Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
1. A method of treating cataplexy or excessive daytime sleepiness in a human patient with narcolepsy, the method comprising orally administering to the patient a pharmaceutical formulation that comprises an immediate-release portion comprising an oxybate and a modified-release portion comprising an oxybate that may be the same as or different than the oxybate of the immediate-release portion, wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, wherein the orally administering occurs only once per day at bedtime, and wherein the patient has statistically significant improvement on the Maintenance of Wakefulness Test (MWT) at a dosage of the pharmaceutical formulation equivalent to 4.5 g, 6 g, 7.5 g, or 9 g of sodium oxybate as compared to placebo.
2. The method of claim 1 , wherein the patient has a latency to sleep onset about 5 minutes or more than placebo.
3. The method of claim 2 , wherein the sleep latency is determined as the number of minutes a patient remains awake during the MWT.
4. The method of claim 2 , wherein the patient has a reduction in weekly cataplexy attacks.
5. The method of claim 4 , wherein the patient has an average total reduction in weekly cataplexy attacks from 4.83 to 6.65 as compared to placebo.
6. The method of claim 1 , wherein the patient is concomitantly on a stimulant.
7. The method of claim 1 , wherein the patient has an average improvement from 4.98 minutes to 6.21 minutes in the change from baseline in the MWT as compared to placebo.
8. The method of claim 1 , wherein the patient has a 42.1% to 77.0% chance of being much improved or very much improved in a Clinical Global Impression-Improvement (CGI-I) score.
9. The method of claim 1 , wherein the MWT measures latency to sleep onset in minutes averaged over five sessions at 2-hour intervals following nocturnal polysomnography.
10. A method of treating cataplexy or excessive daytime sleepiness in a human patient with narcolepsy, the method comprising:
orally administering to the patient a pharmaceutical formulation that comprises an immediate-release portion comprising an oxybate and a modified-release portion comprising an oxybate that may be the same as or different than the oxybate of the immediate-release portion, wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4 h in equally divided doses, and wherein the orally administering occurs only once per day at bedtime at a dosage of the pharmaceutical formulation equivalent to 4.5 g, 6 g, 7.5 g, or 9 g of sodium oxybate, and
inducing the patient to fall asleep within 15 minutes of the orally administering.
11. The method of claim 10 , wherein the inducing comprising inducing the patient to fall asleep within 5 minutes of the orally administering due, at least in part, to the orally administering.
12. The method of claim 1 , wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 85%.
13. The method of claim 10 , wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 85%.
14. The method of claim 1 , wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 90%.
15. The method of claim 10 , wherein the pharmaceutical formulation achieves a relative bioavailability of greater than 90%.
16. The method of claim 1 , wherein the oxybate of the immediate-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
17. The method of claim 16 , wherein the oxybate of the modified-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
18. The method of claim 1 , wherein the oxybate of the modified-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
19. The method of claim 10 , wherein the oxybate of the immediate-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
20. The method of claim 19 , wherein the oxybate of the modified-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
21. The method of claim 10 , wherein the oxybate of the modified-release portion is selected from the group consisting of pharmaceutically acceptable salts of gamma-hydroxybutyric acid, their hydrates, solvates, complexes or tautomers forms, and combinations thereof.
22. The method of claim 1 , wherein the oxybate of the immediate-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.
23. The method of claim 22 , wherein the oxybate of the modified-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.
24. The method of claim 1 , wherein the oxybate of the modified-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.
25. The method of claim 10 , wherein the oxybate of the immediate-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.
26. The method of claim 25 , wherein the oxybate of the modified-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.
27. The method of claim 10 , wherein the oxybate of the modified-release portion is selected from the group consisting of the sodium salt of gamma-hydroxybutyric acid, the potassium salt of gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyric acid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt of gamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyric acid, any other pharmaceutically acceptable salt forms of gamma-hydroxybutyric acid, and combinations thereof.