Modified release compositions of gamma-hydroxybutyric acid derivatives

Abstract

Disclosed are pharmaceutical particles having a functional coating surrounding a core comprising 4-((L-valyl) oxy) butyric acid. The functional coating provides direct release or modified release of 4-((L-valyl) oxy) butyric acid. The pharmaceutical particles can be used in oral pharmaceutical compositions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 087,515 filed on October 5, 2020 under 35 U.S.C. §119(e), which is incorporated herein by reference in its entirety. This application is a divisional application based on Chinese Patent Application No. 202180035470.X. Technical Field

[0003] The present disclosure relates to 4-((L-valyl)oxy)butyric acid-containing pharmaceutical particles with functional coatings. The coated pharmaceutical particles can be used in modified release oral compositions. Background Art

[0004] In certain treatment methods, it is necessary to administer a higher dose of a pharmaceutically active ingredient. In order to minimize the amount of oral pharmaceutical compositions administered to patients in such treatments, it is necessary that the pharmaceutical compositions contain a higher content of the pharmaceutically active ingredient and minimize the amount of pharmaceutical excipients.

[0005] Oral modified release dosage forms may contain pellets coated with a functional coating to provide a desired release profile in the gastrointestinal tract.

[0006] There is a need for modified release compositions comprising drug particles of an active pharmaceutical ingredient having a high bulk density suitable for once or twice a day administration. To improve palatability, it is desirable for the drug particles to have a low average particle size, for example 200 μm to 400 μm. Summary of the invention

[0007] According to the present invention, the modified release drug granules comprise a plurality of coated granules, wherein the granules comprise a core and a modified release coating surrounding the core, wherein the modified release coating comprises: 50 wt % to 85 wt % of a matrix polymer; and 10 wt % to 20 wt % of an antistatic agent; wherein the wt % is based on the total weight of the modified release coating. The drug granules are characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, wherein the PSD is determined by sieve analysis; and the core comprises more than 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the core.

[0008] According to the present invention, the pharmaceutical composition comprises the pharmaceutical particles according to the present invention.

[0009] According to the present invention, a method of coating particles with a coating comprises applying a coating composition to drug particles, wherein the drug particles comprise a plurality of granules comprising 4-((L-valyl)oxy)butyric acid, wherein the coating composition comprises: 6 wt % to 14 wt % solids; 0 wt % to 20 wt % water; and 70 wt % to 95 wt % ethanol, wherein the wt % are based on the total weight of the coating formulation.

[0010] According to the present invention, the pharmaceutical composition comprises: an immediate release (IR) component, wherein the immediate release component comprises 1.2 gram equivalents of γ-hydroxybutyrate to 4.0 gram equivalents of γ-hydroxybutyrate; and a modified release (MR) component, wherein the modified release component comprises: 3 gram equivalents of γ-hydroxybutyrate to 9 gram equivalents of γ-hydroxybutyrate; and modified release particles according to the present invention.

[0011] According to the present invention, a method of treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient comprises orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0012] According to the present invention, a method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient comprises orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to the present invention.

[0013] According to the present invention, the kit comprises the pharmaceutical composition according to the present invention.

[0014] As non-limiting examples, the present application provides the following embodiments:

[0015] Embodiment 1. A modified release drug granule comprising a plurality of coated granules, wherein:

[0016] The coated pellets comprise a core and a modified release coating surrounding the core,

[0017] The modified release coating comprises:

[0018] 80 wt % to 90 wt % of a matrix polymer; and

[0019] 10 to 20 wt % of an antistatic agent;

[0020] wherein the weight % is based on the total weight of the modified release coat, and

[0021] The core comprises more than 85 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the core.

[0022] Embodiment 2. The pharmaceutical particle according to embodiment 1, wherein the pharmaceutical particle is characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, wherein the PSD is determined by sieve analysis.

[0023] Embodiment 3. The pharmaceutical particle according to any one of embodiments 1 to 2, wherein the pharmaceutical particle comprises 50 wt % to 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the pharmaceutical particle.

[0024] Embodiment 4. The pharmaceutical particle according to any one of Embodiments 1 to 3, wherein the matrix polymer comprises a water-insoluble polymer.

[0025] Embodiment 5. The pharmaceutical particle according to embodiment 4, wherein the water-insoluble polymer comprises ethylcellulose.

[0026] Embodiment 6. The pharmaceutical particle according to any one of embodiments 1 to 5, wherein the matrix polymer comprises 0 wt% to 10 wt% of the pore-forming polymer, wherein the wt% is based on the total weight of the matrix polymer.

[0027] Embodiment 7. The pharmaceutical particle according to embodiment 6, wherein the pore-forming polymer comprises a water-soluble polymer.

[0028] Embodiment 8. The pharmaceutical particle according to embodiment 7, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0029] Embodiment 9. The pharmaceutical particle according to any one of embodiments 1 to 8, wherein the antistatic agent comprises talc, magnesium stearate, or a combination thereof.

[0030] Embodiment 10. The pharmaceutical particle according to any one of embodiments 1 to 9, wherein

[0031] The core accounts for 65% to 85% by weight of the total weight of the coated particle; and

[0032] The modified release coating comprises 15 to 40 weight percent of the total weight of the coated particles.

[0033] Embodiment 11. The pharmaceutical particle according to any one of embodiments 1 to 10, wherein the thickness of the modified release coating is 5 μm to 30 μm.

[0034] Embodiment 12. The pharmaceutical particle according to any one of embodiments 1 to 11, wherein the pharmaceutical particle has a water content of less than 2 wt%, wherein the wt% is based on the total weight of the pharmaceutical particle.

[0035] Embodiment 13. The pharmaceutical particle according to any one of embodiments 1 to 12, further comprising a seal coat surrounding the core, and wherein the modified release coat surrounds the seal coat.

