Compositions containing benzenesulfonamide thiazole compounds

Abstract

The present invention relates to pharmaceutical compositions comprising benzenesulfonamido thiazole compounds, their use as medicaments and their use in the prevention and / or treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising N-(4-(6-((5-(dimethylamino)naphthalene)-1-sulfonamido)pyridin-2-yl)thiazol-2-yl)acetamide, their use as medicaments and their use in the prevention and / or treatment of cancer. [Background technology]

[0002] Compounds of formula (I): [ka] has been described for its anti-cancer activity (Cerezo et al., Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance, Cancer Cell, 2016, 29, 1-15).

[0003] However, the bioavailability of the compound of formula (I) after oral administration of the prior art composition containing the compound of formula (I) is very low, less than 3%.Therefore, there is a need to enhance the bioavailability of the compound of formula (I) for oral administration.

[0004] The inventors of the present invention have surprisingly discovered that certain compositions comprising a compound of formula (I) make it possible to obtain a better bioavailability, in particular a bioavailability of more than 60%, after administration by the oral route. Summary of the Invention

[0005] The present invention provides - a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof (Formula (I) is as follows: [ka] ) and 5% v / v to 30% v / v, preferably 10% v / v to 25% v / v, more preferably 15% v / v to 25% v / v, even more preferably about 25% v / v of at least one poly(ethylene glycol) selected from the group consisting of substituted poly(ethylene glycol), unsubstituted poly(ethylene glycol) and mixtures thereof (percentages expressed relative to the total volume of the pharmaceutical composition); - 2% v / v to 10% v / v, preferably 3% v / v to 7% v / v, more preferably 4% v / v to 6% v / v, even more preferably about 5% v / v of at least one solvent selected from the group consisting of ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof (percentages expressed relative to the total volume of the pharmaceutical composition); -water, The present invention relates to a pharmaceutical composition comprising:

[0006] Advantageously, the at least one poly(ethylene glycol) is a mixture of at least one substituted poly(ethylene glycol) and at least one unsubstituted poly(ethylene glycol). Preferably, the at least one poly(ethylene glycol) is a mixture of poly(ethylene glycol) (15)-hydroxystearate and poly(ethylene glycol) 400.

[0007] More advantageously, the unsubstituted poly(ethylene glycol) represents 5% v / v to 15% v / v, preferably 7% v / v to 13% v / v, more preferably 8% v / v to 12% v / v, and even more preferably about 10% v / v, of the total volume of the pharmaceutical composition.

[0008] More advantageously, the substituted poly(ethylene glycol) represents 10% v / v to 20% v / v, preferably 12% v / v to 18% v / v, more preferably 14% v / v to 16% v / v, and even more preferably about 15% v / v, relative to the total volume of the pharmaceutical composition.

[0009] Advantageously, said pharmaceutical composition comprises between 60% v / v and 93% v / v, preferably between 68% v / v and 87% v / v, more preferably between 69% v / v and 81% v / v, even more preferably about 70% v / v of water.

[0010] Advantageously, said pharmaceutical composition comprises between 60% v / v and 93% v / v, preferably between 68% v / v and 87% v / v, more preferably between 69% v / v and 71% v / v, even more preferably about 70% v / v of water.

[0011] Advantageously, said pharmaceutical composition contains 1 mg / mL to 320 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof.

[0012] Advantageously, at least one solvent is ethanol.

[0013] Advantageously, the pharmaceutical composition further comprises at least one additional excipient selected from the group consisting of solvents, diluent carriers, fillers, extenders, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickeners or emulsifiers, stabilizers, absorption enhancers, flavoring agents, taste maskers, preservatives, antioxidants, buffers, gelling agents, solubilizers and combinations thereof.

[0014] The present invention also relates to a pharmaceutical composition according to the invention for use as a medicament.

[0015] The present invention also relates to a pharmaceutical composition according to the present invention for use in the treatment or prevention of cancer in a subject in need thereof.

[0016] Advantageously, said cancer is selected from the group consisting of esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, pancreatic cancer and melanoma.

[0017] Advantageously, the cancer is a solid cancer. Preferably, the solid cancer is selected from the group consisting of esophageal cancer, gastrointestinal cancer, stomach cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urinary tract cancer, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, autonomic ganglion cancer, salivary gland cancer, thyroid cancer, central nervous system cancer, bone cancer, soft tissue cancer, lymphoma, skin cancer, carcinoma, and melanoma. More preferably, the solid cancer is selected from the group consisting of esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, skin cancer, and pancreatic cancer. More preferably, the solid cancer is selected from the group consisting of esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, and pancreatic cancer. Even more preferably, the solid cancer is selected from the group consisting of colorectal cancer, colon cancer, and rectal cancer. More preferably, the solid cancer is colorectal cancer.

[0018] Alternatively, the cancer is a liquid cancer. Preferably, the liquid cancer is selected from the group consisting of lymphoma, leukemia, and hematopoietic cancer. More preferably, the liquid cancer is leukemia. Even more preferably, the liquid cancer is chronic myeloid leukemia.

[0019] Advantageously, said pharmaceutical composition is administered by a route of administration selected from the group consisting of oral, intraperitoneal, intraspinal, intraarterial, intravenous, intramuscular and subcutaneous routes. Preferably, said pharmaceutical composition is administered by oral route.

[0020] Advantageously, the pharmaceutical composition is administered once a day, twice a day, three times a day, four times a day or every third day, every third day or five times a week.

[0021] More preferably, the pharmaceutical composition is administered once daily, twice daily, three times daily or four times daily.

