PHARMACEUTICAL COMPOSITIONS OF CABOZANTINIB
Pharmaceutical compositions are provided, which comprise cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein the inventive compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof. The present invention relates to oral pharmaceutical compositions of cabozantinib, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by cabozantinib.
1 . A pharmaceutical composition suitable for oral administration comprising
a) a therapeutically effective amount of cabozantinib or a pharmaceutically acceptable salt thereof;
b) a pharmaceutically acceptable carrier,
wherein said composition, following oral administration in human subjects exhibits no food effect.
2 . The pharmaceutical composition according to claim 1 , wherein said composition, following oral administration in human subjects under fed condition, provides a geometric mean C max which is about 0.8 to about 1.25 times of a geometric mean C max of said composition having the same dose, following oral administration in human subjects under fasting condition.
3 . The pharmaceutical composition according to claim 1 , wherein said composition, following oral administration in human subjects under fed condition, provides a geometric mean area under the curve AUC 0-72 hr which is about 0.8 to about 1.25 times of a geometric mean area under the curve AUC 0-72 hr of said composition having the same dose, following oral administration in human subjects under fasting condition.
4 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable salt of cabozantinib is cabozantinib (S)-malate.
5 . The pharmaceutical composition according to claim 1 , wherein the moisture content of the composition is less than about 4.5% by weight.
6 . The pharmaceutical composition according to claim 1 , wherein the at least one pharmaceutically acceptable carrier is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinyl pyrrolidine (PVP), and mixtures thereof.
7 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition suitable for oral administration is selected from the group consisting of a tablet, a capsule, a caplet, beads, granules, a powder or an oral suspension.
8 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a tablet.
9 . The pharmaceutical composition according to claim 1 , comprising
a) a therapeutically effective amount of cabozantinib or a pharmaceutically acceptable salt thereof and
b) a pharmaceutically acceptable carrier,
wherein said composition, following oral administration in human subjects under fed condition, provides a geometric mean C max and a geometric mean AUC 0-72 hr , of about 1.2 times to 1.7 times higher than the drug product corresponding to National Drug Code Number 42388-023 and NDA 208692 (CABOMETYX®) having the same dose, following oral administration in human subjects under fasting condition.
10 . The pharmaceutical composition according to claim 9 , wherein the therapeutically effective amount of cabozantinib is equivalent to 2.5 mg, 5 mg, 12 mg, 13 mg, 15 mg, 20 mg, 26 mg, 30 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 50 mg, 55 mg or 60 mg of the cabozantinib free base.
11 . The pharmaceutical composition of claim 8 , wherein the tablet comprises granules of an amorphous solid dispersion of cabozantinib, and further comprises at least one pharmaceutical acceptable excipient having an intra-granular excipient(s) and/or an extra-granular excipient(s).
12 . The pharmaceutical composition of claim 11 , wherein a weight ratio of the amorphous solid dispersion of cabozantinib to the extra-granular excipient(s) is from about 1:0.3 to about 1:5.
13 . The pharmaceutical composition of claim 11 , wherein the amorphous solid dispersion of cabozantinib may be prepared by hot-melt extrusion, spray-drying or co-precipitation.
14 . The pharmaceutical composition of claim 11 , wherein the amorphous solid dispersion of cabozantinib has a weight ratio of the cabozantinib to the pharmaceutically acceptable carrier from about 1:1 to about 1:6, preferably about 1:1 to about 1:5, about 1:1 to about 1:4.
15 . The pharmaceutical composition of claim 14 , wherein the at least one pharmaceutically acceptable carrier is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP/VA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinyl pyrrolidine (PVP), and mixtures thereof.
16 . A method for treating a proliferative disorder comprising administration of the pharmaceutical composition according to claim 1 to a human subject in need thereof.
17 . A method for treating a proliferative disorder comprising administration of the pharmaceutical composition according to claim 1 to a human subject in need thereof, which method comprises: (a) providing the pharmaceutical composition according to claim 1 ; and (b) providing instructions for oral administration of the composition indicating that the composition can be administered to a human subject without regard to food.