[0036] Embodiment 14. The pharmaceutical particle according to embodiment 13, wherein the seal coating comprises:

[0037] Hydroxypropyl cellulose;

[0038] Hydroxypropyl methylcellulose;

[0039] Hydroxypropylcellulose and talc; or

[0040] Hydroxypropyl methylcellulose and talc.

[0041] Embodiment 15. The pharmaceutical particle according to any one of embodiments 13 to 14, wherein the pharmaceutical particle comprises 2 wt% to 15 wt% of the seal coating, wherein the wt% is based on the total weight of the pharmaceutical particle.

[0042] Embodiment 16. The pharmaceutical particle according to any one of embodiments 1 to 15, wherein 30 wt% to 80 wt% of the 4-((L-valyl)oxy)butyric acid is released from the pharmaceutical particle within 2 hours when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0043] Embodiment 17. The pharmaceutical particle according to any one of embodiments 1 to 16, wherein 50 wt% to 90 wt% of the 4-((L-valyl)oxy)butyric acid is released from the pharmaceutical particle within 4 hours when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0044] Embodiment 18. The pharmaceutical particle according to any one of embodiments 1 to 17, wherein 60 wt% to 100 wt% of the 4-((L-valyl)oxy)butyric acid is released from the pharmaceutical particle within 6 hours when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0045] Embodiment 19. The pharmaceutical particle according to any one of embodiments 1 to 18, wherein when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, the modified release pharmaceutical particle exhibits a release rate comparable to that of Figure 6 , 12 and a dissolution profile that is bioequivalent to the dissolution profile shown in any one of 15.

[0046] Embodiment 20. The pharmaceutical particle according to any one of embodiments 1 to 18, wherein when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, the modified release pharmaceutical particle exhibits a release rate comparable to that of Figure 6 , 12 and a dissolution profile that is bioequivalent to the dissolution profile shown in any one of 15.

[0047] Embodiment 21. The pharmaceutical particle according to any one of embodiments 1 to 20, wherein the pharmaceutical particle does not contain a plasticizer.

[0048] Embodiment 22. A pharmaceutical composition comprising the pharmaceutical particles according to any one of embodiments 1 to 20.

[0049] Embodiment 23. The pharmaceutical composition according to Embodiment 22, wherein the pharmaceutical composition is an oral composition.

[0050] Embodiment 24. A pharmaceutical composition according to any one of Embodiments 22 to 23, wherein the oral composition comprises:

[0051] a modified release component, wherein the modified release portion comprises the drug particles; and

[0052] Direct release components.

[0053] Embodiment 25. A pharmaceutical composition according to Embodiment 24, wherein the immediate release component dissolves in water in less than 5 minutes.

[0054] Embodiment 26. The pharmaceutical composition according to any one of Embodiments 23 to 25, wherein the oral composition is a BID formulation.

[0055] Embodiment 27. The pharmaceutical composition of any one of Embodiments 23 to 25, wherein the oral composition is a QD formulation.

[0056] Embodiment 28. The pharmaceutical composition of any one of Embodiments 22 to 27, wherein the pharmaceutical composition comprises 500 milliequivalents to 12 gramequivalents of 4-((L-valyl)oxy)butyric acid.

[0057] Embodiment 29. The pharmaceutical composition according to any one of Embodiments 22 to 28, wherein the pharmaceutical composition comprises a sustained release oral composition, a delayed release composition, an immediate release composition, or a combination of any of the foregoing.

[0058] Embodiment 30. The pharmaceutical composition of any one of Embodiments 22 to 29, wherein the pharmaceutical composition comprises a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid to treat a disease in a patient, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0059] Embodiment 31. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 22 to 30, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0060] Embodiment 32. The method of embodiment 31, wherein the disease is cataplexy associated with narcolepsy.

[0061] Embodiment 33. The method of embodiment 31, wherein the disease is excessive daytime sleepiness associated with narcolepsy.

[0062] Embodiment 34. The method of embodiment 31, wherein the disease is excessive daytime sleepiness in a patient suffering from Parkinson's disease.

[0063] Embodiment 35. The method of embodiment 31, wherein the disease is chronic fatigue in a patient with Parkinson's disease.

[0064] Embodiment 36. The method of any one of embodiments 31 to 35, wherein administration comprises oral administration.

[0065] Embodiment 37. The method of embodiment 36, wherein the administration is orally administered in a fasting state.

[0066] Embodiment 38. The method of embodiment 36, wherein administration is orally administered in a fed state.

[0067] Embodiment 39. A method of coating particles with a coating, comprising applying a coating composition to a drug particle, the drug particle comprising a plurality of pellets comprising 4-((L-valyl)oxy)butyric acid, wherein the coating composition comprises:

[0068] 6 to 14 wt % solids;

[0069] 0 wt % to 20 wt % water; and

[0070] 70% to 95% by weight of ethanol,

[0071] The weight % are based on the total weight of the coating formulation.

[0072] Embodiment 40. The method of embodiment 39, wherein the solid comprises:

[0073] a matrix polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a combination thereof; and

[0074] An antistatic agent selected from talc, magnesium stearate or a combination thereof.

[0075] Embodiment 41. The method of any one of Embodiments 39 to 40, wherein applying comprises spraying.

[0076] Embodiment 42. A pharmaceutical composition comprising:

[0077] an immediate release (IR) component, wherein the immediate release component comprises from 1.2 gram equivalents of gamma-hydroxybutyrate to 4.0 gram equivalents of gamma-hydroxybutyrate; and

[0078] A modified release (MR) component, wherein the modified release component comprises:

[0079] 3 g equivalents of gamma-hydroxybutyrate to 9 g equivalents of gamma-hydroxybutyrate; and

[0080] A modified release particle according to any one of embodiments 1 to 21.