[0022] More preferably, the pharmaceutical composition is administered every other day, every third day or five times a week.

[0023] Advantageously, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject in a single dose ranges from 5 mg to 350 mg per kilogram of the subject's body weight, preferably from 15 mg to 35 mg per kilogram of the subject's body weight.

[0024] definition In the present invention, the following terms have the following meanings:

[0025] The term "about" before a numerical value or number refers to plus or minus 10% of the face value of that numerical value or number. In one embodiment, the term "about" before a numerical value or number refers to plus or minus 5% of the face value of that numerical value or number.

[0026] "Active agent" refers to an agent that has a therapeutic effect. The agent can be a chemical or a biological substance. Preferably, the active agent is a chemical. The therapeutic effect can be prevention, delay, reduction in severity and / or frequency of at least one symptom associated with a pathology, or prevention, slowing or suppression of the underlying cause of the pathology, or amelioration or repair of damage.

[0027] "Bioavailability" refers to the proportion of a drug that reaches the systemic circulation unchanged after administration of said drug. Advantageously, bioavailability F is calculated according to the following formula: F(%)=[AUCinf(PO) * Dose (IV) * 100] / [AUCinf(IV) * Dose (PO)], where AUCinf(PO) and Dose (PO) are the AUCinf obtained after oral administration (PO) of the dose (PO = per os), and AUCinf(IV) and Dose (IV) are the AUCinf obtained after intravenous administration (IV) of the dose (IV = intravenous).

[0028] "Buffer" refers to a mixture of a weak acid and its conjugate base or a mixture of a weak base and its conjugate acid that allows the pH of a pharmaceutical composition to be maintained constant when a small amount of a strong acid or strong base is added to it. "Buffering agent" refers to a specific chemical substance that exists in both acidic and basic forms in a buffer, allowing the pH of a pharmaceutical composition to be maintained constant.

[0029] "Cancer" refers to any disease caused by the transformation of cells to become abnormal or proliferate excessively. "Solid cancer" refers to cancer in which abnormal and proliferating cells are located in a solid organ, such as the breast or prostate. Advantageously, the solid cancer may be selected from the group consisting of esophageal cancer, gastrointestinal cancer, stomach cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urinary tract cancer, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, autonomic ganglion cancer, salivary gland cancer, thyroid cancer, central nervous system cancer, bone cancer, soft tissue cancer, lymphoma, skin cancer, carcinoma, and melanoma. More advantageously, the solid cancer may be selected from the group consisting of gastric cancer, esophageal cancer, and skin cancer. Skin cancer may be selected from the group consisting of melanoma and carcinoma. More advantageously, the solid cancer may be selected from the group consisting of colorectal cancer, colon cancer, and rectal cancer. "Liquid cancer" refers to a cancer in which abnormal and proliferating cells are located in a liquid body fluid, such as blood (i.e., leukemia) or lymph. Advantageously, the liquid cancer may be selected from the group consisting of lymphoma, leukemia, and hematopoietic cancer. Preferably, the liquid cancer may be leukemia. More preferably, the liquid cancer may be chronic myeloid leukemia.

[0030] "Colloidal" refers to a finely divided state, meaning that the molecular or polymolecular particles dispersed in a medium have dimensions of approximately 1 nm to 1 μm in at least one direction, or that discontinuities in the system are visible over distances of that order.

[0031] "Comprising" or "comprise" is to be interpreted in an open and inclusive sense and without limitation.

[0032] "Consisting of" or "consist" is to be interpreted in a closed, non-exhaustive sense, limited to the properties that follow this term.

[0033] "Dose" refers to the amount of active agent administered at one time. In one embodiment, two oral doses are administered to one subject 6 hours to 1 week apart, preferably 8 hours to 48 hours apart, more preferably 12 hours to 24 hours apart, and even more preferably about 24 hours apart. Advantageously, the doses are human doses. A human dose is a standard human dose for a 70 kg human.

[0034] An "emulsion" refers to a fluid colloidal system in which droplets are dispersed in a liquid. The droplets often exceed the normal limit for colloids in size. A "simple emulsion" is designated by the designation O / W (or the term oil-in-water) when the continuous phase is an aqueous solution (=water phase), or by W / O (or the term water-in-oil) when the continuous phase is an organic liquid ("oil"). A "double emulsion" is a more complex emulsion, such as W / O / W (also named water-in-oil-in-water double emulsion, i.e., aqueous droplets contained within oily droplets dispersed in a continuous aqueous phase). In a W(1) / O / W(2) double emulsion, the inner emulsion refers to the emulsion of the innermost aqueous phase W(1) in the oil phase O; the outer emulsion refers to the emulsion of the oil phase O in the outer aqueous phase W(2).

[0035] "Excipient" refers to any inactive ingredient required for the formulation of an active agent in an appropriate dosage form. In one embodiment, "excipient" refers to any and all solvents, diluents, carriers, fillers, extenders, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickeners or emulsifiers, stabilizers, absorption enhancers, flavors, taste maskers, preservatives, antioxidants, buffers, gelling agents, solubilizers, or any combination thereof.

[0036] "X to Y" refers to a range of values ​​between X and Y, limiting X and Y to be included in the range.

[0037] " Oil phase " refers to the phase that is not miscible with the aqueous phase, which means that the amount of the aqueous phase that can be dissolved in the oil phase by weight is 5% or less, preferably less than 1%, more preferably less than 0.5%, and even more preferably 0% based on the total weight of the oil phase, and the amount of the oil phase that can be dissolved in the aqueous phase (by weight) is 5% or less, preferably less than 1%, more preferably less than 0.5%, and even more preferably 0% based on the total weight of the aqueous phase.The oil phase does not necessarily contain oil.The oil phase generally has a viscosity higher than that of water.

