Compositions comprising benzenesulfonamide thiazole compounds

Abstract

The present invention relates to a pharmaceutical composition comprising a benzenesulfonamide thiazole compound, to the use thereof as a medicament and to the use thereof in the prevention and / or treatment of cancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising N-(4-(6-((5-(dimethylamino)naphthalen-1-yl)sulfamoyl)pyridin-2-yl)thiazol-2-yl)acetamide, to its use as a medicine, and to its use in the prevention and / or treatment of cancer. Background Art

[0002] Compounds of formula (I):

[0003]

[0004] have been described as having 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).

[0005] However, after administration of a composition comprising said compound according to the prior art by the oral route, the bioavailability of the compound of formula (I) is very low, less than 3%. Therefore, there is a need to improve the bioavailability of the compound of formula (I) administered by the oral route.

[0006] The inventors of the present invention have surprisingly found that a specific composition comprising a compound of formula (I) can achieve a higher bioavailability, in particular a bioavailability higher than 60%, after administration by the oral route. Summary of the Invention

[0007] The present invention relates to a pharmaceutical composition comprising:

[0008] - a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, wherein formula (I) is as follows:

[0009]

[0010] - from 5% v / v to 30% v / v, preferably from 10% v / v to 25% v / v, more preferably from 15% v / v to 25% v / v, even more preferably about 25% v / v of at least one polyethylene glycol selected from substituted polyethylene glycols, unsubstituted polyethylene glycols and mixtures thereof, the percentages being relative to the total volume of the pharmaceutical composition,

[0011] - From 2% v / v to 10% v / v, preferably from 3% v / v to 7% v / v, more preferably from 4% v / v to 6% v / v, even more preferably about 5% v / v of at least one solvent selected from ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof, the percentages being relative to the total volume of the pharmaceutical composition, and

[0012] - water.

[0013] Advantageously, at least one polyethylene glycol is a mixture of at least one substituted polyethylene glycol and at least one unsubstituted polyethylene glycol. Preferably, at least one polyethylene glycol is a mixture of polyethylene glycol (15)-hydroxystearate and polyethylene glycol 400.

[0014] More advantageously, relative to the total volume of the pharmaceutical composition, the unsubstituted polyethylene glycol is from 5% v / v to 15% v / v, preferably from 7% v / v to 13% v / v, more preferably from 8% v / v to 12% v / v, even more preferably about 10% v / v.

[0015] More advantageously, relative to the total volume of the pharmaceutical composition, the substituted polyethylene glycol is from 10% v / v to 20% v / v, preferably from 12% v / v to 18% v / v, more preferably from 14% v / v to 16% v / v, even more preferably about 15% v / v.

[0016] Advantageously, the pharmaceutical composition comprises from 60% v / v to 93% v / v, preferably from 68% v / v to 87% v / v, more preferably from 69% v / v to 81% v / v, even more preferably about 70% v / v of water.

[0017] Advantageously, the pharmaceutical composition comprises from 60% v / v to 93% v / v, preferably from 68% v / v to 87% v / v, more preferably from 69% v / v to 71% v / v, even more preferably about 70% v / v of water.

[0018] Advantageously, the pharmaceutical composition comprises from 1 mg / mL to 320 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof.

[0019] Advantageously, at least one solvent is ethanol.

[0020] Advantageously, the pharmaceutical composition further comprises at least one other excipient selected from: solvents, diluent carriers, fillers, swelling agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonizing agents, thickeners or emulsifiers, stabilizers, absorption promoters, fragrances, taste masking agents, preservatives, antioxidants, buffers, gelling agents, solubilizers, and combinations thereof.

[0021] The present invention also relates to a pharmaceutical composition according to the present invention for use as a medicament.

[0022] The present invention also relates to a pharmaceutical composition according to the present invention for the treatment or prevention of cancer in a subject in need thereof.

[0023] Advantageously, the cancer is selected from: esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, pancreatic cancer, and melanoma.

[0024] Advantageously, the cancer is a solid cancer. Preferably, the solid cancer is selected from: esophageal cancer, gastrointestinal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urethral 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: esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, skin cancer, and pancreatic cancer. Even more preferably, the solid cancer is selected from: esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, and pancreatic cancer. Even more preferably, the solid cancer is selected from colorectal cancer, colon cancer, and rectal cancer. Even more preferably, the solid cancer is colorectal cancer.

[0025] Alternatively, the cancer is a liquid cancer. Preferably, the liquid cancer is selected from: lymphoma, leukemia, and hematopoietic cancer. More preferably, the liquid cancer is leukemia. Even more preferably, the liquid cancer is chronic myeloid leukemia.

[0026] Advantageously, the pharmaceutical composition is administered by an administration route selected from: oral route, intraperitoneal route, intrathecal route, intraarterial route, intravenous route, intramuscular route, and subcutaneous route. Preferably, the pharmaceutical composition is administered by the oral route.