[0081] Embodiment 43. A pharmaceutical composition according to Embodiment 42, wherein the immediate release component and the modified release component each comprise 4-((L-valyl)oxy)butyric acid.

[0082] Embodiment 44. A pharmaceutical composition according to any one of Embodiments 42 to 43, wherein the γ-hydroxybutyrate equivalent is in the form of γ-((L-valyl)oxy)butyric acid.

[0083] Embodiment 45. A pharmaceutical composition according to any one of Embodiments 43 to 44, wherein

[0084] The immediate release component comprises 10% to 50% by weight of the 4-((L-valyl)oxy)butyric acid; and

[0085] The modified release component comprises 50% to 90% by weight of the 4-((L-valyl)oxy)butyric acid,

[0086] The weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the pharmaceutical composition.

[0087] Embodiment 46. A pharmaceutical composition according to any one of Embodiments 43 to 45, wherein

[0088] The immediate release component comprises 2 g to 7 g of 4-((L-valyl)oxy)butyric acid; and

[0089] The modified release component comprises 7 g to 15 g of 4-((L-valyl)oxy)butyric acid.

[0090] Embodiment 47. A pharmaceutical composition according to any one of Embodiments 42 to 46, wherein

[0091] The immediate release component comprises 1 gram equivalent to 4 gram equivalents of gamma-hydroxybutyrate; and

[0092] The modified release component comprises 3.5 g equivalent to 8.5 g equivalent of gamma-hydroxybutyrate.

[0093] Embodiment 48. A pharmaceutical composition according to any one of Embodiments 42 to 47, wherein the weight ratio of gram equivalents of γ-hydroxybutyrate in the immediate release component to the gram equivalents of γ-hydroxybutyrate in the modified release component is 1.5 to 3.5.

[0094] Embodiment 49. A pharmaceutical composition according to any one of Embodiments 42 to 48, wherein the immediate release component comprises a plurality of immediate release microparticles.

[0095] Embodiment 50. A pharmaceutical composition according to Embodiment 49, wherein the immediate release microparticles comprise greater than 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the immediate release microparticles.

[0096] Embodiment 51. The pharmaceutical composition of any one of Embodiments 49 to 50, wherein the direct release microparticles have a volume mean diameter D(4.3) of 200 μm to 500 μm.

[0097] Embodiment 52. A pharmaceutical composition according to any one of Embodiments 42 to 51, wherein the immediate release component comprises a solution suitable for oral administration.

[0098] Embodiment 53. The pharmaceutical composition of any one of Embodiments 42 to 52, wherein the modified release component comprises a plurality of modified release microparticles.

[0099] Embodiment 54. A pharmaceutical composition according to any one of Embodiments 42 to 53, wherein the modified release component comprises a suspension of modified release microparticles suitable for oral administration.

[0100] Embodiment 55. The pharmaceutical composition of any one of Embodiments 53 to 54, wherein the modified release microparticles comprise a core and a modified release coating surrounding the core.

[0101] Embodiment 56. A pharmaceutical composition according to Embodiment 55, wherein the core comprises greater than 85 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the core.

[0102] Embodiment 57. A pharmaceutical composition according to Embodiment 55, wherein the core comprises greater than 90 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the core.

[0103] Embodiment 58. A pharmaceutical composition according to any one of Embodiments 55 to 57, wherein the core comprises direct release macroparticles comprising 4-((L-valyl)oxy)butyric acid.

[0104] Embodiment 59. A pharmaceutical composition according to any one of Embodiments 53 to 58, wherein the modified release microparticles comprise 10 wt % to 50 wt % of the modified release coating, wherein the wt % is based on the total weight of the modified release microparticles.

[0105] Embodiment 60. A pharmaceutical composition according to any one of Embodiments 53 to 59, wherein the modified release microparticles comprise:

[0106] 24 wt % to 34 wt % of said modified release coating (MR2);

[0107] 28 wt % to 38 wt % of said modified release coating (MR3); or

[0108] 32 wt % to 42 wt % of said modified release coating (MR1);

[0109] The weight % is based on the total weight of the modified release microparticles.

[0110] Embodiment 61. The pharmaceutical composition of any one of Embodiments 42 to 60, wherein after oral administration of an IR component comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butyric acid is characterized by: a mean t of 0.3 to 0.5 hours. 1 / 2 , 0.8 hours to 1.0 hours average T max , 14μg / mL to 18μg / mL average C max , average AUC from 14h×μg / mL to 18h×μg / mL 0-6 , AUC from 14h×μg / mL to 18h×μg / mL 0-inf and CL / F of 44 L / h to 52 L / h).

[0111] Embodiment 62. The pharmaceutical composition of any one of Embodiments 42 to 61, wherein after oral administration of an IR composition comprising 7.25 g 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by: an average t of 0.4 to 0.8 hours. 1 / 2 , 1.1 hours to 1.5 hours average T max , 76μg / mL to 96μg / mL average C max , average AUC from 219h×μg / mL to 259h×μg / mL 0-6 , AUC from 226h×μg / mL to 266h×μg / mL 0-inf and an average CL / F of 21 L / h to 41 L / h.

[0112] Embodiment 63. The pharmaceutical composition of any one of Embodiments 42 to 62, wherein after oral administration of an IR composition comprising 7.25 g 4-((L-valyl)oxy)butyric acid to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a C of 4.9 to 6.9 max ratio and AUC of 14 to 26 0-inf A ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the 4-((L-valyl)oxy)butyric acid value.