[0038] A "pharmaceutical composition" refers to a combination of at least one active agent and at least one pharmaceutically acceptable excipient.

[0039] "Pharmaceutically acceptable" generally refers to something that is safe, non-toxic, and not biologically, physiologically, or otherwise undesirable to mammals, particularly humans, dogs, cats, and non-human primates.

[0040] "Pharmacokinetic parameters": Among the pharmacokinetic parameters, "Cmax" refers to the maximum observed plasma concentration, "Tmax" refers to the time required to reach the maximum observed Cmax plasma concentration, "T1 / 2" refers to the half-life, i.e., the time at which the Cmax plasma concentration is reduced by half (during the elimination phase), "Cl / F" refers to renal clearance, "Vz / F" refers to the volume of distribution (elimination phase), and "AUC inf PO" refers to the area under the curve (corresponding to the subject's exposure to the compound being tested).

[0041] "Poly(ethylene glycol) (15)-hydroxystearate" has a CAS number of 70142-34-6 and has the following formula: [ka] For example, poly(ethylene glycol) (15)-hydroxystearate may be a product commercially available under the trade name Kolliphor® HS15.

[0042] "Salt of a compound" refers to an acid or base addition salt of the compound. Acid addition salts are formed with pharmaceutically acceptable organic or inorganic acids; base addition salts are formed when an acid proton present in the compound is either replaced by a metal ion or coordinated with a pharmaceutically acceptable organic or inorganic base. In one embodiment, the acid addition salt is selected from acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, hydroxybenzo ... In one embodiment, the base addition salt is selected from the group consisting of aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0043] A "solvate of a compound" refers to a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules. A "hydrate of a compound" refers to a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, where the solvent is water.

[0044] "Subject" or "patient" refers to a mammal, where "mammal" refers to a human or non-human mammal. In one embodiment, "subject" refers to a human (male or female). In one embodiment, "subject" refers to a non-human mammal, preferably a non-human mammal selected from the group consisting of cats, dogs, horses, and non-human primates, such as monkeys.

[0045] "Surfactant" refers to a substance that reduces the surface tension of the medium in which it is dissolved and / or the interfacial tension with other phases, and thus is positively adsorbed at liquid / vapor, liquid / liquid, and / or other interfaces.

[0046] A "suspension" refers to a liquid in which solid particles are dispersed.

[0047] A "therapeutically effective amount" or "effective amount" of an active agent or composition refers to a nontoxic but sufficient amount of the active agent or composition to provide the desired therapeutic effect.

[0048] "Treating" or "treatment" refers to any action that prevents, delays, reduces the severity and / or frequency of, or inhibits at least one symptom associated with a pathology, or prevents, delays, or inhibits the underlying cause of a pathology, or allows for the amelioration or cure of damage. In one embodiment, "treatment" refers to curative treatment. In another embodiment, "treatment" refers to prophylactic treatment. In another embodiment, "treatment" refers to prophylactic and / or curative treatment.

[0049] "Ultrapure water" refers to water that has been purified to exceptionally stringent specifications and treated to maximum purity levels for all contaminant types, including organic and inorganic compounds, dissolved and particulate compounds, volatile and non-volatile compounds, reactive and inert compounds, hydrophilic and hydrophobic compounds, and dissolved gaseous compounds. DETAILED DESCRIPTION OF THE INVENTION

[0050] Pharmaceutical Composition The present invention provides - a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof (Formula (I) is as follows: [ka] ) and - 5% v / v to 30% v / v, preferably 10% v / v to 25% v / v, more preferably 15% v / v to 25% v / v, even more preferably about 25% v / v of at least one poly(ethylene glycol) selected from the group consisting of substituted poly(ethylene glycol), unsubstituted poly(ethylene glycol) and mixtures thereof (percentages expressed relative to the total volume of the pharmaceutical composition), - 2% v / v to 10% v / v, preferably 3% v / v to 7% v / v, more preferably 4% v / v to 6% v / v, even more preferably about 5% v / v of at least one solvent selected from the group consisting of ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof (percentages expressed relative to the total volume of the pharmaceutical composition), - water, The present invention relates to a pharmaceutical composition comprising:

[0051] Advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of substituted poly(ethylene glycols) and mixtures thereof. More advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of fatty acid-derived poly(ethylene glycols) and mixtures thereof. Preferably, the at least one poly(ethylene glycol) is poly(ethylene glycol) (15)-hydroxystearate. Preferably, the at least one substituted poly(ethylene glycol), in particular poly(ethylene glycol) (15)-hydroxystearate, represents 10% v / v to 20% v / v, more preferably 12% v / v to 18% v / v, even more preferably 14% v / v to 16% v / v, and even more preferably about 15% v / v, of the total volume of the pharmaceutical composition.

[0052] Advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of unsubstituted poly(ethylene glycol) and mixtures thereof. More advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, poly(ethylene glycol) 800, poly(ethylene glycol) 1000, poly(ethylene glycol) 4000, and mixtures thereof. Even more advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, and mixtures thereof. Preferably, the at least one poly(ethylene glycol) is poly(ethylene glycol) 400. Preferably, the at least one unsubstituted poly(ethylene glycol), in particular poly(ethylene glycol) 400, represents 5% v / v to 15% v / v, more preferably 7% v / v to 13% v / v, even more preferably 8% v / v to 12% v / v, and most preferably about 10% v / v, of the total volume of the pharmaceutical composition.

