Solid dosage forms of palbociclib

Abstract

The present invention relates to solid dosage forms of palbociclib comprising a water-soluble acid. The dosage forms described herein have desirable pharmacokinetic characteristics.

We claim: 
     
         1 . A solid dosage form comprising from about 10 wt % to about 35 wt % of palbociclib, from about 5 wt % to about 25 wt % of a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid, and a pharmaceutically acceptable carrier. 
     
     
         2 . The solid dosage form of  claim 1 , wherein the water-soluble acid is succinic acid. 
     
     
         3 . The solid dosage form of  claim 1 , wherein the pharmaceutically acceptable carrier comprises at least one diluent, and wherein the diluent comprises about 50 wt % to about 75 wt % of the solid dosage form. 
     
     
         4 . The solid dosage form of  claim 3 , wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate and tribasic calcium phosphate. 
     
     
         5 . The solid dosage form of  claim 1 , wherein the pharmaceutically acceptable carrier comprises at least one lubricant, and wherein the lubricant comprises from about 0.5 wt % to about 10 wt % of the solid dosage form. 
     
     
         6 . The solid dosage form of  claim 5 , wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate and sodium stearyl fumarate. 
     
     
         7 . The solid dosage form of  claim 1 , wherein the pharmaceutically acceptable carrier comprises at least one disintegrant, and wherein the disintegrant comprises from about 5 wt % to about 10 wt % of the solid dosage form. 
     
     
         8 . The solid dosage form of  claim 7 , wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate. 
     
     
         9 . The solid dosage form of  claim 1 , in the form of a tablet. 
     
     
         10 . The solid dosage form of  claim 9 , wherein the tablet is film coated. 
     
     
         11 . The solid dosage form of  claim 9 , wherein the tablet is a bilayer tablet. 
     
     
         12 . The solid dosage form of  claim 1 , wherein the dosage form when added to a test medium comprising 500 mL of 10 mM pH 5.5 acetate buffer at 37° C. in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm dissolves: (a) not less than 35% of the palbociclib in 15 minutes; (b) not less than 45% of the palbociclib in 30 minutes; (c) not less than 55% in 60 minutes; or (d) two or more of (a), (b) and (c). 
     
     
         13 . The solid dosage form of  claim 1 , wherein the dosage form when added to a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37° C. in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm dissolves: (a) not less than 40% of the palbociclib in 15 minutes; (b) not less than 35% of the palbociclib in 30 minutes; (c) not less than 25% of the palbociclib in 60 minutes; or (d) two or more of (a), (b) and (c). 
     
     
         14 . A solid dosage form of  claim 1 , wherein the dosage form: (a) has a mean fed/fasted ratio of the area under the plasma concentration versus time curve (AUC) from about 0.8 to about 1.25 after administration of a single oral dose to a subject; (b) has a mean fed/fasted ratio of the maximum plasma concentration (C max ) from about 0.8 to about 1.25 after administration of a single oral dose to a subject; or (c) both (a) and (b). 
     
     
         15 . The solid dosage form of  claim 1 , wherein the dosage form: (a) provides a mean fasted AUC in the range of 80% to 125% of the mean fasted AUC for a control immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject; (b) provides a mean fasted C max  in the range of 80% to 125% of the mean fasted C max  for a control immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject; or (c) both (a) and (b). 
     
     
         16 . The solid dosage form of  claim 1 , wherein the dosage form provides: (a) a mean AUC in the presence of a proton pump inhibitor (PPI) in the range of 80% to 125% of the mean AUC in the absence of the PPI after administration of a single oral dose to a subject; (b) a mean C max  in the presence of a proton pump inhibitor (PPI) in the range of 80% to 125% of the mean C max  in the absence of the PPI after administration of a single oral dose to a subject; or (c) both (a) and (b). 
     
     
         17 . The solid dosage form of  claim 16 , wherein the PPI is rabeprazole. 
     
     
         18 . The solid dosage form of  claim 1 , wherein the dosage form exhibits less than 0.05% acid adduct by weight after storage for 1 years at 25° C. and 60% RH. 
     
     
         19 . The solid dosage form of  claim 1 , wherein the amount of palbociclib in the dosage form is 25 mg, 75 mg, 100 mg or 125 mg. 
     
     
         20 . The solid dosage form of  claim 19 , wherein the amount of palbociclib in the dosage form is 125 mg.