[0113] Embodiment 64. The pharmaceutical composition of any one of Embodiments 42 to 63, wherein after oral administration of a modified release (MR1) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butyric acid is characterized by a mean t of 0.5 to 0.9 hours. 1 / 2, 1.4 hours to 1.8 hours average T max , 2μg / mL to 6μg / mL average C max , average AUC from 7h×μg / mL to 11h×μg / mL 0-6 , average AUC from 7h×μg / mL to 11h×μg / mL 0-inf and an average CL / F of 818 L / h to 858 L / h.

[0114] Embodiment 65. The pharmaceutical composition of any one of Embodiments 42 to 64, wherein after oral administration of a modified release (MR1) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by: a mean t of 0.9 hours to 1.3 hours. 1 / 2 , average T of 2.2 hours to 2.6 hours max , 17μg / mL to 37μg / mL average C max , average AUC from 76h×μg / mL to 96h×μg / mL 0-6 , AUC from 75h×μg / mL to 115h×μg / mL 0-inf and an average CL / F of 85 L / h to 105 L / h.

[0115] Embodiment 66. A pharmaceutical composition according to any one of Embodiments 42 to 65, wherein after oral administration of a modified release (MR1) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile is characterized by: a C of 6.2 to 7.2 max ratio and an AUC of 9.0 to 11.0 0-inf A ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the 4-((L-valyl)oxy)butyric acid value.

[0116] Embodiment 67. The pharmaceutical composition of any one of Embodiments 42 to 66, wherein following oral administration of a modified release (MR2) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butyric acid is characterized by a mean t of 0.5 to 0.9 hours. 1 / 2 , 1.2 hours to 1.6 hours average T max , 4μg / mL to 8μg / mL average C max , average AUC from 8h×μg / mL to 12h×μg / mL 0-6 , average AUC from 8h×μg / mL to 12h×μg / mL0-inf and an average CL / F of 720L / h to 800L / h.

[0117] Embodiment 68. The pharmaceutical composition of any one of Embodiments 42 to 66, wherein following oral administration of a modified release (MR2) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by a mean t of 0.8 to 1.0 hours. 1 / 2 , average T of 2.2 hours to 2.6 hours max , 34μg / mL to 38μg / mL average C max , average AUC from 102h×μg / mL to 122h×μg / mL 0-6 , AUC from 110h×μg / mL to 130h×μg / mL 0-inf and an average CL / F of 62 L / h to 82 L / h.

[0118] Embodiment 69. A pharmaceutical composition according to any one of embodiments 42 to 68, wherein after oral administration of a modified release (MR2) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile is characterized by: a C of 5.9 to 6.7 max ratio and an AUC of 11.5 to 12.3 0-inf A ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the 4-((L-valyl)oxy)butyric acid value.

[0119] Embodiment 70. The pharmaceutical composition of any one of Embodiments 42 to 69, wherein following oral administration of a modified release (MR3) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butyric acid is characterized by a mean t of 0.6 to 1.0 hours. 1 / 2 , 0.9 hours to 1.3 hours average T max , 3μg / mL to 7μg / mL average C max , average AUC from 8h×μg / mL to 12h×μg / mL 0-6 , average AUC from 10h×μg / mL to 12h×μg / mL 0-inf and an average CL / F of 760L / h to 840L / h.

[0120] Embodiment 71. A pharmaceutical composition according to any one of Embodiments 42 to 69, wherein after oral administration of a modified release (MR3) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by: a mean t of 0.9 hours to 1.1 hours. 1 / 2 , 1.7 hours to 2.1 hours average T max , 26μg / mL to 34μg / mL average C max , average AUC from 82h×μg / mL to 122h×μg / mL 0-6 , AUC from 90h×μg / mL to 130h×μg / mL 0-inf and an average CL / F of 69 L / h to 89 L / h.

[0121] Embodiment 72. A pharmaceutical composition according to any one of Embodiments 42 to 71, wherein after oral administration of a modified release (MR3) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the plasma pharmacokinetic profile is characterized by: a C of 6.1 to 6.9 max ratio and an AUC of 11.0 to 11.8 0-inf A ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the 4-((L-valyl)oxy)butyric acid value.

[0122] Embodiment 73. A pharmaceutical composition according to any one of Embodiments 42 to 72, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of an immediate release (IR) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 6 and 7 or Fig.17 and 18 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0123] Embodiment 74. A pharmaceutical composition according to any one of Embodiments 42 to 73, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of a modified release (MR1) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 6 and 7 or Fig.17 and 18 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0124] Embodiment 75. The pharmaceutical composition of any one of Embodiments 42 to 74, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of a modified release (MR2) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 6 and 7 or Fig.17 and 18 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0125] Embodiment 76. A pharmaceutical composition according to any one of Embodiments 43 to 74, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of a modified release (MR3) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 6 and 7 or Fig.17 and 18 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0126] Embodiment 77. A pharmaceutical composition according to any one of Embodiments 42 to 76, wherein

[0127] The immediate release component comprises 2 g to 8 g of 4-((L-valyl)oxy)butyric acid; and

[0128] The modified release component comprises 8 g to 16 g of 4-((L-valyl)oxy)butyric acid.

[0129] Embodiment 78. A pharmaceutical composition according to any one of Embodiments 42 to 77, wherein

[0130] The immediate release component comprises 20% to 40% by weight of 4-((L-valyl)oxy)butyric acid; and

[0131] The modified release component comprises 60 to 80 wt % of 4-((L-valyl)oxy)butyric acid

[0132] The weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid.

[0133] Embodiment 79. A pharmaceutical composition according to any one of embodiments 42 to 78, wherein the weight ratio of 4-((L-valyl)oxy)butyric acid in the immediate release component to 4-((L-valyl)oxy)butyric acid in the modified release component is 1:2 to 1:3.