[0053] Advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of fatty acid-derived poly(ethylene glycol), unsubstituted poly(ethylene glycol), and mixtures thereof. More advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of fatty acid-derived poly(ethylene glycol), poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, poly(ethylene glycol) 800, poly(ethylene glycol) 1000, poly(ethylene glycol) 4000, poly(ethylene glycol) 6000, and mixtures thereof. Even more advantageously, the at least one poly(ethylene glycol) is selected from the group consisting of fatty acid-derived poly(ethylene glycol), poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, poly(ethylene glycol) 800, poly(ethylene glycol) 1000, poly(ethylene glycol) 4000, and mixtures thereof. More preferably, the at least one poly(ethylene glycol) is selected from the group consisting of fatty acid-derived poly(ethylene glycol), poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, and mixtures thereof.

[0054] More preferably, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol)s derived from fatty acids other than poly(ethylene glycol) (15)-hydroxystearate, unsubstituted poly(ethylene glycol), and mixtures thereof. More preferably, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol)s derived from fatty acids other than poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, poly(ethylene glycol) 800, poly(ethylene glycol) 1000, poly(ethylene glycol) 4000, and mixtures thereof. More preferably, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol) derived from a fatty acid other than poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, and mixtures thereof.

[0055] More preferably, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, poly(ethylene glycol) 800, poly(ethylene glycol) 1000, poly(ethylene glycol) 4000, and mixtures thereof. Even more preferably, the at least one poly(ethylene glycol) is selected from the group consisting of poly(ethylene glycol) (15)-hydroxystearate, poly(ethylene glycol) 200, poly(ethylene glycol) 400, poly(ethylene glycol) 600, and mixtures thereof.

[0056] Advantageously, the at least one poly(ethylene glycol) is a mixture of at least one substituted poly(ethylene glycol) and at least one unsubstituted poly(ethylene glycol). More advantageously, the at least one poly(ethylene glycol) is a mixture of poly(ethylene glycol) (15)-hydroxystearate and poly(ethylene glycol) 400. Preferably, - the substituted poly(ethylene glycol), in particular poly(ethylene glycol) (15)-hydroxystearate, represents 10% v / v to 20% v / v, more preferably 12% v / v to 18% v / v, even more preferably 14% v / v to 16% v / v, and most preferably about 15% v / v, relative to the total volume of the pharmaceutical composition; - unsubstituted poly(ethylene glycol), in particular poly(ethylene glycol) 400, represents 5% v / v to 15% v / v, more preferably 7% v / v to 13% v / v, even more preferably 8% v / v to 12% v / v, and most preferably about 10% v / v, of the total volume of the pharmaceutical composition;

[0057] Advantageously, at least one solvent is dimethyl sulfoxide. Preferably, the pharmaceutical composition comprises 2% v / v to 10% v / v, more preferably 3% v / v to 7% v / v, even more preferably 4% v / v to 6% v / v, and most preferably about 5% v / v of dimethyl sulfoxide.

[0058] Advantageously, at least one solvent is dimethylacetamide. Preferably, the pharmaceutical composition comprises 2% v / v to 10% v / v, more preferably 3% v / v to 7% v / v, even more preferably 4% v / v to 6% v / v, and most preferably about 5% v / v of dimethylacetamide.

[0059] More advantageously, at least one solvent is ethanol. Preferably, the pharmaceutical composition comprises 2% v / v to 10% v / v of ethanol, more preferably 3% v / v to 7% v / v, even more preferably 4% v / v to 6% v / v, and most preferably about 5% v / v.

[0060] Ethanol can be used at any alcohol by volume (=ABV). Advantageously, the ethanol can be a solution of at least 50% ABV, preferably at least 70% ABV, more preferably at least 90% ABV, even more preferably at least 96% ABV (also called technical grade ethanol), and even more desirably at least 99% ABV (also called absolute grade ethanol). In one embodiment, the ethanol can be a 96% ABV ethanol solution.

[0061] Advantageously, the water is ultrapure water.

[0062] Advantageously, the pharmaceutical composition comprises water in an amount necessary to make up 100% v / v of the pharmaceutical composition. Preferably, the pharmaceutical composition comprises 60% v / v to 93% v / v, preferably 68% v / v to 87% v / v, more preferably 69% v / v to 81% v / v, and even more preferably about 70% v / v of water.

[0063] Advantageously, the pharmaceutical composition contains 1 mg / mL to 500 mg / mL, preferably 1 mg / mL to 350 mg / mL, more preferably 1 mg / mL to 320 mg / mL, even more preferably 50 mg / mL to 320 mg / mL, and more desirably about 150 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or mixture thereof. For clarity, "1 mg / mL of the compound of formula (I)" refers to 1 milligram of the compound of formula (I) per milliliter of pharmaceutical composition.

[0064] Advantageously, the pharmaceutical composition contains about 150 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof.

[0065] In one embodiment, the pharmaceutical composition comprises: a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, as defined above; - 10% v / v to 20% v / v, more preferably 12% v / v to 18% v / v, even more preferably 14% v / v to 16% v / v, and even more preferably about 15% v / v of poly(ethylene glycol) (15)-hydroxystearate (percentages expressed relative to the total volume of the pharmaceutical composition); - 5% v / v to 15% v / v, more preferably 7% v / v to 13% v / v, even more preferably 8% v / v to 12% v / v, and even more preferably about 10% v / v of poly(ethylene glycol) 400 (percentages expressed relative to the total volume of the pharmaceutical composition); - 2% v / v to 10% v / v, preferably 3% v / v to 7% v / v, more preferably 4% v / v to 6% v / v, even more preferably about 5% v / v of ethanol (percentages expressed relative to the total volume of the pharmaceutical composition), - water, Includes.

