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):	Claire Megret, Herve Guillard, Jean-Francois Dubuisson
Assignee:	Flamel Ireland Ltd
Application Number:	US16/419,516
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,052,061
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 AUCinf 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 Tmax 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 C8h 60% to 130% of the mean C8h 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 AUCinf 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 C8h from 50% to 130% of the mean C8h 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 C8h achieved by the formulation is from 60% to 90% of the mean C8h 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 AUCinf of greater than 340 hr×microgram/mL, and wherein the 7.5 g dose of the formulation achieves a mean C8h from 50% to 130% of the mean C8h 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 AUCinf is greater than 375 hr×microgram/mL. 13. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11, wherein the mean AUCinf is greater than 400 hr×microgram/mL. 14. The once-nightly modified release formulation of gamma-hydroxybutyrate of claim 11, wherein the mean C8h achieved by the formulation is from 60% to 90% of the mean C8h 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 t0 and t4h 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 AUCinf is greater than 375 hr×microgram/mL. 22. The modified release formulation of gamma-hydroxybutyrate of claim 1, wherein the mean AUCinf is greater than 400 hr×microgram/mL. 23. The modified release formulation of gamma-hydroxybutyrate of claim 1, wherein the mean AUCinf is greater than 425 hr×microgram/mL. 24. The modified release formulation of gamma-hydroxybutyrate of claim 1, wherein the mean AUCinf is greater than 450 hr×microgram/mL.