[0027] Advantageously, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day, or every 2 days, every 3 days, or 5 times a week.

[0028] More advantageously, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day.

[0029] More preferably, the pharmaceutical composition is administered every two days, every three days or five times a week.

[0030] Advantageously, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate thereof or mixture thereof in a single administration to a subject is from 5 mg to 350 mg per kg of subject body weight, preferably from 15 mg to 35 mg per kg of subject body weight.

[0031] Definitions

[0032] In the present invention, the following terms have the following meanings:

[0033] "About" in front of a numerical value or number means plus or minus 10% of the face value of that numerical value or number. In one embodiment, "about" in front of a numerical value or number means plus or minus 5% of the face value of that numerical value or number.

[0034] "Active agent" means a reagent having a therapeutic effect. The reagent can be a chemical or a biological substance. Preferably, the active agent is a chemical substance. The therapeutic effect can be prevention, delay, reduction in severity and / or reduction in its frequency, or inhibition of at least one symptom associated with a pathological condition, or prevention, slowing or inhibition of the root cause of a pathological condition, or improvement or repair of an injury.

[0035] "Bioavailability" means the proportion of the drug that reaches the systemic circulation unchanged after administration of the drug. Advantageously, the bioavailability F can be measured using 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 of the dose (PO) (PO = oral), and where AUCinf(IV) and dose(IV) are the AUCinf obtained after intravenous administration of the dose (IV) (IV = intravenous).

[0036] "Buffer" means a mixture of a weak acid and its conjugate base, or a mixture of a weak base and its conjugate acid, which can keep the pH value of the pharmaceutical composition constant when a small amount of strong acid or strong base is added. "Buffering agent" means a specific chemical substance that exists in both acidic and basic forms in the buffer and can keep the pH value of the pharmaceutical composition constant.

[0037] "Cancer" refers to any disease caused by the transformation of abnormally and excessively proliferating cells. "Solid cancer" refers to cancer in which the abnormally and proliferating cells are located in solid organs such as the breast or prostate. Advantageously, solid cancer can be selected from: esophageal cancer, gastrointestinal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urethral 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, solid cancer can be selected from gastric cancer, esophageal cancer, and skin cancer. Skin cancer can be selected from melanoma and carcinoma. More advantageously, solid cancer can be selected from colorectal cancer, colon cancer, and rectal cancer. "Liquid cancer" refers to cancer in which the abnormally and proliferating cells are located in liquid body fluids, such as in blood (i.e., leukemia) or lymph. Advantageously, liquid cancer can be selected from lymphoma, leukemia, and hematopoietic cancer. Preferably, liquid cancer can be leukemia. More preferably, liquid cancer can be chronic myeloid leukemia.

[0038] "Colloid" refers to a subdivision state, which means that the molecular particles or multimolecular particles dispersed in a medium have dimensions of approximately 1 nm to 1 μm in at least one direction, or in this system, there are discontinuities at distances of this order of magnitude.

[0039] "Comprising" should be interpreted in an open, inclusive sense, but not limited to this.

[0040] "Consisting of" should be interpreted in a closed, non-inclusive sense, which is limited to the features following this term.

[0041] "Dose" refers to the amount of active agent administered at one time. In one embodiment, two oral doses administered to a subject are spaced 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 approximately 24 hours apart. Advantageously, the dose is a human dose. A human dose refers to the standard human dose for a 70 kg male.

[0042] "Emulsion" refers to a fluid colloid system in which droplets are dispersed in a liquid. The particle size of the droplets generally exceeds the general limit of colloids. If the continuous phase is an aqueous solution (= aqueous phase), "single emulsion" is denoted by the symbol O / W (or the term oil-in-water); if the continuous phase is an organic liquid ("oil"), it is denoted by the symbol W / O (or the term water-in-oil). "Double emulsion" is a more complex emulsion, such as W / O / W (also known as water-in-oil-in-water double emulsion, i.e., oil droplets containing water droplets are dispersed in a continuous aqueous phase). In the 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; and the outer emulsion refers to the emulsion of the oil phase O in the outer aqueous phase W(2).

[0043] "Excipient" means any inactive ingredient required to formulate an active agent into a suitable dosage form. In one embodiment, "excipient" means any and all solvents, diluents, carriers, fillers, swelling agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonic agents, thickening agents or emulsifiers, stabilizers, absorption enhancers, fragrances, taste masking agents, preservatives, antioxidants, buffers, gelling agents, solubilizers, or any combination thereof.

[0044] "X to Y" means a numerical range between X and Y, including the boundaries X and Y in said range.

[0045] "Oil phase" means a phase immiscible with the aqueous phase, which means that based on the total weight of the oil phase, the amount of the aqueous phase that can be dissolved in the oil phase is less than 5% by weight or equal to 5% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and even more preferably 0% by weight; based on the total weight of the aqueous phase, the amount of the oil phase that can be dissolved in the aqueous phase is less than 5% by weight or equal to 5% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and even more preferably 0% by weight. The oil phase does not necessarily contain oil. The viscosity of the oil phase is generally greater than that of the aqueous phase.