[0066] In a preferred embodiment, the pharmaceutical composition comprises: 1 mg / mL to 320 mg / mL of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, as defined above; - poly(ethylene glycol) (15)-hydroxystearate in an amount of about 15% v / v based on the total volume of the pharmaceutical composition; - about 10% v / v of poly(ethylene glycol) 400 based on the total volume of the pharmaceutical composition; - about 5% v / v ethanol based on the total volume of the pharmaceutical composition; - the amount of water required to make 100% v / v, Includes.

[0067] In a more preferred embodiment, the pharmaceutical composition comprises: 1 mg / mL to 320 mg / mL of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, as defined above; - poly(ethylene glycol) (15)-hydroxystearate in an amount of about 15% v / v based on the total volume of the pharmaceutical composition; - about 10% v / v of poly(ethylene glycol) 400 based on the total volume of the pharmaceutical composition; - about 5% v / v ethanol based on the total volume of the pharmaceutical composition; - about 70% v / v of water based on the total volume of the pharmaceutical composition; It consists of:

[0068] Advantageously, the pharmaceutical composition is an emulsion. The emulsion may be selected from the group consisting of a simple emulsion and a double emulsion. More advantageously, the pharmaceutical composition is a simple emulsion.

[0069] Advantageously, the pharmaceutical composition is a suspension.

[0070] Advantageously, the pharmaceutical composition is a solution, preferably a clear solution.

[0071] Advantageously, said pharmaceutical composition is for oral administration, in other words, advantageously said pharmaceutical composition is an oral pharmaceutical composition.

[0072] Advantageously, the pharmaceutical composition further comprises at least one additional excipient selected from the group consisting of solvents, diluents / carriers, fillers, extenders, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickeners or emulsifiers, stabilizers, absorption enhancers, flavoring agents, taste maskers, preservatives, antioxidants, buffers, gelling agents, solubilizers, and combinations thereof. More advantageously, the pharmaceutical composition further comprises at least one flavoring agent and / or taste masker. Preferably, when additional excipients are present in the pharmaceutical composition according to the present invention, the additional excipients are generally present in an amount of 0.001% to 5% by weight, preferably 0.001% to 1% by weight, each based on the total weight of the pharmaceutical composition. Needless to say, one skilled in the art will carefully select these optional excipients so that the advantageous properties inherently associated with the pharmaceutical compositions of the present invention are not adversely affected, or are not substantially adversely affected, by the excipient in question.

[0073] Pharmaceutical compositions for use as medicines The present invention also relates to a pharmaceutical composition according to the invention as described above for use as a medicament in a subject in need thereof.

[0074] The present invention also relates to a method for treating and / or preventing a disease by administering to a subject in need thereof an effective amount of a pharmaceutical composition according to the present invention as described above.

[0075] The present invention also relates to the use of a pharmaceutical composition according to the invention as described above for the manufacture of a medicament.

[0076] The present invention also relates to the use of a pharmaceutical composition according to the present invention as described above for the treatment and / or prevention of a disease in a subject in need thereof.

[0077] In this application, a drug can be a human drug or a veterinary drug.

[0078] Pharmaceutical Compositions for Use in the Treatment or Prevention of Disease The present invention also relates to a pharmaceutical composition according to the invention as described above for use in the treatment and / or prevention of cancer in a subject in need thereof.

[0079] The present invention also relates to a method for treating and / or preventing cancer by administering to a subject in need thereof an effective amount of a pharmaceutical composition according to the present invention as described above.

[0080] The present invention also relates to the use of a pharmaceutical composition according to the present invention as described above for the manufacture of a medicament for the treatment and / or prevention of cancer in a subject in need thereof.

[0081] The present invention also relates to the use of a pharmaceutical composition according to the present invention as described above for the treatment and / or prevention of cancer in a subject in need thereof.

[0082] Advantageously, the cancer is a solid tumor.

[0083] Preferably, the cancer is selected from the group consisting of esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, pancreatic cancer and melanoma. More preferably, the cancer is selected from the group consisting of colorectal cancer and melanoma. Even more preferably, the cancer is colorectal cancer.

[0084] Advantageously, the cancer may be selected from the group consisting of esophageal cancer, gastrointestinal cancer, stomach cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urinary tract cancer, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, autonomic ganglion cancer, salivary gland cancer, thyroid cancer, central nervous system cancer, bone cancer, soft tissue cancer, lymphoma, skin cancer, carcinoma, and melanoma. More advantageously, the cancer may be selected from the group consisting of gastric cancer, esophageal cancer, and skin cancer. Skin cancer may be selected from the group consisting of melanoma and carcinoma. More advantageously, the cancer may be selected from the group consisting of colorectal cancer, colon cancer, and rectal cancer.

[0085] More preferably, the cancer may be colorectal cancer.

[0086] More preferably, the cancer may be colon cancer.

[0087] More preferably, the cancer may be rectal cancer.

[0088] More preferably, the cancer may be melanoma.

[0089] Preferably, the pharmaceutical composition is administered by a route of administration selected from the group consisting of oral, intraperitoneal, intraspinal, intraarterial, intravenous, intramuscular and subcutaneous routes, and more preferably, by oral route.

[0090] Advantageously, the pharmaceutical composition is administered once, twice, three or four times a day. More advantageously, the pharmaceutical composition is administered by oral route once, twice, three or four times a day.

[0091] Advantageously, the pharmaceutical composition is administered daily, every two days, every three days or five times a week. More advantageously, the pharmaceutical composition is administered by oral route daily, every two days, every three days or five times a week.