[0134] Embodiment 80. The pharmaceutical composition according to any one of embodiments 42 to 79, wherein after oral administration to a group of fasting healthy subjects of a combined release composition (CR1) comprising:

[0135] The IR component contained 4.1 g of 4-((L-valyl)oxy)butyric acid; and

[0136] said modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butyric acid;

[0137] Following oral administration of the pharmaceutical composition to a group of patients, the plasma pharmacokinetic profile of 4-((L-valyl)oxy)butyric acid was characterized by an average t of 1.0 to 1.2 hours. 1 / 2 , 1.3 hours to 1.5 hours average T max , 12μg / mL to 18μg / mL average C max , average AUC from 20h×μg / mL to 30h×μg / mL 0-6 , average AUC from 22h×μg / mL to 32h×μg / mL 0-inf and an average CL / F of 536L / h to 576L / h.

[0138] Embodiment 81. A pharmaceutical composition according to any one of Embodiments 42 to 79, wherein after oral administration to a group of fasting healthy subjects of a combined release composition (CR1) comprising:

[0139] an IR component comprising 4.1 g of 4-((L-valyl)oxy)butyric acid; and

[0140] a modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butyric acid,

[0141] Following oral administration of the pharmaceutical composition to a group of patients, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by an average t of 1.0 to 1.2 hours. 1 / 2 , 2.5 hours to 2.9 hours average T max , 88μg / mL to 128μg / mL average C max , average AUC from 380h×μg / mL to 420h×μg / mL 0-6 , average AUC from 514h×μg / mL to 554h×μg / mL 0-inf and an average CL / F of 22 L / h to 42 L / h.

[0142] Embodiment 82. The pharmaceutical composition according to any one of Embodiments 80 to 81, wherein after oral administration to a group of fasting healthy subjects of a combined release composition (CR1) comprising:

[0143] an IR component comprising 4.1 g of 4-((L-valyl)oxy)butyric acid; and

[0144] a modified release (MR1) component comprising 10 g of 4-((L-valyl)oxy)butyric acid,

[0145] Following oral administration of the pharmaceutical composition to a group of patients, the plasma pharmacokinetic profile is characterized by:

[0146] C from 7.0 to 9.0 max ratio and AUC of 18.3 to 20.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding 4-((L-valyl)oxy)butyric acid value.

[0147] Embodiment 83. A pharmaceutical composition according to any one of Embodiments 42 to 79, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of a combined release (CR1) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 10 and 11 or Fig.19 and 20 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0148] Embodiment 84. The pharmaceutical composition according to any one of Embodiments 42 to 79, wherein after oral administration to a group of fasting healthy subjects of a combined release composition (CR2) comprising:

[0149] an IR component comprising 4.5 g of 4-((L-valyl)oxy)butyric acid; and

[0150] a modified release (MR2) component comprising 10 g of 4-((L-valyl)oxy)butyric acid,

[0151] Following oral administration of the pharmaceutical composition to a group of patients, the plasma pharmacokinetic profile of 4-((L-valyl)butyric acid was characterized by a mean t of 0.9 to 1.1 hours. 1 / 2 , 1.1 hours to 1.5 hours average T max , 10μg / mL to 14μg / mL average C max , average AUC from 16h×μg / mL to 24h×μg / mL 0-6, average AUC from 11h×μg / mL to 31h×μg / mL 0-inf and an average CL / F of 660L / h to 740L / h.

[0152] Embodiment 85. The pharmaceutical composition according to any one of Embodiments 42 to 79, wherein after oral administration to a group of fasting healthy subjects of a combined release composition (CR2) comprising:

[0153] an IR component comprising 4.5 g of 4-((L-valyl)oxy)butyric acid; and

[0154] a modified release (MR2) component comprising 10 g of 4-((L-valyl)oxy)butyric acid,

[0155] Following oral administration of the pharmaceutical composition to a group of patients, the plasma pharmacokinetic profile of γ-hydroxybutyrate is characterized by an average t of 0.8 to 1.0 hours. 1 / 2 , 2.0 hours to 2.4 hours average T max , 73μg / mL to 93μg / mL average C max , average AUC from 302h×μg / mL to 342h×μg / mL 0-6 , average AUC from 366h×μg / mL to 406h×μg / mL 0-inf and an average CL / F of 33 L / h to 53 L / h.

[0156] Embodiment 86. The pharmaceutical composition according to any one of Embodiments 84 to 85, wherein after oral administration of a combined release composition (CR2) comprising:

[0157] an IR component comprising 4.5 g of 4-((L-valyl)oxy)butyric acid; and

[0158] After oral administration of the pharmaceutical composition to a group of patients and oral administration of a modified release (MR2) component comprising 10 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy individuals, the plasma pharmacokinetic profile was characterized by a C of 6.8 to 8.8. max ratio and AUC of 16.3 to 20.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding 4-((L-valyl)oxy)butyric acid value.

[0159] Embodiment 87. The pharmaceutical composition of any one of Embodiments 42 to 79, wherein the plasma pharmacokinetic profiles of 4-((L-valyl)oxy)butyric acid and gamma-hydroxybutyrate following oral administration of a combined release (CR2) composition comprising 7.25 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects are comparable to those presented in Tables 10 and 11 or Fig.19 and 20 The plasma pharmacokinetic profiles shown in the bioequivalence.

[0160] Embodiment 88. The pharmaceutical composition of any one of Embodiments 42 to 87, wherein 6 hours after oral administration of the pharmaceutical composition to a group of fasting healthy individuals, the concentration of gamma-hydroxybutyrate in the plasma of the individual is less than 15 μg / mL, less than 10 μg / mL, or less than 5 μg / mL.

[0161] Embodiment 89. The pharmaceutical composition of any one of Embodiments 42 to 88, wherein after oral administration of a pharmaceutical composition comprising 10 g to 20 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects, the concentration of γ-hydroxybutyrate in the plasma of the subjects is greater than the sum of: (a) the AUC of γ-hydroxybutyrate after oral administration of the immediate release component. inf ; and (b) the AUC of γ-hydroxybutyrate after oral administration of the modified release component to the group of fasting healthy individuals inf .

