Claims for Patent: 11,052,061

Summary for Patent: 11,052,061

Title:	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Abstract:	Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
Inventor(s):	Megret Claire, Guillard Herve, Dubuisson Jean-Francois
Assignee:	Flamel Ireland Limited
Application Number:	US16419516
Patent Claims:	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 AUCof 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 Tas 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 C60% to 130% of the mean Cprovided 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 AUCis 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 Cfrom 50% to 130% of the mean Cprovided 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 Cachieved by the formulation is from 60% to 90% of the mean Cprovided 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 claim 6 ,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, andwherein 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 AUCof greater than 340 hr×microgram/mL claim 9 , and wherein the 7.5 g dose of the formulation achieves a mean Cfrom 50% to 130% of the mean Cprovided 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 AUCis greater than 375 hr×microgram/mL.13. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11 , wherein the mean AUCis greater than 400 hr×microgram/mL.14. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11 , wherein the mean Cachieved by the formulation is from 60% to 90% of the mean Cprovided 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 claim 11 ,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, andwherein 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.18. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 17 , wherein the 4.5 g claim 17 , 6 g claim 17 , 7.5 g claim 17 , 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 claim 17 , 6 g claim 17 , 7.5 g claim 17 , 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 claim 17 , 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 tand tin equally divided doses claim 17 , when administered approximately two hours after a standardized evening meal.21. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUCis greater than 375 hr×microgram/mL.22. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUCis greater than 400 hr×microgram/mL.23. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUCis greater than 425 hr×microgram/mL.24. The modified release formulation of gamma-hydroxybutyrate of claim 1 , wherein the mean AUCis greater than 450 hr×microgram/mL.