[0092] Advantageously, the pharmaceutical composition is administered, in particular by oral route, every two days, every three days or five times a week, and during the days of administration, the pharmaceutical composition is administered once a day, twice a day, three times a day or four times a day.

[0093] Advantageously, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject in a single dose ranges from 5 mg to 350 mg, preferably from 5 mg to 250 mg, more preferably about 150 mg / kg of the subject's body weight.More advantageously, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject in a single dose by oral route ranges from 5 mg to 350 mg, preferably from 5 mg to 250 mg, more preferably about 150 mg / kg of the subject's body weight.

[0094] Advantageously, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject in a single dose ranges from 5 mg to 50 mg, preferably 15 mg to 35 mg per kg of the subject's body weight. More advantageously, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof administered to a subject in a single dose by oral route ranges from 5 mg to 50 mg, preferably 15 mg to 35 mg per kg of the subject's body weight.

[0095] Advantageously, the subject is a human, preferably a human over 18 years of age, preferably over 40 years of age, more preferably over 50 years of age, even more preferably over 65 years of age. [Brief explanation of the drawings]

[0096] [Figure 1]FIG. 1 is a graph showing the mean plasma concentration of the compound of formula (I) according to the present invention as a function of time after oral administration of a pharmaceutical composition according to the present invention to three Swiss albino mice at a dose of 150 mg of the compound of formula (I) per kg of each mouse. [Figure 2] FIG. 2 is a graph showing tumor volume as a function of time after oral administration of either a pharmaceutical composition according to the present invention to 10 BALB / C mice bearing CT26 (colorectal) tumors, or a placebo to 10 BALB / C mice bearing CT26 tumors, at a dose of 150 mg of the compound of formula (I) per kg of each mouse. [Figure 3] FIG. 3 is a graph showing the mean plasma concentration of the compound of formula (I) according to the invention as a function of time after oral administration of either pharmaceutical composition F according to the invention to three Swiss albino mice at a dose of 150 mg of the compound of formula (I) per kg of each mouse, or pharmaceutical composition E according to the prior art to three Swiss albino mice at a dose of 150 mg of the compound of formula (I) per kg of each mouse.

[0097] Example The present invention is further illustrated by the following examples. In all examples, the bioavailability F is calculated using the following formula: F(%) = [AUCinf(PO) * Dose (IV) * 100] / [AUCinf(IV) * Dose (PO)] was measured using.

[0098] Example 1: Preparation of two compositions according to the invention Composition A according to the present invention An organic vehicle was prepared containing the following: 50% v / v Kolliphor® HS15, 33.33% v / v PEG400, and 16.67% v / v ethanol. Thus, in 1.940 mL of the organic vehicle, there was 0.9700 mL Kolliphor® HS15, 0.6466 mL PEG400, and 0.3234 mL ethanol.

[0099] 96.99 mg of the compound of formula (I) according to the present invention was weighed into a Wheaton vial on a microbalance. The compound was dissolved in 1.9400 mL of the above organic vehicle (corresponding to 3 parts of the final vehicle volume), and the dosing solution was thoroughly mixed using a magnetic stirrer for approximately 30 minutes. After this, the final vehicle component, 4.5266 mL of ultrapure water (corresponding to 7 parts of the final vehicle volume), was slowly added to the Wheaton vial and thoroughly mixed by end-over-end mixing. The final dosing composition was a slightly turbid fluorescent green / yellow solution, containing 15 mg of the compound of formula (I) per milliliter of solution.

[0100] Composition B according to the present invention An organic vehicle was prepared containing 50% v / v Kolliphor® HS15, 33.33% v / v PEG 400, and 16.67% v / v ethanol, so in 1.940 mL of the organic vehicle, there was 0.9700 mL Kolliphor® HS15, 0.6466 mL PEG 400, and 0.3234 mL ethanol.

[0101] 206.93 mg of the compound of formula (I) according to the present invention was weighed into a Wheaton vial on a microbalance. The compound was dissolved in 1.9400 mL of the above organic vehicle (corresponding to 3 parts of the final vehicle volume), and the dosing solution was thoroughly mixed using a magnetic stirrer for approximately 30 minutes. After this, the final vehicle component, 4.5266 mL of ultrapure water (corresponding to 7 parts of the final vehicle volume), was slowly added to the Wheaton vial and thoroughly mixed by end-over-end mixing. The final dosing composition was a fine green-yellow suspension, containing 32 mg of the compound of formula (I) per milliliter of suspension.

[0102] Example 2: Evaluation of the bioavailability of the compound of formula (I) after administration of composition A according to the invention prepared in Example 1

[0103] Materials and Methods Composition A according to the invention prepared in Example 1 was administered as a single dose by oral route to three male Swiss albino mice at a dose of 150 mg / kg per mouse (corresponding to a volumetric dose of 10 mL / kg by oral route). The mice were dosed orally via a gastric gavage needle.

[0104] Furthermore, a composition designated as Composition IV was administered as a single dose to three other male Swiss albino mice via the intravenous route at a dose of 1 mg / kg per mouse (corresponding to a volume administration rate of 10 mL / kg via the intravenous route). Composition IV contained 0.1 mg of the compound of formula (I) according to the present invention per milliliter of the above Composition IV, and a vehicle containing 10% v / v Kolliphor® EL and 90% v / v saline solution (= an aqueous solution containing 0.9% w / v NaCl). Composition IV was prepared as follows: Kolliphor® EL and saline solution were premixed in an appropriate ratio (1 / 9, v / v), and then the compound of formula (I) according to the present invention was dissolved in the required volume to obtain Composition IV.

