Claims for Patent: 11,400,065

Summary for Patent: 11,400,065

Title:	Gamma-hydroxybutyrate compositions having improved pharmacokinetics in the fed state
Abstract:	Oral pharmaceutical compositions of sodium oxybate having improved pharmacokinetic properties when administered less than two hours after eating are provided, and therapeutic uses thereof.
Inventor(s):	Julien Grassot, Cendrine Grangeon, Jordan Dubow
Assignee:	Flamel Ireland Ltd
Application Number:	US16/804,966
Patent Claims:	1. A method of treating narcolepsy and associated disorders and symptoms in a patient in need thereof comprising: administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate less than two hours after eating. 2. A method of treating narcolepsy and associated disorders and symptoms in a patient in need thereof comprising: administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate once daily, wherein the composition is dose proportional. 3. A method of treating narcolepsy and associated disorders and symptoms in a patient in need thereof comprising: administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate once daily, wherein most AEs occur close to Tmax, during the Cmax period. 4. A method of reducing the amount of adverse events (AEs) in a patient with narcolepsy, cataplexy, or excessive daytime sleepiness comprising: administering an oral pharmaceutical composition comprising gamma-hydroxybutyrate once daily, wherein the gamma-hydroxybutyrate composition has fewer Cmax periods than an equal dose of immediate release sodium oxybate formulation administered more frequently than once-daily. 5. The method of claim 1, wherein the administering occurs only once nightly. 6. The method of claim 1, wherein the administering occurs up to 1.5 hours after eating. 7. The method of claim 1, wherein the administering occurs up to 1 hour after eating. 8. The method of claim 1, wherein the administering occurs up to 30 minutes after eating. 9. The method of claim 1, wherein the administering occurs while eating. 10. The method of claim 1, wherein the administering occurs immediately after eating. 11. The method of claim 1, wherein, after the administering, the composition is effective to induce sleep for at least six consecutive hours. 12. The method of claim 1, wherein, after the administering, the composition is effective to induce sleep for at least eight consecutive hours. 13. The method of claim 1, wherein, after the administering, the composition is effective to induce sleep for at least ten consecutive hours. 14. The method of claim 1, wherein, after the administering, the composition provides a PK profile similar to the PK profile of an equal dose of such composition when orally administered to a patient in need thereof while fasting or at least 2 hours after eating. 15. The method of claim 1, wherein, after the administering, the composition provides an AUCinf bioequivalent to the AUCinf when an equal dose of the composition is administered to a patient in need thereof at least two hours after eating or while fasting. 16. The method of claim 1, wherein, after the administering, the composition provides an AUCinf with a 90% CI that falls within the bioequivalence range of an equal dose of the composition administered in the fasted state with no effect boundaries. 17. The method of claim 1, wherein, after the administering, the composition provides a Cmax bioequivalent to a Cmax of an equal dose of the composition when administered to a patient in need thereof at least two hours after eating or while fasting. 18. The method of claim 1, wherein, after the administering, the composition provides an AUCinf bioequivalent to an AUCinf of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 19. The method of claim 1, wherein, after the administering, the composition provides a Cmax that is less than the Cmax of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 20. The method of claim 1, wherein one or more symptoms of narcolepsy is selected from excessive daytime sleepiness or cataplexy. 21. The method of claim 1, wherein the administering occurs at bedtime. 22. The method of claim 1, wherein the composition comprises gamma-hydroxybutyrate in amounts equivalent to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g or 12 g of sodium oxybate. 23. The method of claim 1, further comprising: opening a sachet, stick-pack, or other discrete packaging unit; pouring the composition out of the sachet, stick-pack or other discrete packaging unit after the opening; and mixing the composition with water after the pouring and before the orally administering. 24. The method of claim 1, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release formulation. 25. The method of claim 24, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release portion and an immediate release portion. 26. The method of claim 2, wherein the administering occurs only once nightly. 27. The method of claim 2, wherein the administering occurs up to 1.5 hours after eating. 28. The method of claim 2, wherein the administering occurs up to 1 hour after eating. 29. The method of claim 2, wherein the administering occurs up to 30 minutes after eating. 30. The method of claim 2, wherein the administering occurs while eating. 31. The method of claim 2, wherein the administering occurs immediately after eating. 32. The method of claim 2, wherein, after the administering, the composition is effective to induce sleep for at least six consecutive hours. 33. The method of claim 2, wherein, after the administering, the composition is effective to induce sleep for at least eight consecutive hours. 34. The method of claim 2, wherein, after the administering, the composition is effective to induce sleep for at least ten consecutive hours. 35. The method of claim 2, wherein, after the administering, the composition provides a PK profile similar to the PK profile of an equal dose of such composition when orally administered to a patient in need thereof while fasting or at least 2 hours after eating. 