Treatment of migraine
The present disclosure provides methods for the acute treatment of migraine with or without aura, comprising the administration of ubrogepant. In particular, the present disclosure provides methods for the acute treatment of migraine in patients having hepatic impairment; in patients with renal impairment; and in patients concurrently taking CYP3A4 modulators or BCRP and/or P-gp only inhibitors.
1. A rapidly-disintegrating pharmaceutical tablet comprising:
(a) an extrudate comprising:
(i) a polymer matrix,
(ii) a compound of Formula Ia,
wherein each of R b is —H, and
(iii) a dispersing agent,
wherein the compound of Formula Ia is dispersed within the polymer matrix, and
(b) a disintegration system;
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 according to claim 1 , wherein the disintegration system comprises croscarmellose sodium and sodium chloride.
3. The tablet according to claim 2 , wherein croscarmellose sodium and sodium chloride are present in a 1:1 weight ratio.
4. The tablet according to claim 1 , wherein the dispersing agent is selected from the group consisting of d-alpha-tocopheryl polyethyleneglycol succinate and polyethoxylated castor oil.
5. The tablet according to claim 4 , wherein the dispersing agent is d-alpha-tocopheryl polyethyleneglycol succinate.
6. The tablet according to claim 3 , wherein the dispersing agent is d-alpha-tocopheryl polyethyleneglycol succinate.
7. The tablet according to claim 5 , wherein the dispersing agent is present in an amount of at least about 5 wt % of the extrudate.
8. The tablet according to claim 6 , wherein the dispersing agent is present in an amount of at least about 5 wt % of the extrudate.
9. The tablet according to claim 1 , wherein the polymer matrix comprises an excipient selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer and HPMCAS.
10. The tablet according to claim 8 , wherein the polymer matrix comprises an excipient selected from the group consisting of polyvinylpyrrolidone-vinyl acetate copolymer and HPMCAS.
11. The tablet according to claim 1 , wherein the extrudate comprises less than about 0.77 mole % degradation products of the compound of Formula Ia.
12. The tablet according to claim 9 , wherein the extrudate comprises less than about 0.77 mole % degradation products of the compound of Formula Ia.
13. The tablet according to claim 1 , wherein the tablet has a hardness of from about 12 kP to about 18 kP.
14. The tablet according to claim 8 , wherein the tablet has a hardness of from about 12 kP to about 18 kP.
15. The tablet according to claim 1 , 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 Ia contained therein in less than about 20 minutes.
16. The tablet according to claim 11 , 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 Ia contained therein in less than about 20 minutes.
17. The tablet according to claim 1 , wherein the tablet comprises about 50 mg of the compound of Formula Ia.
18. The tablet according to claim 8 , wherein the tablet comprises about 50 mg of the compound of Formula Ia.
19. The tablet according to claim 10 , wherein the tablet comprises about 50 mg of the compound of Formula Ia.
20. The tablet according to claim 1 , wherein the tablet further comprises mannitol, colloidal silica, microcrystalline cellulose, and sodium stearyl fumarate.
21. A rapidly-disintegrating pharmaceutical tablet comprising:
(a) an extrudate comprising:
(i) a polymer matrix selected from the group consisting of polyvinylpyrrolidone vinyl acetate copolymer and HPMCAS,
(ii) d-alpha-tocopheryl polyethyleneglycol succinate,
(iii) a compound of Formula Ia,
wherein each of R b is —H, and
wherein the compound of Formula Ia is dispersed within the polymer matrix; and
(b) a disintegration system comprising sodium chloride and croscarmellose sodium;
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.
22. The tablet according to claim 21 , wherein the tablet further comprises mannitol.
23. The tablet according to claim 21 , wherein the tablet further comprises colloidal silica.
24. The tablet according to claim 21 , wherein the tablet further comprises sodium stearyl fumarate.
25. The tablet according to claim 21 , wherein the tablet further comprises microcrystalline cellulose.
26. The tablet according to claim 21 , wherein the tablet further comprises mannitol, colloidal silica, sodium stearyl fumarate, and microcrystalline cellulose.
27. The tablet according to claim 26 , wherein the d-alpha-tocopheryl polyethyleneglycol succinate is present in an amount of at least about 5 wt % of the extrudate.
28. The tablet according to claim 27 , wherein the sodium chloride and the croscarmellose sodium are present in a 1:1 weight ratio.
29. A rapidly-disintegrating pharmaceutical tablet comprising:
(a) an extrudate comprising:
(i) a polymer matrix, wherein the polymer matrix comprises an excipient selected from the group consisting of polyvinylpyrrolidone and HPMCAS,
(ii) d-alpha-tocopheryl polyethyleneglycol succinate present in an amount of at least about 5 weight % of the extrudate,
(iii) a compound of Formula Ia,
wherein each of R b is —H, and
wherein the compound of Formula Ia is dispersed within the polymer matrix;
(b) a disintegration system comprising sodium chloride and croscarmellose sodium in a 1:1 weight ratio;
(c) mannitol;
(d) colloidal silica;
(e) microcrystalline cellulose; and
(f) sodium stearyl fumarate;
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.
30. The tablet according to claim 29 , wherein the tablet comprises about 50 mg of the compound of Formula Ia.