[0105] For each of six mice, blood samples were collected in the saphenous vein at different endpoints (TO+0.5 hours, TO+1 hours, TO+2 hours, TO+4 hours, and TO+8 hours after oral or intravenous administration at TO) and centrifuged to separate plasma. The plasma concentration of the compound of formula (I) according to the present invention was measured by LC-MS / MS. Pharmacokinetic parameters were calculated for the mean concentration by a non-compartmental model using Phoenix software version 8.1.

[0106] result The mean plasma concentrations of the compound of formula (I) as a function of time following administration of a composition according to the invention prepared in Example 1 are shown in Figure 1. As can be seen in Figure 1, the plasma concentrations of the compound of formula (I) declined over 8 hours.

[0107] The pharmacokinetic parameters were as follows: [Table 1]

[0108] The bioavailability of compound (I) was 96%. Composition A according to the invention therefore allows a bioavailability of compound (I) of more than 90% after a single administration by the oral route.

[0109] Example 3: Effect of Composition A according to the invention prepared in Example 1 in the treatment of colorectal cancer Materials and Methods Tumor cell transplantation: 5 × 10 5 CT26 cells were subcutaneously implanted into the flanks of 20 female BALB / c mice. Tumors were approximately 50–100 mm 3 Once tumor size reached 100 mg / kg, mice bearing similarly sized tumors were randomly assigned to treatment groups (either "test group" or "control group"). Treatment (a composition according to the invention prepared in Example 1 for the test group, or a placebo for the control group) began 7 days after tumor cell implantation. All dosing solution preparations were performed in a sterile biosafety cabinet.

[0110] Composition A according to the invention, as prepared in Example 1, was administered daily for 13 days (starting from day 1, to 10 female BALB / C mice bearing CT26 tumors, at a dose of 150 mg / kg per mouse by oral route (corresponding to a volume dose of 10 mL / kg by oral route) (corresponding to the "test group").

[0111] A vehicle (containing 50% v / v Kolliphor® HS15, 33.33% v / v PEG400 and 16.67% v / v ethanol, percentages expressed relative to the total volume of the vehicle) was administered daily for 13 days (starting on day 1) by oral route to 10 other female BALB / C mice bearing CT26 tumors as placebo (corresponding to the "control group").

[0112] Follow-up for all mice included: twice weekly body weight measurements, daily clinical observations (gross signs / symptoms), three times weekly tumor volume measurements, tumor analysis, and blood analysis.

[0113] Tumors were measured using digital calipers. The length, width, and depth of the tumor were measured and used to calculate tumor volume.

[0114] Additionally, tumors were weighed on day 13 after they were removed from the mice's bodies.

[0115] result The tumor volume of n as a function of time after administration of the composition prepared in Example 1 or a placebo is shown in Figure 2. As can be seen in Figure 2, oral administration of the composition according to the present invention prepared in Example 1 reduced tumor volume by 3-fold on day 13 compared to the control group.

[0116] Furthermore, the average tumor weight on day 13 was 970 mg for the control group and 341 mg for the test group. Thus, administration of the composition according to the present invention by oral route reduced CT26 tumors in BALB / c mice by approximately one-third compared to the control group.

[0117] Furthermore, body weight measurements showed no statistically significant differences between the control and test groups, indicating that oral administration of the composition according to the invention prepared in Example 1 is well tolerated.

[0118] Example 4: Comparison of the bioavailability of the compound of formula (I) after administration of a composition according to the invention and a composition according to the prior art Materials and Methods Oral route of administration Two compositions were prepared: Composition F according to the present invention: An organic vehicle was prepared containing 50% v / v Kolliphor® HS15, 33.33% v / v PEG400, and 16.67% v / v ethanol. Thus, in 1.940 mL of the organic vehicle, 0.9700 mL of Kolliphor® HS15, 0.6466 mL of PEG400, and 0.3234 mL of ethanol were present. A compound of formula (I) according to the present invention was weighed into a Wheaton vial on a microbalance. The compound was dissolved in 1.9400 mL of the organic vehicle, and the dosing solution was thoroughly stirred at 800 rpm at 25°C using a magnetic stirrer for approximately 30 minutes. The final vehicle component, 4.5266 mL of ultrapure water, was then slowly added to the Wheaton vial and thoroughly mixed by end-over-end stirring. The final composition, designated Composition F, contained 15% v / v Kolliphor® HS15, 10% v / v PEG 400, 5% v / v ethanol, and 70% v / v ultrapure water and 0.3 mg of the compound of formula (I) per milliliter of Composition F.

[0119] Composition E from a prior study: A compound of formula (I) according to the present invention was added to a mixture containing 1.2% v / v methylcellulose, 0.1% v / v Tween® 80 (polyethylene glycol sorbitan monooleate, CAS number 9005-65-6), and 100% v / v deionized water. The resulting suspension, designated Composition E, contained 5 mg of the compound of formula (I) per milliliter of Composition E.

[0120] Dosage: Composition F according to the invention was administered as a single dose by the oral route to three healthy male Swiss albino mice at a dose of 150 mg / kilogram of compound of formula (I) for each mouse.

[0121] Composition E from the previous study was administered as a single dose by oral route to three healthy male Swiss albino mice at a dose of 150 mg / kilogram of the compound of formula (I) to each mouse.

