Low sodium oxybate once nightly composition

Abstract

Compositions providing a once-a-night dose of oxybate are provided. The compositions containing bilayer-coated oxybate anion exchange resin complex multiparticulates provide modified release of the oxybate for 5 to 8 hours post-dosing. Also provided are methods of treating patients in need thereof with pharmaceutical compositions containing the oxybate – anion exchange resin complex.

Description

This abstract provides compositions for providing a once-nightly dose of hydroxybutyrate. Compositions comprising multiparticles of a bilayer-coated hydroxybutyrate anion exchange resin complex provide modulated release of hydroxybutyrate over 5 to 8 hours after administration. Methods for treating patients in need with pharmaceutical compositions containing hydroxybutyrate-anion exchange resin complexes are also provided.

Claims

CLAIMS:

1. An extended release oxybate powder for oral suspension (POS) which provides a once-a-night oxybate dose, said powder for oral suspension comprising a blend of oxybate-containing multiparticulates having different release profiles as defined in (a), (b) and (c):(a) immediate release oxybate - anion exchange resin complex multiparticulates which comprises oxybate bound to ion exchange sites in an anion exchange resin:(b) pH-independent diffusion barrier coated oxybate - anion exchange resin complex - optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a w ater-insoluble film-forming polymer which confers an extended release to the oxybate, and wherein the pH-independent diffusion barrier coating layer is over the oxybate - anion exchange resin complex - optional matrix;(c) small intestine targeted drug coating system (SITCS) coated oxybate multiparticulates which comprise a blended coating layer over pH-independent diffusion barrier coated oxybate - anion exchange resin complex - optional matrix multiparticulates, wherein the pH-independent diffusion barrier coating layer comprises a water-insoluble filmforming polymer, and wherein the pH-independent diffusion barrier coating layer is over the oxybate -anion exchange resin complex - optional matrix; wherein the blended coating layer comprises a pH-dependent polymer and a pH-independent polymer, wherein the bilayer coating confers a delayed and extended release profile to the oxybate in the bilayer coated oxybate - anion exchange resin - optional matrix of (c), and wherein the oxybate - anion exchange resin complex - optional matrix of (a), (b) or (c) comprise oxy bate bound to ion exchange sites in an anion exchange resin in an optional matrix which further comprises at least one hydrophilic or hydrophobic polymer, w herein the complex - optional matrix in each of (a), (b), or (c) may be tire same or may differ from each other;(d) the equivalent of about 1 mEq to about 12 mEq of calcium chloride per 9 gm oxybate dose of the POS; and wherein the POS contains less than the equivalent of 200 mg of total sodium per 9 gm oxybate dose of the POS.

2. The extended release oxybate powder for oral suspension (POS) of claim 1. wherein about 10% w / w to about 80% w / w of the total oxybate in the POS is in the immediate release multiparticulates (a).

3. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 3, wherein about 30% w / w to about 75% w / w of the total oxybatc in the POS is in the immediate release multiparticulates (a).

4. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 3, wherein about 50% w / w to about 70% w / w of the total oxybate in the POS is in the immediate release multiparticulates (a).

5. The extended release oxybate powder for oral suspension (POS) of any one of claim 1 to 4, wherein about 25% w / w to about 70% w / w of the total oxybate in the POS is in the extended release components (b) and (c).

6. The extended release oxybatc powder for oral suspension (POS) of any one of claims 1 to 5, wherein about 25% w / w to about 50% w / w of the total oxybate in the POS is in the extended release components (b) and (c).

7. The extended release oxybatc powder for oral suspension (POS) of any one of claims 1 to 6, wherein about 40% w / w of the total oxybate in tire POS is in the extended release components (b) and (c).

8. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 7, wherein about 5% w / w to about 30% w / w of the total oxybate in the POS is in the extended release components.

9. The extended release oxybate powder for oral suspension (POS) of claim 8. wherein about 10% w / w to about 15% w / w of tire total oxybate in the POS is in extended release components (b).

10. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 7, wherein the POS contains the equivalent of 175 mg or less of total sodium per 9 gm dose.11 The extended release oxybate powder for oral suspension (POS) of any one of claims1 to 8, wherein the POS contains the equivalent of about 5 mg to about 175 mg of total sodium per 9 gm dose.

12. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 9, wherein the POS contains the equivalent of about 150 mg of total sodium per 9 gm dose.

13. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 9, wherein the POS contains the equivalent of about 1 g, 4.5 g, 6 g, 7.5 g, 9 g, or 10 gm dose oxybate, as determined based on the equivalent of sodium oxybate.

14. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 13, wherein the calcium chloride equivalent comprises one or more of: magnesium chloride, sodium chloride, zinc chloride, potassium chloride, calcium carbonate, potassium carbonate, sodium bicarbonate and / or combination thereof.

15. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 14, wherein the oxybate - anion exchange resin complex of comprises about 15% w / w to about 35% w / w oxybate, based on the total weight of the oxybate - anion exchange resin absent any matrix or coating component.

16. The extended release oxybate powder for oral suspension (POS) of claim 12, wherein the oxybatc - anion exchange resin complex comprises 25 % w / w to about 30% w / w oxybatc, based on the total weight of the oxybate - anion exchange resin absent any matrix or coating component.

17. The extended release oxybate powder for oral suspension (POS) of any one of claims 1 to 16, wherein the extended release coated oxybate - anion exchange resin complex of (b)and / or (c) comprises a matrix in an amount of about 20% w / w to about 40% w / w matrix forming polymer, based on the total weight of the oxybate - anion exchange resin - matrix, absent any coating component.

18. The extended release oxy bate power for oral suspension (POS) of any one of claims 1 to 16, wherein tire POS further comprises an interpenetrating polymer network (IPN) release forming system, optionally wherein tire IPN forming system comprises two independently crosslinked moieties cross-linked to at least one crosslinking agent, an optional gas generating agent.

19. The extended release oxybate pow er for oral suspension (POS) of any one of claims 1 to 18, wherein the POS further comprises a potassium bicarbonate, a calcium bicarbonate, carrageenan gum, gellan gum, a pH adjuster, a polysorbate, a glidant, a bulking agent, a filler, a colorant, or combinations thereof.

20. An extended release oxybate powder for oral suspension (POS) which provides a once-a-night extended release oxybate dose, said powder for oral suspension comprising:(a) immediate release oxybate - anion exchange resin complex multiparticulates which comprises oxybate bound to ion exchange sites in an anion exchange resin;(b) at least tw o different extended release oxybate components comprising a drug - ion exchange resin complex;(c) the equivalent of about 1 mEq to about 12 mEq of calcium chloride per 9 gm oxybate dose of the POS; and(d) less than the equivalent of 200 mg of total sodium per 9 gm oxybate dose of the POS, wherein post-administration to a patient, a suspension comprising the POS provides a pharmacokinetic profile for oxybate of at least one of: a Cmax of (i) 87.98 pg / mL to 126 pg / mL, or about 107 pg / mL, a Cmax of 85.6 pg / mL to 133.76 pg / mL, or 77.04 pg / mL to 117.711 pg / mL, as calculated using arithmetic mean and / or (ii) a Cmax of about 105 pg / mL, or 84.38 pg / mL to 131.84 pg / mL, 94.92 pg / mL to 116.01 pg / mL, as calculated using geometric mean; an AUCinf of (i) 518.20 hr*pg / mL to 719.725 hr*pg / mL; or about 575 hr*pg / mL, or of 304.11 hr*pg / mL to 846.67 hr*pg / mL, 460.62 hr*pg / mL to 719.725 hr*pg / mL, ascalculated using arithmetic mean and / or (ii) an AUCinf of about 520 hr* pg / mL, or 428.58 hr*pg / mL to 669.66 hr*pg / mL; or about 482. 16 hr*pg / mL to 589.30 hr*pg / mL, as calculated using geometric mean.

21. A reconstituted suspension comprising the extended release oxybate powder for oral suspension of any one of claims 1 to 20, wherein the suspension comprises about 20 mL to about 300 mL aqueous suspending agent.

22. The reconstituted suspension of claim 21, wherein the suspension comprises about 100 mL to about 250 mL aqueous suspending agent.

23. The reconstituted suspension of claim 21, wherein the suspension comprises about 175 mL to about 225 mL aqueous suspending agent.

24. The reconstituted suspension of any one of claims 21 to 23. wherein the composition comprises a dose of 1g oxybate, as measured based on equivalents to sodium oxybate25. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a dose of 4.5 g oxybate, as measured based on equivalents to sodium oxybate.

26. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a dose of 6 g oxybate, as measured based on equivalents to sodium oxybate .

27. The reconstituted suspension of any one of claims 21 to 24. wherein the composition comprises a dose of 7.5 g oxybate, as measured based on equivalents to sodium oxy bate.

28. The reconstituted suspension of any one of claims 21 to 24, wherein the composition comprises a dose of 9 g oxybatc. as measured based on equivalents to sodium oxybatc .

29. The reconstituted suspension of any one of claims 21 to 24. wherein tire composition comprises a dose of 10 g oxybate, as measured based on equivalents to sodium oxybate .

30. A method for treating narcolepsy, idiopathic hypersomnia, or cataplexy, said method comprising dosing a patient with a reconstituted suspension of any one of claims 21 to 29.

31. Use of the POS of any one of claims 1 to 20 or the reconstituted suspension of any one of claims 21 to 29.

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