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 once-nightly modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions suitable for administration once-nightly for a human patient in need thereof, wherein a 7.5 g dose of the formulation achieves a mean AUC inf of greater than 340 hr×microgram/mL.
2. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the once-nightly modified release formulation is equivalent to an equal dose of an immediate release liquid solution of gamma-hydroxybutyrate administered twice-nightly.
3. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 2 , wherein the once-nightly modified release formulation has a later median T max as compared to the initial dose of an immediate release liquid solution of gamma-hydroxybutyrate administered twice-nightly.
4. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 2 , wherein the once-nightly modified release formulation has a mean C 8h 60% to 130% of the mean C 8h provided by an equal dose of an immediate release liquid solution of sodium oxybate administered twice-nightly.
5. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 4 , wherein the mean AUC inf is greater than 450 hr×microgram/mL.
6. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the 7.5 g dose of the formulation achieves a mean C 8h from 50% to 130% of the mean C 8h provided by an equal dose of an immediate release liquid solution of sodium oxybate administered at to and to in equally divided doses approximately two hours after a standardized evening meal.
7. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 6 , wherein the mean C 8h achieved by the formulation is from 60% to 90% of the mean C 8h provided by the immediate release liquid solution of sodium oxybate.
8. A once-nightly modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions for a human patient in need thereof,
wherein the once-nightly formulation releases at least 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm, and
wherein the once-nightly formulation releases from 10% to 65%, of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.
9. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 8 , wherein the once-nightly modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for two hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.
10. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 9 , wherein the formulation releases greater than 60% of its gamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.
11. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 9 , wherein a 7.5 g dose of the formulation achieves a mean AUC inf of greater than 340 hr×microgram/mL, and wherein the 7.5 g dose of the formulation achieves a mean C 8h from 50% to 130% of the mean C 8h provided by an equal dose of an immediate release liquid solution of sodium oxybate administered at to and to in equally divided doses approximately two hours after a standardized evening meal.
12. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11 , wherein the mean AUC inf is greater than 375 hr×microgram/mL.
13. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11 , wherein the mean AUC inf is greater than 400 hr×microgram/mL.
14. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11 , wherein the mean C 8h achieved by the formulation is from 60% to 90% of the mean C 8h provided by the immediate release liquid solution of sodium oxybate.
15. A once-nightly modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions for a human patient in need thereof,
wherein the immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm,
wherein the modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm, and
wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.
16. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 15 , wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for two hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.
17. A once-nightly modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions, wherein a 4.5 g, 6 g, 7.5 g, or 9 g dose of the formulation achieves a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at to and to in equally divided doses, when administered approximately two hours after a standardized evening meal.
18. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 17 , wherein the 4.5 g, 6 g, 7.5 g, or 9 g dose of the formulation is a 4.5 g dose of the formulation.
19. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 17 , wherein the 4.5 g, 6 g, 7.5 g, or 9 g dose of the formulation is a 9 g dose of the formulation.
20. A once-nightly modified release formulation of gamma-hydroxybutyrate comprising immediate release and modified release portions for a human patient in need thereof, wherein a 7.5 g dose of the formulation given once nightly exhibits a similar PK profile to 9 g of an immediate release liquid solution of sodium oxybate administered at t 0 and t 4h in equally divided doses, when administered approximately two hours after a standardized evening meal.
21. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUC inf is greater than 375 hr×microgram/mL.
22. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUC inf is greater than 400 hr×microgram/mL.
23. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUC inf is greater than 425 hr×microgram/mL.
24. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUC inf is greater than 450 hr×microgram/mL.