was 32±1°C.

[0238] The results obtained regarding the amount of binimetinib recovered and penetrated into the layers of human skin after 4, 10 and 24 hours of exposure to the tested compositions are presented in Table 17.

[0239] [Tablesl7] Measured parameters Compositions tested Composition 5 Oil-in-water emulsion Composition 6 Aqueous gel Composition 7 Micellar solution Binimetinib concentration (mg / g of composition) 1.1 1.5 2.7 Amount of binimetinib deposited (pg)* 20.8 27.0 49.9 Total amount of binimetinib recovered (%)* 107% 112% 112% Amount of binimetinib recovered in donor fluid (%)* 107% 111% 112% Penetration (%) after 4h of exposure (n=3) Corneal layer 0.18 0.48 0.09 Epidermis 0.08 0.05 0.02 Dermis 0.00 0.00 0.00 Receptor fluid 0.00 0.00 0.00 Penetration (%) after 10h of exposure (n=3) Corneal layer 0.28 0.52 0.11 Epidermis 0.04 0.07 0.00 Dermis 0.00 0.00 0.01 Receptor fluid 0.00 0.00 0.00 Penetration (%) after 24h of exposure (n=3) Corneal layer 0.42 0.39 0.19 Epidermis 0.13 0.14 0.04 Dermis 0.04 0.00 0.10 Receptor fluid 0.00 0.00 0.00

[0240]

[0241]

[0242]

[0243]

[0244] * Average of measurements from 9 Franz cells Regardless of the tested composition and exposure time, the mean penetration was less than 1%, corresponding to a mean penetration of 164 ng, 128 ng, and 141 ng of binimetinib respectively for the three compositions 5, 6, and 7. The majority was recovered in the stratum corneum, but also, depending on the exposure time, in the deeper layers of human skin down to the dermis. Regardless of the tested composition, no amount of binimetinib was detected in the receiving fluid. This example therefore shows that all the tested compositions allow the penetration of binimetinib into the skin. In addition, since binimetinib was not found in the receiving fluid, it can be expected that there would be no blood exposure to binimetinib. List of cited documents • WO 03 / 077914 • WO 2014 / 063024 • WO2020 / 106304 Tran & Cohen 2020, Expert Opin. Drug Discov. 15(7): 745-754

Claims

Claims

1. A topical composition comprising: - binimetinib or a pharmaceutically acceptable salt thereof; - water in an amount of at least 40% by weight relative to the total weight of the composition; and - a polar organic solvent in an amount of less than or equal to 55% by weight relative to the total weight of the composition.

2. Topical composition according to claim 1, characterized in that it comprises at least 0.01%, preferably from 0.05% to 2% and more preferably from 0.05% to 0.1% by weight of binimetinib or a pharmaceutically acceptable salt thereof relative to the total weight of the composition.

3. A composition according to any one of claims 1 and 2, characterized in that said polar organic solvent comprises a main polar organic solvent and optionally a co-solvent, the main polar organic solvent being selected from the group consisting of acetonitrile, polyethylene glycol 400, diethylene glycol monoethyl ether, dimethylisosorbide and mixtures thereof, and the co-solvent being selected from the group consisting of propylene glycol, polysorbates, ethoxylated fatty acids, fatty acid esters of propylene glycol, ethoxylated esters of fatty acids of glycerol, polyglycerol, propylene glycol, polyethylene glycol or sorbitan, and mixtures thereof.

4. A topical composition according to claim 3, characterized in that the main polar organic solvent is polyethylene glycol 400, diethylene glycol monoethyl ether, or a mixture thereof; and the co-solvent is propylene glycol, polysorbate 80, or a mixture thereof.

5. Composition according to any one of claims 1 to 4, characterized in that it is stable for at least one month.

6. Topical composition according to any one of claims 1 to 5, characterized in that it is in the form of an emulsion, a gel, or a solution, preferably micellar.

7.

8.

9.

10.

11.

12.

13.

14. Topical composition according to claim 6, characterized in that it is in the form of an emulsion further comprising an oil and a surfactant. Topical composition according to claim 7, characterized in that it further comprises at least one ingredient chosen from a preservative, a buffering agent, a consistency agent, a stabilizing agent and their mixtures. Topical composition according to claim 6, characterized in that it is in the form of a gel further comprising a gelling agent. Topical composition according to claim 9, characterized in that it further comprises a preservative. Topical composition according to claim 6, characterized in that it is in the form of a micellar solution comprising at least one surfactant. Topical composition according to claim 11, characterized in that it further comprises a preservative. Composition according to any one of claims 1 to 12, for use as a medicament. Composition according to any one of claims 1 to 12, for its use in the treatment of a skin tumor, more particularly skin cancer.