Tablet Formulation of 2-Fluoro-N-Methyl-4-[7-(Quinolin-6-Ylmethyl) Imidazo [1,2-B] [1,2,4] Triazin-2-YL] Benzamide

Abstract

The present invention is related to tablets comprising of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, processes for the production thereof, and uses in the treatment of certain cancers.

1 . A tablet comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The tablet of  claim 1 , wherein the tablet comprises, by weight, 10-30% 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof, 50-70% of one or more fillers, 3-20% of one or more disintegrants, 0.2-2% of one or more lubricants, and 0.2-2% of one or more glidants. 
     
     
         3 . The tablet of  claim 1 , which comprises mannitol, microcrystalline cellulose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, colloidal silicon dioxide, and magnesium stearate. 
     
     
         4 . The tablet  claim 1 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 5 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 500 mg of the free base form. 
     
     
         5 . The tablet of  claim 1 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 50 mg of the free base form. 
     
     
         6 . The tablet of  claim 1 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 100 mg of the free base form. 
     
     
         7 . The tablet of  claim 1 , wherein the 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide is present as the dihydrochloride salt. 
     
     
         8 . A tablet comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof, wherein the tablet further comprises:
 (a) an intra-granular phase; and   (b) an extra-granular phase.   
     
     
         9 . The tablet of  claim 8 , wherein the tablet comprises, by weight, 10-30% 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof, 50-70% of one or more fillers, 3-20% of one or more disintegrants, 0.2-2% of one or more lubricants, and 0.2-2% of one or more glidants. 
     
     
         10 . The tablet of  claim 8 , wherein the intra-granular phase comprises 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide or a pharmaceutically acceptable salt thereof, mannitol, microcrystalline cellulose, polyvinylpolypyrrolidone, and polyvinylpyrrolidone. 
     
     
         11 . The tablet of  claim 8 , wherein the intra-granular phase comprises, by weight of the tablet, 10-30% 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide or a pharmaceutically acceptable salt thereof; 10-30% mannitol; 10-30% microcrystalline cellulose; and 0.1-10.0% each of polyvinylpolypyrrolidone, and polyvinylpyrrolidone. 
     
     
         12 . The tablet of  claim 8 , wherein the intra-granular phase comprises, by weight of the tablet, about 24% 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide or a pharmaceutically acceptable salt thereof; about 20% mannitol; about 20% microcrystalline cellulose; about 5% polyvinylpolypyrrolidone; and about 4% polyvinylpyrrolidone. 
     
     
         13 . The tablet of  claim 8 , wherein the extra-granular phase comprises microcrystalline cellulose, colloidal silicon dioxide, polyvinylpolypyrrolidone, and magnesium stearate. 
     
     
         14 . The tablet of  claim 8 , wherein the extra-granular phase comprises, by weight of the tablet, 10-30% microcrystalline cellulose and 0.1-10.0% each of colloidal silicon dioxide, polyvinylpolypyrrolidone, and magnesium stearate. 
     
     
         15 . The tablet of  claim 8 , wherein the extra-granular phase comprises, by weight of the tablet, about 21% microcrystalline cellulose; about 0.5% colloidal silicon dioxide; 5% polyvinylpolypyrrolidone; and about 0.75% magnesium stearate. 
     
     
         16 . The tablet of  claim 8 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 5 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 500 mg of the free base form. 
     
     
         17 . The tablet of  claim 8 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 50 mg of the free base form. 
     
     
         18 . The tablet of  claim 8 , comprising an amount of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptably salt thereof, wherein the amount corresponds to 100 mg of the free base form. 
     
     
         19 . The tablet of  claim 8 , wherein the 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide is present as the dihydrochloride salt. 
     
     
         20 . A method of treating cancer in an individual in need thereof, comprising administering to the individual the tablet of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the cancer is a solid tumor. 
     
     
         22 . The method of  claim 20 , wherein the cancer is lung cancer, liver cancer, gastric cancer, a glioblastoma, breast cancer, gastric cancer, kidney cancer, or nasopharyngeal cancer. 
     
     
         23 . The method of  claim 20 , wherein the cancer is non-small cell lung cancer, hepatocellular carcinoma, or renal cell carcinoma. 
     
     
         24 . The method of  claim 20 , wherein the treatment comprises the administration of an additional anticancer agent selected from the group consisting of erlotinib, gefitinib, and buparlisib. 
     
     
         25 . A tablet comprising 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof, wherein the tablet comprises:
 (a) an intragranular phase comprising, by weight:
 10-30% of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide dihydrochloric acid salt, 
 10-30% of mannitol, 
 10-30% of microcrystalline cellulose, 
 0-1% of sodium dodecyl sulfate, 
 1-10% of polyvinylpolypyrrolidone, and 
 1-10% of polyvinylpyrrolidone; and 
   (b) an extragranular phase comprising, by weight:
 10-30% of microcrystalline cellulose, 
 0.1-1% of colloidal silicon dioxide, 
 1-10% of polyvinylpolypyrrolidone, and 
 0.1-1% of magnesium stearate; 
   wherein the percentages given for the respective ingredients are relative to the total weight of the tablet.   
     
     
         26 . (canceled) 
     
     
         27 . (canceled)