Tablet formulation for CGRP active compounds
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 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.
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:
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,
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° 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:
wherein, each of “R b ” is —H or each of “R 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:
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° 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° 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-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-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)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide.
14. The tablet of claim 7 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.
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:
wherein all of R b are either —H or all of R 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 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.
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-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-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)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[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.