[0046] "Pharmaceutical composition" means a combination of at least one active agent and at least one pharmaceutically acceptable excipient.

[0047] "Pharmaceutically acceptable" means that for mammals, especially for humans, dogs, cats, and non-human primates, it is generally safe, non-toxic, neither biologically undesirable nor physiologically undesirable and not otherwise undesirable.

[0048] "Pharmacokinetic parameters": In 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 time, i.e., the time when the Cmax plasma concentration is halved (during the elimination phase), "Cl / F" refers to the renal clearance rate, "Vz / F" refers to the volume of distribution (elimination phase), and "AUC inf PO" refers to the area under the curve (corresponding to the exposure of the subject to the tested compound).

[0049] "Polyethylene glycol (15)-hydroxystearate" refers to a molecule with CAS number 70142-34-6 and having the following formula:

[0050]

[0051] For example, polyethylene glycol (15)-hydroxystearate may be a product sold under the name HS15.

[0052] "Salt of a compound" refers to an acid addition salt or a base addition salt of the said compound. Acid addition salts are formed with pharmaceutically acceptable organic or inorganic acids; base addition salts are formed when the acidic protons present in the compound are replaced by metal ions or coordinated with pharmaceutically acceptable organic or inorganic bases. In one embodiment, the acid addition salts are selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfonate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts. In one embodiment, the base addition salts are selected from aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diethanolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0053] "Solvate of a compound" refers to a molecular complex comprising the said compound and one or more pharmaceutically acceptable solvent molecules. "Hydrate of a compound" refers to a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, wherein the solvent is water.

[0054] "Subject" or "patient" refers to a mammal, wherein "mammal" refers to a human or a 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 cats, dogs, horses, and non-human primates such as monkeys.

[0055] "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 can be positively adsorbed at liquid / vapor, liquid / liquid, and / or other interfaces.

[0056] "Suspension" refers to a liquid in which solid particles are dispersed.

[0057] A "therapeutically effective amount" or "effective amount" of an active agent or composition means an amount of the active agent or composition that is non-toxic but sufficient to provide the desired therapeutic effect.

[0058] "Treatment" refers to any action that can prevent, delay, reduce the severity and / or reduce the frequency of, or inhibit at least one symptom associated with a pathological condition, or prevent, slow down or inhibit the root cause of a pathological condition, or improve or repair 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 therapeutic treatment.

[0059] "Ultra-pure water" refers to water purified according to extremely strict specifications and treated to the highest purity for all types of contaminants, 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

[0060] Pharmaceutical composition

[0061] The present invention relates to a pharmaceutical composition comprising:

[0062] - a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, wherein formula (I) is as follows:

[0063]

[0064] - from 5% v / v to 30% v / v, preferably from 10% v / v to 25% v / v, more preferably from 15% v / v to 25% v / v, even more preferably about 25% v / v of at least one polyethylene glycol selected from substituted polyethylene glycols, unsubstituted polyethylene glycols and mixtures thereof, the percentages being relative to the total volume of the pharmaceutical composition,

[0065] - from 2% v / v to 10% v / v, preferably from 3% v / v to 7% v / v, more preferably from 4% v / v to 6% v / v, even more preferably about 5% v / v of at least one solvent selected from: ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof, the percentages being relative to the total volume of the pharmaceutical composition, and

[0066] - water.

[0067] Advantageously, at least one polyethylene glycol is selected from substituted polyethylene glycols and mixtures thereof. More advantageously, at least one polyethylene glycol is selected from fatty acid-derived polyethylene glycols and mixtures thereof. Preferably, at least one polyethylene glycol is polyethylene glycol (15)-hydroxystearate. Preferably, relative to the total volume of the pharmaceutical composition, at least one substituted polyethylene glycol, in particular polyethylene glycol (15)-hydroxystearate, is from 10% v / v to 20% v / v, more preferably from 12% v / v to 18% v / v, even more preferably from 14% v / v to 16% v / v, and more preferably about 15% v / v.

[0068] Advantageously, at least one polyethylene glycol is selected from unsubstituted polyethylene glycols and mixtures thereof. More advantageously, at least one polyethylene glycol is selected from polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 4000 and mixtures thereof. Even more advantageously, at least one polyethylene glycol is selected from polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600 and mixtures thereof. Preferably, at least one polyethylene glycol is polyethylene glycol 400. Preferably, relative to the total volume of the pharmaceutical composition, at least one unsubstituted polyethylene glycol, in particular polyethylene glycol 400, is from 5% v / v to 15% v / v, more preferably from 7% v / v to 13% v / v, even more preferably from 8% v / v to 12% v / v, and more preferably about 10% v / v.

