Tofacitinib oral sustained release dosage forms

Abstract

The present invention relates to oral sustained release formulations of tofacitinib and pharmaceutical acceptable salts thereof. The formulations described herein have desirable pharmacokinetic characteristics.

1 .- 114 . (canceled) 
     
     
         115 . A once daily pharmaceutical dosage form comprising:
 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, or 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof,   wherein said dosage form is a sustained release dosage form, and when added to a test medium comprising 900 ml of 0.05M pH 6.8 potassium phosphate buffer at 37° C. in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 1 hour, and not less than 35% and not more than 75% of the tofacitinib, or a pharmaceutically acceptable salt thereof, in 2.5 hours and not less than 75% of the tofacitinib, or pharmaceutically acceptable salt thereof, in 5 hours.   
     
     
         116 . A once daily pharmaceutical dosage form comprising:
 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof,   wherein the dosage form is a sustained release dosage form and when administered orally to a subject provides an AUC in the range of 80% to 125% of the AUC of 5 mg of tofacitinib or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof administered as an immediate release formulation BID.   
     
     
         117 . The pharmaceutical dosage form of  claim 116 , wherein the AUC range is 90% to 110% and the geometric mean plasma of Cmax to Cmin from 20 to 40. 
     
     
         118 . The pharmaceutical dosage form of  claim 117 , wherein the geometric mean plasma Cmax to Cmin from 20 to 30. 
     
     
         119 . The pharmaceutical dosage form of  claim 118 , wherein when the dosage form is administered orally to the subject provides a geometric mean plasma Cmax in the range of 70% to 125% of the mean plasma Cmax of tofacitinib administered as the immediate release formulation BID at steady state. 
     
     
         120 . The pharmaceutical dosage form of  claim 116 , wherein when the dosage form is administered orally to the subject provides a drug holiday in the range of 80% to 110% of the drug holiday of tofacitinib administered as the immediate release formulation BID over a 24 hour period. 
     
     
         121 . The pharmaceutical dosage form of  claim 116 , having a drug holiday from 15 to 18 hours over the 24 hour period. 
     
     
         122 . A once daily pharmaceutical dosage form comprising
 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, or 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof,   wherein said dosage form is a sustained release dosage form, and when administered to a subject has a mean area under the plasma concentration curve versus time following administration from 17 ng-hr/mL per mg of tofacitinib dosed to 42 ng-hr/mL per mg of tofacitinib dosed and a ratio of geometric mean plasma Cmax to Cmin from 10 to 100.   
     
     
         123 . The pharmaceutical dosage form of  claim 122 , wherein the ratio of geometric mean plasma Cmax to Cmin from 20 to 40. 
     
     
         124 . The pharmaceutical dosage form of  claim 123 , wherein the ratio of geometric mean plasma Cmax to Cmin from 20 to 30. 
     
     
         125 . The pharmaceutical dosage form of  claim 122 , wherein the subject has a single, continuous time above 17 ng/ml from 6 to 15 hours and a single, continuous time below 17 ng/ml from 9 to 18 hours over a dosing 24 hours interval. 
     
     
         126 . The pharmaceutical dosage form of  claim 125 , wherein the subject has a single, continuous time above 17 ng/ml from 6 to 9 hours. 
     
     
         127 . The pharmaceutical dosage form of  claim 125 , wherein the subject has a single, continuous time below 17 ng/ml from 15 to 18 hours. 
     
     
         128 . The pharmaceutical dosage form of  claim 122 , wherein the subject has a mean maximum plasma concentration (Cmax) from 3 ng/mL per mg to 6 ng/mL per mg of tofacitinib dosed. 
     
     
         129 . A once daily pharmaceutical dosage form comprising:
 22 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof,   wherein the dosage form is a sustained release dosage form and when administered orally to a subject provides an AUC in the range of 80% to 125% of the AUC of 10 mg of tofacitinib or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof administered as an immediate release formulation BID.   
     
     
         130 . The pharmaceutical dosage form of  claim 129 , wherein the AUC range is 90% to 110% and the geometric mean plasma of Cmax to Cmin from 20 to 40. 
     
     
         131 . The pharmaceutical dosage form of  claim 130 , wherein the geometric mean plasma Cmax to Cmin from 20 to 30. 
     
     
         132 . The pharmaceutical dosage form of  claim 129 , wherein when the dosage form is administered orally to the subject provides a geometric mean plasma Cmax in the range of 70% to 125% of the mean plasma Cmax of tofacitinib administered as the immediate release formulation BID at steady state. 
     
     
         133 . The pharmaceutical dosage form of  claim 129 , wherein when the dosage form is administered orally to the subject provides a drug holiday in the range of 80% to 110% of the drug holiday of tofacitinib administered as the immediate release formulation BID over a 24 hour period. 
     
     
         134 . The pharmaceutical dosage form of  claim 129 , having a drug holiday from 15 to 18 hours over the 24 hour period.