[0162] Embodiment 90. A pharmaceutical composition according to any one of embodiments 42 to 89, wherein at a time between 6 hours and 8 hours after oral administration of a pharmaceutical composition comprising 10 g to 20 g of 4-((L-valyl)oxy)butyric acid to a population of fasting healthy individuals, the concentration of γ-hydroxybutyrate in the plasma of the individual is greater than the sum of: (a) the concentration of γ-hydroxybutyrate at a time between 6 hours and 8 hours after oral administration of the immediate release component; and (b) the concentration of γ-hydroxybutyrate at a time between 6 hours and 8 hours after oral administration of the modified release component to the population of fasting healthy individuals.

[0163] Embodiment 91. A pharmaceutical composition according to any one of embodiments 42 to 90, wherein following oral administration of a pharmaceutical composition comprising 10 g to 20 g of 4-((L-valyl)oxy)butyric acid to a group of fasting healthy individuals, the concentration at 6 hours to 8 hours after administration is greater than the concentration of γ-hydroxybutyrate in the plasma of the individuals following administration of the modified release component alone.

[0164] Embodiment 92. A pharmaceutical composition according to any one of embodiments 42 to 91, wherein the average γ-hydroxybutyrate AUC after oral administration of the immediate release component and the modified release component to a group of fasting healthy subjects is 0-inf Greater than the mean γ-hydroxybutyrate AUC following oral administration of the immediate release component alone 0-inf and mean γ-hydroxybutyrate AUC after oral administration of the modified release component alone 0-inf The sum of the sum.

[0165] Embodiment 93. The pharmaceutical composition of any one of Embodiments 42 to 92, wherein the average 4-((L-valyl)oxy)butyric acid AUC after oral administration of the immediate release component and the modified release component to a population of subjects is 0-inf Compared to the mean 4-((L-valyl)oxy)butyric acid AUC after oral administration of the immediate release component alone 0-inf and the mean 4-((L-valyl)oxy)butyric acid AUC after oral administration of the modified release component alone 0-inf The sum of is essentially the same.

[0166] Embodiment 94. The pharmaceutical composition of any one of Embodiments 42 to 92, wherein the mean γ-hydroxybutyrate AUC after oral administration of a pharmaceutical composition comprising an immediate release component comprising 4.52 g 4-((L-valyl)oxy)butyric acid and a modified release component comprising 10 g 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects is 0-inf Greater than the mean γ-hydroxybutyrate AUC following oral administration of the immediate release component containing 7.25 g 4-((L-valyl)oxy)butyric acid alone 0-inf and mean γ-hydroxybutyrate AUC after oral administration of a modified release component containing 7.25 g 4-((L-valyl)oxy)butyric acid alone 0-inf sum.

[0167] Embodiment 95. The pharmaceutical composition of any one of Embodiments 42 to 93, wherein the mean 4-((L-valyl)oxy)butyric acid AUC following oral administration of a pharmaceutical composition comprising an immediate release component comprising 4.52 g 4-((L-valyl)oxy)butyric acid and a modified release component comprising 10 g 4-((L-valyl)oxy)butyric acid to a group of fasting healthy subjects is 0-inf Compared to the mean 4-((L-valyl)oxy)butyric acid AUC after oral administration of only the immediate release component containing 7.25 g 4-((L-valyl)oxy)butyric acid 0-infand the mean 4-((L-valyl)oxy)butyric acid AUC after oral administration of only the modified release component containing 7.25 g 4-((L-valyl)oxy)butyric acid 0-inf The sum is essentially the same.

[0168] Embodiment 96. A method of treating fatigue or excessive daytime sleepiness associated with narcolepsy in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0169] Embodiment 97. A method of treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0170] Embodiment 98. A method of treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0171] Embodiment 99. A method of treating REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0172] Embodiment 100. A method of treating symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0173] Embodiment 101. A method of treating a sleep disorder associated with a bacterial infection in a patient, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0174] Embodiment 102. The method of embodiment 101, wherein the bacterial infection is a COVID-19 infection.

[0175] Embodiment 103. A method of enhancing cognitive function in a patient suffering from a neurological disorder, comprising orally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 42 to 95.

[0176] Embodiment 104. The method of any one of Embodiments 97 to 103, wherein administration comprises QD administration.

[0177] Embodiment 105. The method of any one of Embodiments 97 to 103, wherein administration comprises BID administration.

[0178] Embodiment 106. The method of any one of embodiments 97 to 103, wherein administering comprises administering once nightly.

[0179] Embodiment 107. A kit comprising the pharmaceutical composition according to any one of Embodiments 42 to 95. BRIEF DESCRIPTION OF THE DRAWINGS

[0180] Those skilled in the art should understand that the drawings described herein are for illustration purposes only and are not intended to limit the scope of the present disclosure.

[0181] Figure 1 The particle size distribution of pellets comprising a hydroxypropylmethylcellulose seal coat as described in Example 1 is shown.

[0182] FIG. 2A to FIG. 2E Scanning electron microscopy (SEM) images of seal-coated pellets as described in Example 1 are shown at different magnifications.

[0183] Figure 3 The particle size distribution of pellets comprising a hydroxypropylcellulose seal coat as described in Example 2 is shown.

[0184] FIG. 4A to FIG. 4E SEM images of seal-coated pellets as described in Example 2 are shown at different magnifications.

[0185] Figure 5 The particle size distribution of coated granules as described in Example 3 comprising a 40% wg ethylcellulose / hydroxypropylcellulose functional coating is shown.