[0069] Advantageously, at least one polyethylene glycol is selected from fatty acid-derived polyethylene glycols, unsubstituted polyethylene glycols and mixtures thereof. More advantageously, at least one polyethylene glycol is selected from fatty acid-derived polyethylene glycols, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 4000, polyethylene glycol 6000 and mixtures thereof. More advantageously, at least one polyethylene glycol is selected from fatty acid-derived polyethylene glycols, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 4000 and mixtures thereof. More advantageously, at least one polyethylene glycol is selected from fatty acid-derived polyethylene glycols, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600 and mixtures thereof.

[0070] More preferably, at least one polyethylene glycol is selected from polyethylene glycol (15)-hydroxystearate, fatty acid-derived polyethylene glycols other than polyethylene glycol (15)-hydroxystearate, unsubstituted polyethylene glycols, and mixtures thereof. More preferably, at least one polyethylene glycol is selected from polyethylene glycol (15)-hydroxystearate, fatty acid-derived polyethylene glycols other than polyethylene glycol (15)-hydroxystearate, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 4000, and mixtures thereof. More preferably, at least one polyethylene glycol is selected from polyethylene glycol (15)-hydroxystearate, fatty acid-derived polyethylene glycols other than polyethylene glycol (15)-hydroxystearate, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and mixtures thereof.

[0071] More preferably, at least one polyethylene glycol is selected from polyethylene glycol (15)-hydroxystearate, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 4000, and mixtures thereof. More preferably, at least one polyethylene glycol is selected from polyethylene glycol (15)-hydroxystearate, polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and mixtures thereof.

[0072] Preferably, at least one polyethylene glycol is a mixture of at least one substituted polyethylene glycol and at least one unsubstituted polyethylene glycol. More preferably, at least one polyethylene glycol is a mixture of polyethylene glycol (15)-hydroxystearate and polyethylene glycol 400. Preferably:

[0073] - With respect to the total volume of the pharmaceutical composition, the substituted polyethylene glycol, particularly polyethylene glycol (15)-hydroxystearate, is 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; and

[0074] - With respect to the total volume of the pharmaceutical composition, the unsubstituted polyethylene glycol, particularly polyethylene glycol 400, is 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.

[0075] Preferably, at least one solvent is dimethyl sulfoxide. Preferably, the pharmaceutical composition contains 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.

[0076] 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.

[0077] More advantageously, at least one solvent is ethanol. 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 ethanol.

[0078] Ethanol of any ethanol volume fraction (= ABV) can be used. Advantageously, the ethanol can be an ethanol solution of at least 50% ABV, preferably an ethanol solution of at least 70% ABV, more preferably an ethanol solution of at least 90% ABV, even more preferably an ethanol solution of at least 96% ABV (also known as industrial grade ethanol), and most preferably an ethanol solution of at least 99% ABV (also known as anhydrous ethanol). In one embodiment, the ethanol can be an ethanol solution of 96% ABV.

[0079] Preferably, the water is ultrapure water.

[0080] Preferably, the pharmaceutical composition comprises water in an amount that satisfies 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.

[0081] Advantageously, the pharmaceutical composition comprises 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 most preferably about 150 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture thereof. For clarity, "1 mg / mL of the compound of formula (I)" means that 1 milligram of the compound of formula (I) is contained in every 1 milliliter of the pharmaceutical composition.

[0082] Advantageously, the pharmaceutical composition comprises about 150 mg / mL of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture thereof.

[0083] In one embodiment, the pharmaceutical composition comprises:

[0084] - A compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, wherein formula (I) is as described above,

[0085] - 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, most preferably about 15% v / v of polyethylene glycol (15)-hydroxystearate, the percentage being relative to the total volume of the pharmaceutical composition,

[0086] - 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, most preferably about 10% v / v of polyethylene glycol 400, the percentage being relative to the total volume of the pharmaceutical composition,

[0087] - 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, the percentage being relative to the total volume of the pharmaceutical composition, and

[0088] - Water.

[0089] In a preferred embodiment, the pharmaceutical composition comprises:

[0090] - 1 mg / mL to 320 mg / mL of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, wherein formula (I) is as described above,

[0091] - About 15% v / v of polyethylene glycol (15)-hydroxystearate relative to the total volume of the pharmaceutical composition,

[0092] - About 10% v / v of polyethylene glycol 400 relative to the total volume of the pharmaceutical composition,

[0093] - About 5% v / v of ethanol relative to the total volume of the pharmaceutical composition, and

[0094] - A sufficient amount of 100% v / v water.

[0095] In a more preferred embodiment, the pharmaceutical composition consists of:

[0096] - 1 mg / mL to 320 mg / mL of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a mixture thereof, wherein formula (I) is as described above,

[0097] - About 15% v / v of polyethylene glycol (15)-hydroxystearate relative to the total volume of the pharmaceutical composition,

[0098] - polyethylene glycol 400 at about 10 volume / volume % relative to the total volume of the pharmaceutical composition,

[0099] - ethanol at about 5 volume / volume % relative to the total volume of the pharmaceutical composition, and

[0100] - water at about 70 volume / volume % relative to the total volume of the pharmaceutical composition.