36. The method of claim 2, wherein, after the administering, the composition provides an AUCinf bioequivalent to the AUCinf when an equal dose of the composition is administered to a patient in need thereof at least two hours after eating or while fasting. 37. The method of claim 2, wherein, after the administering, the composition provides an AUCinf with a 90% CI that falls within the bioequivalence range of an equal dose of the composition administered in the fasted state with no effect boundaries. 38. The method of claim 2, wherein, after the administering, the composition provides a Cmax bioequivalent to a Cmax of an equal dose of the composition when administered to a patient in need thereof at least two hours after eating or while fasting. 39. The method of claim 2, wherein, after the administering, the composition provides an AUCinf bioequivalent to an AUCinf of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 40. The method of claim 2, wherein, after the administering, the composition provides a Cmax that is less than the Cmax of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 41. The method of claim 2, wherein one or more symptoms of narcolepsy is selected from excessive daytime sleepiness or cataplexy. 42. The method of claim 2, wherein the administering occurs at bedtime. 43. The method of claim 2, wherein the composition comprises gamma-hydroxybutyrate in amounts equivalent to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g or 12 g of sodium oxybate. 44. The method of claim 2, further comprising: opening a sachet, stick-pack, or other discrete packaging unit; pouring the composition out of the sachet, stick-pack or other discrete packaging unit after the opening; and mixing the composition with water after the pouring and before the orally administering. 45. The method of claim 2, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release formulation. 46. The method of claim 45, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release portion and an immediate release portion. 47. The method of claim 3, wherein the administering occurs only once nightly. 48. The method of claim 3, wherein the administering occurs up to 1.5 hours after eating. 49. The method of claim 3, wherein the administering occurs up to 1 hour after eating. 50. The method of claim 3, wherein the administering occurs up to 30 minutes after eating. 51. The method of claim 3, wherein the administering occurs while eating. 52. The method of claim 3, wherein the administering occurs immediately after eating. 53. The method of claim 3, wherein, after the administering, the composition is effective to induce sleep for at least six consecutive hours. 54. The method of claim 3, wherein, after the administering, the composition is effective to induce sleep for at least eight consecutive hours. 55. The method of claim 3, wherein, after the administering, the composition is effective to induce sleep for at least ten consecutive hours. 56. The method of claim 3, wherein, after the administering, the composition provides a PK profile similar to the PK profile of an equal dose of such composition when orally administered to a patient in need thereof while fasting or at least 2 hours after eating. 57. The method of claim 3, wherein, after the administering, the composition provides an AUCinf bioequivalent to the AUCinf when an equal dose of the composition is administered to a patient in need thereof at least two hours after eating or while fasting. 58. The method of claim 3, wherein, after the administering, the composition provides an AUCinf with a 90% CI that falls within the bioequivalence range of an equal dose of the composition administered in the fasted state with no effect boundaries. 59. The method of claim 3, wherein, after the administering, the composition provides a Cmax bioequivalent to a Cmax of an equal dose of the composition when administered to a patient in need thereof at least two hours after eating or while fasting. 60. The method of claim 3, wherein, after the administering, the composition provides an AUCinf bioequivalent to an AUCinf of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 61. The method of claim 3, wherein, after the administering, the composition provides a Cmax that is less than the Cmax of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 62. The method of claim 3, wherein one or more symptoms of narcolepsy is selected from excessive daytime sleepiness or cataplexy. 63. The method of claim 3, wherein the administering occurs at bedtime. 64. The method of claim 3, wherein the composition comprises gamma-hydroxybutyrate in amounts equivalent to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g or 12 g of sodium oxybate. 65. The method of claim 3, further comprising: opening a sachet, stick-pack, or other discrete packaging unit; pouring the composition out of the sachet, stick-pack or other discrete packaging unit after the opening; and mixing the composition with water after the pouring and before the orally administering. 66. The method of claim 3, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release formulation. 67. The method of claim 66, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release portion and an immediate release portion. 68. The method of claim 4, wherein the administering occurs only once nightly. 69. The method of claim 4, wherein the administering occurs up to 1.5 hours after eating. 70. The method of claim 4, wherein the administering occurs up to 1 hour after eating. 71. The method of claim 4, wherein the administering occurs up to 30 minutes after eating. 72. The method of claim 4, wherein the administering occurs while eating. 73. The method of claim 4, wherein the administering occurs immediately after eating. 74. The method of claim 4, wherein, after the administering, the composition is effective to induce sleep for at least six consecutive hours. 