[0186] Figure 6 Shown is the dissolution profile of 4-((L-valyl)oxy)butyric acid from pellets containing an ethylcellulose / hydroxypropylcellulose functional coating as described in Example 3 at different % wg indicated.

[0187] FIG. 7A to FIG. 7D SEM images of 40% wg coated pellets as described in Example 3 are shown at different magnifications.

[0188] Fig. 7E SEM image showing a cross section of 40% wg coated pellets as described in Example 3.

[0189] Figure 8 The particle size distribution of coated pellets as described in Example 4 comprising a 40% wg ethylcellulose / hydroxypropylcellulose functional coating is shown.

[0190] Fig. 9 Shown is the dissolution profile of 4-((L-valyl)oxy)butyric acid from pellets containing an ethylcellulose / hydroxypropylcellulose functional coating as described in Example 4 at different % wg indicated.

[0191] FIG. 10A to FIG. 10D SEM images of 40% wg coated pellets as described in Example 4 are shown at different magnifications.

[0192] Fig.10E SEM image showing a cross section of 40% wg coated pellets as described in Example 4.

[0193] Fig.11 The particle size distribution of coated pellets as described in Example 5 comprising a 40% wg ethylcellulose / hydroxypropylcellulose functional coating is shown.

[0194] Fig.12 Shown is the dissolution profile of 4-((L-valyl)oxy)butyric acid from pellets containing an ethylcellulose / hydroxypropylcellulose functional coating as described in Example 5 at different % wg indicated.

[0195] FIG. 13A to FIG. 13D SEM images of 40% wg coated pellets as described in Example 5 are shown at different magnifications.

[0196] Fig.13E SEM image showing a cross section of 40% wg coated pellets as described in Example 5.

[0197] Fig.14 The particle size distribution of coated pellets as described in Example 6 comprising a 40% wg ethylcellulose functional coating is shown.

[0198] Fig.15 Shown are the dissolution profiles of the active pharmaceutical ingredient from granules as described in Example 6 containing the ethylcellulose functional coating at different % wg indicated.

[0199] FIG. 16A to FIG. 16D SEM images of 40% wg coated pellets as described in Example 6 are shown at different magnifications.

[0200] Fig.16E SEM image showing a cross section of 40% wg coated pellets as described in Example 8.

[0201] Fig.17 Shown are mean plasma concentrations of compound (1) following oral administration of an immediate release (IR) composition or three modified release (MR1-MR3) compositions containing compound (1) to fasting healthy subjects.

[0202] Fig.18 Shown are mean plasma γ-hydroxybutyrate concentrations following oral administration of an immediate release (IR) composition or three modified release (MR1-MR3) compositions containing compound (1) to fasting healthy subjects.

[0203] Fig.19 Shown are the mean plasma concentrations of compound (1) after oral administration of two controlled-release compositions containing compound (1) to fasting healthy subjects.

[0204] Fig. 20 Shown are mean plasma γ-hydroxybutyrate concentrations following oral administration of two controlled release compositions containing compound (1) to fasting healthy subjects. DETAILED DESCRIPTION

[0205] Unless expressly stated to the contrary, for the purpose of the following detailed description, it should be understood that the embodiments provided by the present disclosure may adopt various alternative variations and step sequences. In addition, except in any operating examples or when otherwise indicated, all numerals used to express, for example, the number of components in the specification and claims should be understood to be modified with the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the accompanying claims are approximate values, which may vary depending on the desired characteristics to be obtained by the present invention. At a minimum, and without attempting to limit the application of the principle of equivalents to the scope of the claims, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques.

[0206] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0207] It should also be understood that any numerical range described herein is intended to include all sub-ranges contained therein. For example, a range of "1 to 10" is intended to include all sub-ranges between the recited minimum value of 1 and the recited maximum value of 10 (and including 1 and 10), i.e., the minimum value is equal to or greater than 1 and the maximum value is equal to or less than 10.

[0208] "Functional coatings" include immediate release coatings, controlled release coatings, modified release coatings, sustained release coatings, pH release coatings, pulsatile release coatings, timed release coatings, and delayed release coatings. The functional coatings are formulated to impart desired properties to the particles comprising 4-((L-valyl)oxy)butyric acid, such as a desired release profile in the gastrointestinal tract after oral administration.

[0209] "Direct release" refers to a pharmaceutical composition that releases substantially all of the active pharmaceutical ingredient into the gastrointestinal tract of a patient within less than 1 hour after oral administration, e.g., within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, a direct release dosage form can release more than 90%, more than 95%, or more than 98% of the active pharmaceutical ingredient in the pharmaceutical composition into the gastrointestinal tract within less than 1 hour after oral administration, e.g., less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes. Direct release pharmaceutical compositions can be suitable for administering active pharmaceutical ingredients that are absorbed from the upper portion of the gastrointestinal tract into the systemic circulation.

[0210] "Modified release" pharmaceutical compositions include controlled release compositions, delayed release compositions, extended release compositions, sustained release compositions, timed release compositions, pulsatile release compositions, and pH-dependent release compositions. These compositions are intended to release the active pharmaceutical ingredient from the pharmaceutical composition at a desired rate and / or at a desired time after oral administration to a patient and / or at one or more locations in the gastrointestinal tract and / or at a certain pH value in the gastrointestinal tract. The USP defines a modified release system as a system that selects the time course or location of drug release or both to achieve the goal of therapeutic efficacy or convenience that cannot be met by a direct release dosage form. Modified release oral dosage forms may include extended release components and delayed release components. Delayed release dosage forms are dosage forms that release all of the drug at a certain time after administration rather than immediately at one time. Modified release compositions may include delayed release achieved using enteric coatings; site-specific or timed release, such as for colon delivery; extended release, including, for example, compositions that can provide a zero-order, first-order, or biphasic release profile; and programmed release, such as pulsatile and delayed extended release.