[0101] Advantageously, the pharmaceutical composition is an emulsion. The emulsion can be selected from single emulsions and double emulsions. More advantageously, the pharmaceutical composition is a single emulsion.

[0102] Advantageously, the pharmaceutical composition is a suspension.

[0103] Advantageously, the pharmaceutical composition is a solution, preferably a clear solution.

[0104] Advantageously, the pharmaceutical composition is for oral administration. In other words, advantageously, the pharmaceutical composition is an oral pharmaceutical composition.

[0105] Advantageously, the pharmaceutical composition further comprises at least one excipient selected from: solvents, diluent carriers, fillers, swelling agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonizing agents, thickening agents or emulsifying agents, stabilizers, absorption promoters, flavoring agents, taste masking agents, preservatives, antioxidants, buffers, gelling agents, solubilizers and combinations thereof. More advantageously, the pharmaceutical composition further comprises at least one flavoring agent and / or taste masking agent. Preferably, according to the present invention, when other excipients are present in the pharmaceutical composition, the amount of the other excipients is generally present in an amount of 0.001 wt% to 5 wt%, preferably 0.001 wt% to 1 wt% relative to the total weight of the pharmaceutical composition. It goes without saying that those skilled in the art will carefully select these optional excipients such that the advantageous properties inherent in the pharmaceutical composition of the present invention are not adversely affected, or are substantially not adversely affected, by one or more of the envisaged excipients.

[0106] The pharmaceutical composition is used as a medicine

[0107] The present invention also relates to the above pharmaceutical composition according to the present invention for use as a medicament in a subject in need thereof.

[0108] The present invention also relates to a method for treating and / or preventing a disease by administering an effective amount of the above pharmaceutical composition according to the present invention to a subject in need thereof.

[0109] The present invention also relates to the use of the above pharmaceutical composition according to the present invention for the preparation of a medicament.

[0110] The present invention also relates to the use of the above-mentioned pharmaceutical composition according to the present invention for treating and / or preventing a disease in a subject in need thereof.

[0111] In the present application, the medicament can be a medicament for human use or a veterinary medicament.

[0112] The pharmaceutical composition is used for treating or preventing diseases

[0113] The present invention also relates to the above-mentioned pharmaceutical composition according to the present invention for treating and / or preventing cancer in a subject in need thereof.

[0114] The present invention also relates to a method for treating and / or preventing cancer by administering an effective amount of the above-mentioned pharmaceutical composition according to the present invention to a subject in need thereof.

[0115] The present invention also relates to the use of the pharmaceutical composition according to the present invention for preparing a medicament for treating and / or preventing cancer in a subject in need thereof.

[0116] The present invention also relates to the use of the pharmaceutical composition according to the present invention for treating and / or preventing cancer in a subject in need thereof.

[0117] Advantageously, the cancer is a solid cancer.

[0118] Advantageously, the cancer is selected from: esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, pancreatic cancer, and melanoma. More advantageously, the cancer is selected from colorectal cancer and melanoma. Even more advantageously, the cancer is colorectal cancer.

[0119] Advantageously, the cancer can be selected from: esophageal cancer, gastrointestinal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urethral 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 can be selected from gastric cancer, esophageal cancer, and skin cancer. Skin cancer can be selected from melanoma and carcinoma. More advantageously, the cancer can be selected from colorectal cancer, colon cancer, and rectal cancer.

[0120] More advantageously, the cancer can be colorectal cancer.

[0121] More advantageously, the cancer can be colon cancer.

[0122] More advantageously, the cancer can be rectal cancer.

[0123] More advantageously, the cancer can be melanoma.

[0124] Advantageously, the pharmaceutical composition is administered by an administration route selected from the following: oral route, intraperitoneal route, intrathecal route, intraarterial route, intravenous route, intramuscular route, and subcutaneous route. More advantageously, the pharmaceutical composition is administered by the oral route.

[0125] Advantageously, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day. More advantageously, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day by the oral route.

[0126] Advantageously, the pharmaceutical composition is administered daily, every 2 days, every 3 days, or 5 times a week. More advantageously, the pharmaceutical composition is administered daily, every 2 days, every 3 days, or 5 times a week by the oral route.

[0127] Advantageously, the pharmaceutical composition is administered daily, every 2 days, every 3 days, or 5 times a week, particularly by the oral route, wherein during the day of administration, the pharmaceutical composition is administered once a day, twice a day, three times a day, or four times a day.

[0128] Advantageously, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, its solvate, or its mixture in a single administration to a subject is 5 mg to 350 mg per kilogram of the subject's body weight, preferably 5 mg to 250 mg, more preferably about 150 mg. More advantageously, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or mixture in a single administration to a subject by the oral route is 5 mg to 350 mg per kilogram of the subject's body weight, preferably 5 mg to 250 mg, more preferably about 150 mg.

