Tablet formulation for cgrp active compounds

Abstract

wherein “Ra” is independently —H or —F, in a water-soluble polymer matrix which further comprises a disintegration system allowing a tablet made therefrom to rapidly disintegrate in the environment in which the API is to be released.

1 - 21 . (canceled) 
     
     
         22 . A method of treating a migraine in a subject in need thereof, comprising administration of an oral dosage composition comprising:
 (a) an extrudate comprising:
 (i) a polymer matrix which is a water soluble polyvinylpyrrolidone/vinyl acetate copolymer; 
 (ii) a dispersing agent; and 
 (iii) a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof: 
   
       
         
           
           
               
               
           
         
         wherein “R a ” is independently —H or —F, and 
         wherein the dispersing agent and compound of Formula I is dispersed within said polymer matrix; and, 
         (b) a disintegration system. 
       
     
     
         23 . The method  claim 22 , wherein the disintegration system comprises powdered sodium chloride and corscarmellose sodium. 
     
     
         24 . The method of  claim 22 , wherein the disintegration system comprises a 1:1 weight ratio of powdered sodium chloride and croscarmellose sodium. 
     
     
         25 . The method of  claim 22 , wherein the dispersing agent in said extrudate is d-alpha-tocopheryl polyethyleneglycol succinate (TPGS). 
     
     
         26 . The method of  claim 22 , wherein said composition further comprises (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate. 
     
     
         27 . The method of  claim 22 , wherein said extrudate comprises about 50 wt % of said composition and said extrudate comprises about 5 wt % to about 23 wt % of a compound of Formula I. 
     
     
         28 . The method of  claim 22 , wherein the composition has a hardness from about 12 kP to about 18 kP, and wherein when said composition is subjected to a dissolution test complying with USP 30 NF25 Chapt. 711, in a paddle-stirring apparatus equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid at pH 1.8 at 37° C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes. 
     
     
         29 . The method of  claim 22 , wherein the composition has a tensile strength of 1.75 MPa, and wherein when said composition is subjected to a dissolution test complying with USP 30 NF25 Chapt. 711, in a paddle-stirring apparatus equipped with USP 2 paddles, operated at 50 rpm, in 900 ml of simulated gastric fluid at pH 1.8 at 37° C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes. 
     
     
         30 . The method of  claim 22 , wherein the compound is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide. 
     
     
         31 . The method of  claim 22 , wherein the compound is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide. 
     
     
         32 . The method of  claim 22 , wherein the compound is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide trihydrate. 
     
     
         33 . The method of  claim 22 , wherein said powdered sodium chloride has: (i) a d 50  value of less than about 210 microns; (ii) a d 10  value of less than about 50 microns; and (iii) a d 90  value of less than about 470 microns. 
     
     
         34 . The method of  claim 22 , wherein the water-soluble polymer matrix of said extrudate is a copolymer having about a 6:4 polyvinylpyrrolidone/vinyl acetate monomer unit ratio. 
     
     
         35 . A process for preparing an extrudate comprising:
 (a) forming a pre-mix by dry-blending an amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and water soluble polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer:   
       
         
           
           
               
               
           
         
         wherein “R a ” is independently —H or —F; 
         (b) feeding an amount of said pre-mix and an amount of molten d-alpha-tocopherol-propylene glycol succinate (TPGS) into an extruder apparatus; and, 
         (c) maintaining the extruder apparatus at a barrel temperature, feed rate and screw speed to form an extrudate comprising a solid solution of the compound of Formula I dispersed within said polymer matrix comprising. 
       
     
     
         36 . The process of  claim 35 , wherein the pre-mix of the compound of Formula I and polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer is in a weight ratio from about 1:3 to about 1:4. 
     
     
         37 . The process of  claim 35 , wherein the weight ratio of the pre-mix of the compound of Formula I and polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer to TPGS is in a weight ratio of about 19:1. 
     
     
         38 . The process of  claim 35 , wherein the compound of Formula I is the crystalline form. 
     
     
         39 . The process of  claim 35 , wherein the compound is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide. 
     
     
         40 . The process of  claim 35 , wherein the compound is (S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide. 
     
     
         41 . The process of  claim 35 , wherein the barrel temperature ranges from about 146° C. to about 160° C.; wherein the feed rate ranges from about 30 g/min to about 52 g/min; and wherein the screw speed ranges from about 2000 rpm to about 6000 rpm.