Claims for Patent: 10,117,836

Summary for Patent: 10,117,836

Title:	Tablet formulation for CGRP active compounds
Abstract:	The present invention is directed to compositions comprising an extrudate or solid solution of a compound, or a salt thereof, of Formula I (API): Formula I, wherein "R.sup.a" 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. ##STR00001##
Inventor(s):	Johnson; Mary Ann (West Point, PA), Allain; Leonardo Resende (Lansdale, PA), Eickhoff; W. Mark (Lansdale, PA), Ikeda; Craig B. (Harleysville, PA), Brown; Chad D. (Quakertown, PA), Flanagan, Jr.; Francis J. (North Wales, PA), Nofsinger; Rebecca (Lansdale, PA), Marota; Melanie (Lansdale, PA), Lupton; Lisa (South San Francisco, CA), Patel; Paresh B. (Langhorne, PA), Xi; Hanmi (Furlong, PA), Xu; Wei (North Wales, PA)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	15/115,026
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,117,836
Patent Claims:	1. A tablet comprising: (a) an extrudate comprising: (i) a water-soluble polymer matrix; (ii) a dispersing agent; and (iii) a compound of Formula I, or a pharmaceutically acceptable salt thereof: ##STR00007## wherein "R.sup.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, wherein said tablet has a hardness of from about 12 kP to about 18 kP, and wherein said tablet achieves complete disintegration in less than about 5 minutes in a tablet disintegration test complying with USP 31-NF26 Chapt. 701 using aqueous HCl at pH 1.8 at 37.degree. C. 2. The tablet of claim 1 wherein the polymer matrix in said extrudate is a water soluble polyvinylpyrrolidone/vinyl acetate (PVP-VA) copolymer. 3. The tablet of claim 1 wherein said disintegration system comprises powdered sodium chloride and croscarmellose sodium. 4. The tablet of claim 1 wherein the compound of Formula I is a compound of Formula Ia, or a salt thereof: ##STR00008## wherein, each of "R.sup.b" is --H or each of "R.sup.b" is --F. 5. The tablet of claim 4 which further comprises: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate. 6. The tablet of claim 1 wherein said extrudate comprises about 50 wt % of said tablet and said extrudate is comprised of from about 5 wt % to about 23 wt % of a compound of Formula I. 7. A tablet 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 compound of Formula I, or a pharmaceutically acceptable salt thereof: ##STR00009## wherein "IV" 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 comprising powdered sodium chloride and croscarmellose sodium. 8. The tablet of claim 7 wherein the disintegration system comprises a 1:1 weight ratio of powdered sodium chloride and croscarmellose sodium. 9. The tablet of claim 8 wherein the dispersing agent in said extrudate is d-alpha-tocopheryl polyethyleneglycol succinate (TPGS). 10. The tablet of claim 7 wherein the tablet has a hardness of from about 12 kP to about 18 kP, and wherein when said tablet 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.degree. C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes. 11. The tablet of claim 7 wherein the tablet has a tensile strength of 1.75 MPa, and wherein when said tablet 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.degree. C. releases at least about 90% of the compound of Formula I contained therein in less than about 20 minutes. 12. The tablet of claim 7 wherein the compound is (S)--N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifl- uorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]p- yridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide. 13. The tablet of claim 7 wherein the compound is (S)--N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperi- din-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrr- olo[2,3-b]pyridine]-3-carboxamide. 14. The tablet of claim 7 wherein said powdered sodium chloride has: (i) a d.sub.50 value of less than about 210 microns; (ii) a d.sub.10 value of less than about 50 microns; and (iii) a d.sub.90 value of less than about 470 microns. 15. The tablet of claim 7 wherein the water-soluble polymer matrix of said extrudate is a copolymer having about a 6:4 polyvinylpyrrolidone/vinyl acetate monomer unit ratio. 16. A formulation suitable for pressing into a tablet, said formulation comprising: a) an extrudate composition comprising a water-soluble polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA copolymer) matrix and dispersed therein: (i) a compound of Formula Ia, or a pharmaceutically acceptable salt thereof: ##STR00010## wherein all of R.sup.b are either --H or all of R.sup.b are --F; and and (ii) tocopherol polyethylene glycol succinate (TPGS), wherein said compound of Formula Ia comprises from about 5 wt % to about 23 wt % of said extrudate and TPGS comprises at least about 5 wt % of said extrudate; and b) a disintegration system comprising: (i) croscarmellose sodium; and (ii) powdered sodium chloride, wherein said disintegration system comprises about 20 wt % of said formulation. 17. The formulation of claim 16 further comprising: (a) mannitol; (b) colloidal silica; (c) microcrystalline cellulose; and (d) sodium stearyl fumarate, and wherein said powdered sodium chloride is characterized by: (i) a d.sub.50 value of less than about 210 microns; (ii) a d.sub.10 value of less than about 50 microns; and (iii) a d.sub.90 value of less than about 470 microns. 18. The formulation of claim 17 wherein the weight ratio of compound of Formula Ia: powdered sodium chloride:croscarmellose sodium is 9:10:10. 19. The formulation of claim 18 wherein said compound of Formula Ia is (S)--N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifl- uorophenyl)piperidin-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]p- yridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide or (S)--N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperi- din-3-yl)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrr- olo[2,3-b]pyridine]-3-carboxamide. 20. The formulation of claim 17 wherein said extrudate is present in an amount of about 50 wt % of the formulation. 21. A tablet made by pressing a formulation of claim 16 in a tableting press to provide a tablet with a tensile strength of about 1.75 MPa.