[0129] Advantageously, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or mixture in a single administration to a subject is 5 mg to 50 mg per kilogram of the subject's body weight, preferably 15 mg to 35 mg. More advantageously, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, its solvate, or its mixture in a single administration to a subject by the oral route is 5 mg to 50 mg per kilogram of the subject's body weight, preferably 15 mg to 35 mg.

[0130] Advantageously, the subject is a human, preferably a human over 18 years old, preferably a human over 40 years old, more preferably a human over 50 years old, even more preferably a human over 65 years old. Description of the Drawings

[0131] Figure 1It is a graph showing the average plasma concentration of the compound of formula (I) according to the present invention as a function of time after orally administering a pharmaceutical composition according to the present invention to 3 Swiss albino mice at a dose of 150 mg of the compound of formula (I) per kg of body weight per mouse.

[0132] Figure 2 It is a graph showing the tumor volume as a function of time after orally administering a pharmaceutical composition according to the present invention or a placebo to 10 BALB / C mice bearing CT26 (colorectal) tumors at a dose of 150 mg of the compound of formula (I) per kg of body weight per mouse.

[0133] Figure 3 It is a graph showing the average plasma concentration of the compound of formula (I) according to the present invention as a function of time after orally administering a pharmaceutical composition F according to the present invention or a pharmaceutical composition E according to the prior art to 3 Swiss albino mice at a dose of 150 mg of the compound of formula (I) per kg of body weight per mouse.

[0134] Examples

[0135] The present invention is further illustrated by the following examples. In all examples, the bioavailability F was measured using the following formula: F (%) = [AUCinf(PO) * dose(IV) * 100] / [AUCinf(IV) * dose(PO)].

[0136] Example 1: Preparation of two compositions according to the present invention

[0137] Composition A according to the present invention

[0138] Prepare an organic carrier, which comprises: 50% v / v of HS15, 33.33% v / v of PEG400 and 16.67% v / v of ethanol. Thus, in 1.940 mL of the organic carrier, there is 0.9700 mL of HS15, 0.6466 mL of PEG400 and 0.3234 mL of ethanol.

[0139] Weigh 96.99 mg of the compound of formula (I) according to the present invention on a microbalance and place it in a Wheaton vial. Dissolve the compound in 1.9400 mL of the above-mentioned organic carrier (corresponding to 3 parts of the final carrier volume), and use a magnetic stir bar to mix the dosing solution well for about 30 minutes. Subsequently, slowly add 4.5266 mL of ultrapure water (corresponding to 7 parts of the final carrier volume) of the final carrier component to the Wheaton vial and invert to mix evenly. The final dosing composition is a slightly turbid fluorescent green / fluorescent yellow solution containing 15 mg of the compound of formula (I) per milliliter of the solution.

[0140] Composition B according to the present invention

[0141] Prepare an organic carrier, which comprises: 50 volume / volume % of HS15, 33.33 volume / volume % of PEG400 and 16.67 volume / volume % of ethanol. Thus, in 1.940 mL of the said organic carrier, there is 0.9700 mL of HS15, 0.6466 mL of PEG400 and 0.3234 mL of ethanol.

[0142] Weigh 206.93 mg of the compound of formula (I) according to the present invention on a microbalance and place it in a Wheaton vial. Dissolve the compound in 1.9400 mL of the above-mentioned organic carrier (corresponding to 3 parts of the final carrier volume), and use a magnetic stir bar to mix the dosing solution well for about 30 minutes. Subsequently, slowly add 4.5266 mL of ultrapure water (corresponding to 7 parts of the final carrier volume) of the final carrier component to the Wheaton vial and invert to mix evenly. The final dosing composition is a green to yellow ultrafine suspension containing 32 mg of the compound of formula (I) per milliliter of the suspension.

[0143] Example 2: After administering Composition A according to the present invention prepared in Example 1 of to the compound of formula (I) the bioavailability is evaluated

[0144] Materials and methods

[0145] Administer Composition A according to the present invention prepared in Example 1 to 3 male Swiss albino mice by the oral route at a dose of 150 mg / kg per mouse (corresponding to a volume dose of 10 mL / kg by the oral route) as a single dose. The mice are orally administered through a gavage needle.

[0146] In addition, a composition named Composition IV was administered to another 3 male Swiss albino mice via the intravenous route at a dose of 1 mg / kg per mouse (corresponding to a volume dose of 10 mL / kg via the intravenous route) as a single dose. Each milliliter of Composition IV contains 0.1 mg of the compound of formula (I) according to the present invention and a carrier containing 10% (v / v) of EL and 90% (v / v) of saline solution (an aqueous solution containing 0.9% (w / v) of NaCl). Composition IV was prepared as follows: EL and the saline solution were premixed in a suitable 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.