[0122] Blood Sampling: Approximately 40-50 μL of blood samples per mouse were collected by saphenous vein puncture at different endpoints (TO+0.25, TO+0.5, TO+1, TO+2, TO+4, and TO+8 hours after oral administration at TO). Blood was collected into collection tubes containing anticoagulant (lithium heparin). The tubes were centrifuged (2000 g, 10 minutes, 4°C) to obtain plasma. Samples were stored in propylene tubes at <-65°C until LC-MS / MS analysis (n=126). Pharmacokinetic parameters were calculated from non-compartmental analysis (NCA) of the PK profiles using Phoenix WinNonlin 7.0 software.

[0123] result Pharmacokinetic parameters after oral administration were as follows: [Table 2]

[0124] As can be seen, after a single oral administration of composition F according to the present invention, the maximum concentration C of the compound of formula (I) according to the present invention is obtained 30 minutes to 1 hour after administration, which is 29.75 μM when a dose of 150 mg / kg is administered. After a single oral administration of composition E according to the prior art, the maximum concentration C of the compound of formula (I) according to the present invention is obtained 30 minutes to 2 hours after administration, which is 4.69 μM when a dose of 150 mg / kg is administered. Thus, the maximum concentration C is greater after oral administration of composition F according to the present invention than after oral administration of composition E according to the prior art.

[0125] Considering the results, composition F according to the invention allows a faster absorption (see Tmax) and a better exposure (AUC 0-inf (See reference).

[0126] Furthermore, the oral bioavailability is about 62.46% after a single oral administration of composition F according to the present invention and about 2.81% after a single oral administration of composition E according to the prior art.

[0127] Thus, composition F according to the invention allows a better oral bioavailability of the compound of formula (I) than composition E according to the prior art.

Claims

1. a compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof (Formula (I) is as follows: 【Chemical 1】 ) and - 5% v / v to 30% v / v, preferably 10% v / v to 25% v / v, more preferably 15% v / v to 25% v / v, even more preferably about 25% v / v of at least one poly(ethylene glycol) selected from the group consisting of substituted poly(ethylene glycol), unsubstituted poly(ethylene glycol) and mixtures thereof, said percentages being expressed relative to the total volume of the pharmaceutical composition; - 2% v / v to 10% v / v, preferably 3% v / v to 7% v / v, more preferably 4% v / v to 6% v / v, even more preferably about 5% v / v of at least one solvent selected from the group consisting of ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof, said percentages being expressed relative to the total volume of the pharmaceutical composition; - water, A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the at least one poly(ethylene glycol) is a mixture of substituted and unsubstituted poly(ethylene glycol); preferably, the at least one poly(ethylene glycol) is a mixture of poly(ethylene glycol) (15)-hydroxystearate and poly(ethylene glycol) 400.

3. 3. The pharmaceutical composition according to claim 2, wherein the unsubstituted poly(ethylene glycol) represents 5% v / v to 15% v / v, preferably 7% v / v to 13% v / v, more preferably 8% v / v to 12% v / v, and even more preferably about 10% v / v, relative to the total volume of the pharmaceutical composition.

4. 4. The pharmaceutical composition according to claim 2 or 3, wherein the substituted poly(ethylene glycol) represents 10% v / v to 20% v / v, preferably 12% v / v to 18% v / v, more preferably 14% v / v to 16% v / v, and even more preferably about 15% v / v, relative to the total volume of the pharmaceutical composition.

5. 5. A pharmaceutical composition according to any one of claims 1 to 4, comprising 60% v / v to 93% v / v of water, preferably 68% v / v to 87% v / v, more preferably 69% v / v to 81% v / v, even more preferably about 70% v / v.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, comprising 1 mg / mL to 320 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, preferably 3 mg / mL to 20 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, more preferably about 15 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the at least one solvent is ethanol.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, further comprising at least one additional excipient selected from the group consisting of solvents, diluents carriers, fillers, extenders, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonicity agents, thickeners or emulsifiers, stabilizers, absorption enhancers, flavors, taste maskers, preservatives, antioxidants, buffers, gelling agents, solubilizers, and combinations thereof.

9. A pharmaceutical composition according to any one of claims 1 to 8 for use as a medicament.

10. 9. A pharmaceutical composition according to any one of claims 1 to 8 for use in the treatment or prevention of cancer in a subject in need thereof.

11. 11. The pharmaceutical composition for use according to claim 10, wherein the cancer is a solid cancer, preferably selected from the group consisting of esophageal cancer, gastrointestinal cancer, stomach cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urinary tract cancer, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, autonomic ganglion cancer, salivary gland cancer, thyroid cancer, central nervous system cancer, bone cancer, soft tissue cancer, lymphoma, skin cancer, carcinoma and melanoma, more preferably selected from the group consisting of esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer and pancreatic cancer, even more preferably selected from the group consisting of colorectal cancer, colon cancer and rectal cancer.

12. The pharmaceutical composition for use according to claim 10, wherein the cancer is a liquid cancer, preferably a liquid cancer selected from the group consisting of lymphoma, leukemia and hematopoietic cancer.

13. 13. The pharmaceutical composition for use according to any one of claims 9 to 12, which is administered by a route of administration selected from the group consisting of oral, intraperitoneal, intraspinal, intraarterial, intravenous, intramuscular and subcutaneous routes, preferably by oral route.

14. 14. The pharmaceutical composition for use according to any one of claims 9 to 13, which is administered once daily, twice daily, three times daily or four times daily.

15. 15. The pharmaceutical composition for use according to any one of claims 9 to 14, wherein the dose of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or mixture thereof administered in a single administration to the subject is in the range of 5 mg to 250 mg per kilogram of subject body weight, preferably 5 mg to 150 mg per kilogram of subject body weight, more preferably 5 mg to 50 mg per kilogram of subject body weight, and even more preferably 15 mg to 35 mg per kilogram of subject body weight.

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