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 stable amorphous solid dispersion comprising: (a) cabozantinib; and (b) at least one pharmaceutically acceptable carrier; wherein the dispersion is substantially free of cabozantinib crystals when stored at 40° C./75% RH for at least 3 months; and
when a moisture content of the dispersion is controlled to be less than about 4.0% by weight.
2. The stable amorphous solid dispersion according to claim 1 , wherein the cabozantinib comprises cabozantinib (S)-malate.
3. The stable amorphous solid dispersion according to claim 1 , which is prepared by hot-melt extrusion.
4. The stable amorphous solid dispersion according to claim 1 , wherein the amorphous solid dispersion of cabozantinib has a weight ratio of the cabozantinib to the at least one pharmaceutically acceptable carrier from about 1:1 to about 1:6.
5. The stable amorphous solid dispersion 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.
6. The stable amorphous solid dispersion according to claim 1 , which comprises from about 2.5 mg to about 140 mg of the cabozantinib.
7. The stable amorphous solid dispersion according to claim 1 , wherein the amorphous solid dispersion is stable for at least 6 months at 40° C./75% RH (“relative humidity”) or 25° C./60% RH (“relative humidity”).
8. The stable amorphous solid dispersion according to claim 1 , wherein the amorphous solid dispersion further comprises at least one pharmaceutically acceptable excipient, and is in a dosage form suitable for oral administration to a patient.
9. The stable amorphous solid dispersion according to claim 8 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, surfactants, plasticizers, pore-forming agents, stabilizing agents, antioxidants, coating agents and combinations thereof.
10. The stable amorphous solid dispersion according to claim 9 , wherein the dosage form suitable for oral administration to a patient is selected from the group consisting of a tablet, a capsule, a caplet, beads, granules, a powder and an oral suspension.
11. The stable amorphous solid dispersion according to claim 10 , wherein the dosage form is a tablet, and wherein the tablet comprises granules of the amorphous solid dispersion of cabozantinib, and further wherein the at least one pharmaceutical acceptable excipient comprises an intra-granular excipient(s) and/or an extra-granular excipient(s).
12. The stable amorphous solid dispersion according to 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.