[0147] Blood samples were collected from the saphenous veins of each of the six mice at different endpoints (T0 + 0.5 hours, T0 + 1 hour, T0 + 2 hours, T0 + 4 hours, and T0 + 8 hours after oral administration or intravenous administration at T0), and the plasma was separated by centrifugation. The plasma concentration of the compound of formula (I) according to the present invention was determined by LC-MS / MS. The pharmacokinetic parameters of the mean concentration were calculated by the non-compartmental model using Phoenix software version 8.1.

[0148] Results

[0149] Figure 1 showed the mean plasma concentration of the compound of formula (I) as a function of time after administration of the composition according to the present invention prepared in Example 1. It can be seen from Figure 1 that the plasma concentration of the compound of formula (I) decreased within 8 hours.

[0150] The pharmacokinetic parameters are as follows:

[0151]

[0152] The bioavailability of compound (I) was 96%. Therefore, after a single oral administration of Composition A according to the present invention, the bioavailability of compound (I) was higher than 90%.

[0153] Example 3: Efficacy of Composition A according to the present invention prepared in Example 1 in treating colorectal cancer

[0154] Materials and Methods

[0155] Tumor cell implantation: 5×10 5 CT26 cells were subcutaneously implanted into the flanks of 20 female BALB / c mice. When the tumors reached approximately 50 mm 3 to 100 mm 3At that time, mice with similar tumor sizes were randomly assigned to the treatment groups ("experimental group" or "control group"). Treatment was initiated 7 days after tumor cell implantation (the experimental group used the composition of the present invention prepared in Example 1 or the control group used a placebo). The preparation of all dosing solutions was carried out in a sterile biosafety cabinet.

[0156] Composition A according to the present invention prepared in Example 1 was administered orally to 10 female BALB / C mice bearing CT26 tumors (corresponding to the "experimental group") at a dose of 150 mg / kg per mouse (corresponding to a volume dose of 10 mL / kg via the oral route) daily for 13 days (starting from Day 1) via the oral route.

[0157] The vehicle (containing 50% v / v of HS15, 33.33% v / v of PEG400 and 16.67% v / v of ethanol, the percentages being relative to the total volume of the vehicle) was administered orally to another 10 female BALB / C mice bearing CT26 tumors daily for 13 days (starting from Day 1) via the oral route as a placebo (corresponding to the "control group").

[0158] The follow-up of each mouse included: body weight measurement twice a week, daily clinical observation (general signs / general symptoms), tumor volume measurement three times a week, tumor analysis, and blood analysis.

[0159] The tumor was measured using a digital caliper. The length, width, and depth of the tumor were measured and used to calculate the tumor volume.

[0160] In addition, after removing the tumor from the mouse, the tumor was weighed on Day 13.

[0161] Results

[0162] Figure 2 showed the tumor volume as a function of time after administration of the composition prepared in Example 1 or the placebo. It can be seen from Figure 2 that compared with the control group, oral administration of the composition according to the present invention prepared in Example 1 reduced the tumor volume to one-third of the original on Day 13.

[0163] In addition, on Day 13, the average tumor weight of the control group was 970 mg and that of the experimental group was 341 mg. Therefore, compared with the control group, oral administration of the composition according to the present invention reduced the CT26 tumor in BALB / c mice to approximately one-third of the original.

[0164] In addition, the body weight measurement results showed that there was no significant statistical difference between the control group and the experimental group, indicating that oral administration of the composition according to the present invention prepared in Example 1 had good tolerance.

[0165] Example 4: Comparison of the bioavailability of the compound of formula (I) after administering the composition according to the present invention and the composition according to the prior art by oral route

[0166] Materials and Methods

[0167] administered

[0168] Two compositions were prepared:

[0169] Composition F according to the present invention: An organic carrier was prepared, which comprised: 50% v / v of HS15, 33.33% v / v of PEG400 and 16.67% v / v of ethanol. Thus, in 1.940 mL of said organic carrier, there was 0.9700 mL of HS15, 0.6466 mL of PEG400 and 0.3234 mL of ethanol. The compound of formula (I) according to the present invention was weighed on a microbalance and placed in a Wheaton vial. The compound was dissolved in 1.9400 mL of the above organic carrier and the dosing solution was stirred well for about 30 minutes at 25 °C with a magnetic stir bar at 800 rpm. Subsequently, 4.5266 mL of ultrapure water, the final carrier component, was slowly added to the Wheaton vial and mixed thoroughly by inverting. The final composition was named Composition F, which contained 15% v / v of HS15, 10% v / v of PEG400, 5% v / v of ethanol and 70% v / v of ultrapure water, and 0.3 mg of the compound of formula (I) per mL of Composition F.

[0170] Composition E according to the prior art: The compound of formula (I) according to the present invention was added to a mixture containing 1.2% v / v of methylcellulose, 0.1% v / v of Tween 80 (polyethylene glycol sorbitan monooleate, CAS No.: 9005-65-6), and sufficient 100% v / v of deionized water. The resulting suspension was named Composition E, which comprised 5 mg of the compound of formula (I) per mL of Composition E.