75. The method of claim 4, wherein, after the administering, the composition is effective to induce sleep for at least eight consecutive hours. 76. The method of claim 4, wherein, after the administering, the composition is effective to induce sleep for at least ten consecutive hours. 77. The method of claim 4, wherein, after the administering, the composition provides a PK profile similar to the PK profile of an equal dose of such composition when orally administered to a patient in need thereof while fasting or at least 2 hours after eating. 78. The method of claim 4, wherein, after the administering, the composition provides an AUCinf bioequivalent to the AUCinf when an equal dose of the composition is administered to a patient in need thereof at least two hours after eating or while fasting. 79. The method of claim 4, wherein, after the administering, the composition provides an AUCinf with a 90% CI that falls within the bioequivalence range of an equal dose of the composition administered in the fasted state with no effect boundaries. 80. The method of claim 4, wherein, after the administering, the composition provides a Cmax bioequivalent to a Cmax of an equal dose of the composition when administered to a patient in need thereof at least two hours after eating or while fasting. 81. The method of claim 4, wherein, after the administering, the composition provides an AUCinf bioequivalent to an AUCinf of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 82. The method of claim 4, wherein, after the administering, the composition provides a Cmax that is less than the Cmax of an equal dose of an immediate release liquid solution of sodium oxybate administered at t0 and t4h in equally divided doses at least two hours after eating. 83. The method of claim 4, wherein the administering occurs at bedtime. 84. The method of claim 4, wherein the composition comprises gamma-hydroxybutyrate in amounts equivalent to 0.5 g, 1.0 g, 1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g or 12 g of sodium oxybate. 85. The method of claim 4, further comprising: opening a sachet, stick-pack, or other discrete packaging unit; pouring the composition out of the sachet, stick-pack or other discrete packaging unit after the opening; and mixing the composition with water after the pouring and before the orally administering. 86. The method of claim 4, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release formulation. 87. The method of claim 86, wherein the pharmaceutical composition comprises gamma-hydroxybutyrate in a modified release portion and an immediate release portion. 88. The method of claim 2, wherein the composition is dose proportional by a factor of about 1 to about 1.3 with respect to one or both Cmax and AUC of the composition. 89. The method of claim 2, wherein the composition exhibits proportional increases in plasma levels with increasing doses. 90. The method of claim 2, wherein the composition is dose proportional by a factor of about 1 to about 1.3. 91. The method of claim 2, wherein the composition is dose proportional with respect to Cmax of the composition. 92. The method of claim 2, wherein Cmax of the composition is dose proportional across once daily doses of 4.5 g, 6 g, 7.5 g, and 9 g of the composition. 93. The method of claim 2, wherein the composition wherein dose proportionality is maintained across the dosage range. 94. The method of claim 2, wherein Cmax of a 6 g dose of the composition is proportional to Cmax of a 9 g dose of the composition. 95. The method of claim 2, wherein Cmax of the composition increases 2.0-fold as the once daily dose increases from 4.5 g to 9 g. 96. The method of claim 2, wherein Cmax of a 4.5 g dose of the composition is proportional to Cmax of a 6 g dose of the composition. 97. The method of claim 2, wherein Cmax of a 6 g dose of the composition is proportional to Cmax of a 7.5 g dose of the composition. 98. The method of claim 2, wherein Cmax of the composition is dose proportional by a factor of about 1. 99. The method of claim 2, wherein, after the administering, plasma levels of gamma-hydroxybutyrate increase dose-proportionally for Cmax and more than dose-proportionally for AUC. 100. The method of claim 2, wherein the composition provides an AUC that is dose proportional. 101. The method of claim 2, wherein AUC of the composition is dose proportional by a factor of about 1.3. 102. The method of claim 2, wherein the composition provides an AUC that is more dose proportional than the AUC of an immediate release liquid solution of sodium oxybate. 103. The method of claim 2, wherein the compositing provides an AUC that increases 2.3-fold as the once daily dose increases from 4.5 g to 9 g. 104. The method of claim 2, wherein a 4.5 g dose of the composition provides an AUC that is proportional to the AUC of a 6 g dose of the composition. 105. The method of claim 2, wherein a 6 g dose of the composition provides an AUC that is proportional to the AUC of a 7.5 g dose of the composition. 106. The method of claim 2, wherein the composition has a more favorable safety profile than an equal dose of an immediate release liquid solution of sodium oxybate administered in equally divided doses. 107. The method of claim 2, wherein the composition has a more favorable safety profile than an equal dose of an immediate release liquid solution of sodium oxybate administered in equally divided doses. 108. The method of claim 2, wherein any adverse events are mild to moderate in severity even without titration. 109. The method of claim 2, wherein administering the composition reduces safety concerns associated with administering an equal dose of an immediate release liquid solution of sodium oxybate administered in equally divided doses. 110. The method of claim 107, wherein the Cmax of the composition is between the Cmax of the first peak and the Cmax of the second peak of the immediate release liquid solution of sodium oxybate.