[0171] Administration:

[0172] Composition F according to the present invention was administered orally as a single dose at a dose of 150 mg of the compound of formula (I) per kg of body weight per mouse to 3 healthy male Swiss albino mice.

[0173] Composition E according to the prior art was administered orally as a single dose at a dose of 150 mg of the compound of formula (I) per kg of body weight per mouse to 3 healthy male Swiss albino mice.

[0174] Blood samples: For each mouse, approximately 40 μL to approximately 50 μL of blood samples were collected at different endpoints (at T0 + 0.25 hours, T0 + 0.5 hours, T0 + 1 hour, T0 + 2 hours, T0 + 4 hours, and T0 + 8 hours after oral administration at T0) by puncturing the saphenous vein; the blood was collected into a collection tube containing an anticoagulant (lithium heparin); the collection tube was centrifuged (2000 g, 10 minutes, 4 °C) to obtain plasma. Before LC-MS / MS analysis, the samples were stored in polypropylene tubes at a temperature < -65 °C (n = 126). Pharmacokinetic parameters were calculated by non-compartmental analysis (NCA) of the PK curves using Phoenix WinNonlin 7.0 software.

[0175] Results

[0176] The pharmacokinetic parameters after oral administration were as follows:

[0177]

[0178] It can be seen that after single oral administration of Composition F according to the present invention, the maximum concentration Cmax of the compound of formula (I) according to the present invention was reached 30 minutes to 1 hour after administration; it was 29.75 μM for an administration dose of 150 mg / kg. After single oral administration of Composition E according to the prior art, the maximum concentration Cmax of the compound of formula (I) according to the present invention was reached 30 minutes to 2 hours after administration; it was 4.69 μM for a dose of 150 mg / kg. Therefore, the maximum concentration Cmax after oral administration of Composition F according to the present invention is greater than the maximum concentration Cmax after oral administration of Composition E according to the prior art.

[0179] In view of the above results, it can be concluded that compared with Composition E according to the prior art, Composition F according to the present invention enables the compound of formula (I) to have faster absorption (see Tmax) and better exposure (see AUC 0-inf ).

[0180] In addition, the oral bioavailability after single oral administration of Composition F according to the present invention was approximately 62.46%, while the oral bioavailability after single oral administration of Composition E according to the prior art was approximately 2.81%.

[0181] Therefore, compared with Composition E in the prior art, Composition F according to the present invention enables the compound of formula (I) to have better oral bioavailability.

Claims

1. A pharmaceutical composition comprising: - A compound of formula (I) or a pharmaceutically acceptable salt, solvate or mixture thereof, wherein formula (I) is as follows: - At least one polyethylene glycol in an amount of 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, selected from substituted polyethylene glycols, unsubstituted polyethylene glycols and mixtures thereof, the percentage being relative to the total volume of the pharmaceutical composition, - At least one solvent in an amount of 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, selected from ethanol, dimethyl sulfoxide, dimethylacetamide and mixtures thereof, the percentage being relative to the total volume of the pharmaceutical composition, and - Water.

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

3. The pharmaceutical composition according to claim 2, wherein the unsubstituted polyethylene glycol is in an amount of 5% v / v to 15% v / v, preferably 7% v / v to 13% v / v, more preferably 8% v / v to 12% v / v, even more preferably about 10% v / v, relative to the total volume of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 2 or 3, wherein the substituted polyethylene glycol is in an amount of 10% v / v to 20% v / v, preferably 12% v / v to 18% v / v, more preferably 14% v / v to 16% v / v, even more preferably about 15% v / v, relative to the total volume of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein 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, even more preferably about 70% v / v of water.

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

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

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises at least one other excipient selected from: solvents, diluent carriers, fillers, swelling agents, binders, disintegrants, polymers, lubricants, glidants, surfactants, isotonizing agents, thickening agents or emulsifying agents, stabilizers, absorption promoters, fragrances, taste masking agents, preservatives, antioxidants, buffers, gelling agents, solubilizers and combinations thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, which is used as a medicine.

10. The pharmaceutical composition according to any one of claims 1 to 8, which is used for treating or preventing cancer in a subject in need thereof.

11. The pharmaceutical composition for the use according to claim 10, wherein the cancer is a solid cancer, preferably, the solid cancer is selected from: esophageal cancer, gastrointestinal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, biliary tract cancer, liver cancer, kidney cancer, lung cancer, pleural cancer, urethral 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: esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, colon cancer, rectal cancer and pancreatic cancer, even more preferably, the solid cancer is selected from: colorectal cancer, colon cancer and rectal cancer.

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

13. The pharmaceutical composition for the use according to any one of claims 9 to 12, wherein the pharmaceutical composition is administered by an administration route selected from: oral route, intraperitoneal route, intrathecal route, intraarterial route, intravenous route, intramuscular route and subcutaneous route, preferably, the pharmaceutical composition is administered by the oral route.

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

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

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