[0211] "Sustained release" pharmaceutical compositions and coatings provide a dissolution rate that is released over a longer period of time after oral administration. Granules comprising granules with sustained release coatings may be referred to as sustained release granules. Pharmaceutical compositions comprising sustained release granules may be referred to as sustained release pharmaceutical compositions.

[0212] "pH release" pharmaceutical compositions and coatings provide an increased dissolution rate at a predetermined pH.

[0213] "Pulsatile release" pharmaceutical compositions and coatings exhibit an increased dissolution rate over a time interval, where the release time interval can be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsatile release systems include capsule systems, osmotic systems, systems with erodible membranes, and systems with rupturable coatings. Examples of stimuli include temperature, chemicals, electrical stimuli, and magnetic stimuli.

[0214] "Timed release" pharmaceutical compositions and coatings have a dissolution rate that varies over time. Timed release pharmaceutical compositions or coatings include, for example, delayed release, sustained release, and extended release pharmaceutical compositions and coatings.

[0215] "Delayed release" pharmaceutical compositions and coatings provide an increased rate of dissolution at a predetermined time after administration.

[0216] "Immediate release component" refers to a component of a pharmaceutical composition comprising direct release microparticles provided by the present disclosure.

[0217] "Modified release component" refers to a component of a pharmaceutical composition comprising modified release microparticles provided by the present disclosure.

[0218] "Controlled release pharmaceutical composition" refers to a pharmaceutical composition comprising the direct release microparticles provided by the present disclosure and the modified release microparticles provided by the present disclosure.

[0219] The terms pellet and microparticle are used interchangeably.

[0220] "Patient" refers to a mammal, such as a human.

[0221] "Pharmaceutically acceptable" means approved or permitted to be approved by a regulatory agency of the Federal or a state government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0222] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed from inorganic acids and one or more protonatable functional groups, such as primary, secondary or tertiary amines in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts can be formed from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. When one or more acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions or aluminum ions or combinations thereof; or coordinated with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc., a salt may be formed. A pharmaceutically acceptable salt may be a hydrochloride. A pharmaceutically acceptable salt may be a sodium salt. In compounds having two or more ionizable groups, a pharmaceutically acceptable salt may include one or more counterions, such as a double salt, such as a dihydrochloride.

[0223] The term "pharmaceutically acceptable salt" includes hydrates and other solvates, as well as salts in crystalline or non-crystalline form. When a specific pharmaceutically acceptable salt is disclosed, it is understood that the specific salt (e.g., hydrochloride) is an example of a salt, and other salts can be formed using techniques known to those skilled in the art. In addition, those skilled in the art will be able to convert pharmaceutically acceptable salts into the corresponding compounds, free bases and / or free acids using techniques generally known in the art.

[0224] "Percent weight gain" or "% wg", such as in a "35% wg" coating, refers to a coated granule or particle wherein the weight of the coated granule or particle is a specified percentage (%) greater than the weight of the uncoated granule or particle. For example, a 35% wg particle has a coating that increases the weight of the uncoated particle by 35%. For example, for a granule having an initial weight of 100 gm, the addition of a 35% wg coating increases the weight of the granule to 135 gm. The coating accounts for 25.9 weight % of the total weight of the granule.

[0225] The dissolution profile was measured using a Type 2 USP dissolution apparatus and a sodium acetate buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm.

[0226] A "bioequivalent" value is one that exhibits substantially similar pharmacokinetic profiles and / or therapeutic effects, e.g., C max Or AUC. Bioequivalence can be demonstrated by several in vivo and in vitro methods. These methods can include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. Bioequivalence can be demonstrated using any suitable pharmacokinetic measurement method or combination of pharmacokinetic measurements known in the art, including loading dose, steady-state dose, initial or steady-state drug concentration, biological half-life, elimination rate, area under the curve (AUC), clearance, peak blood or plasma concentration (C max ), time to reach peak concentration (T max ), bioavailability and potency. When AUC and / or C max A value may be bioequivalent to a reference pharmacokinetic value when the geometric mean of is between 80% and 125% of the reference pharmacokinetic value (eg, at a 90% confidence interval).

[0227] A similar or bioequivalent pharmacokinetic profile is one in which the mean AUC of the drug combination in an appropriately designed crossover study is 0-inf is the mean AUC of the reference composition 0-inf 80% to 125% of the 8-hour average plasma concentration of the drug composition C 8h is the 8-hour mean plasma concentration C of the reference composition 8h 40% to 130% of the maximum plasma concentration (C max ) is the C of the reference composition max 50% to 140%.

[0228] The "fed state" refers to the period from just after food is consumed until two hours after consumption. The fed state may include the period of less than two hours after eating.

[0229] The "fasting state" refers to the period after 8 hours after food consumption.

[0230] "Prodrug" refers to a derivative of a drug molecule that needs to be transformed in vivo to provide an active drug. A prodrug is usually, but not necessarily, pharmacologically inactive before being converted to a parent drug. A prodrug can be obtained by bonding a promoiety to a parent drug, typically via a functional group.

[0231] To "cure" a disease means to eliminate the disease or condition, or to eliminate the symptoms of the disease or condition.

[0232] "Treating" or "treatment" of a disease or disorder refers to reducing the severity of one or more clinical symptoms of the disease or disorder, delaying the onset of one or more clinical symptoms of the disease or disorder, and / or alleviating one or more clinical symptoms of the disease or disorder.

[0233] "Treating" or "treatment" of a disease or disorder refers to inhibiting the disease or disorder or one or more clinical symptoms of the disease or disorder; arresting the development of the disease or disorder or one or more clinical symptoms of the disease or disorder; alleviating the disease or disorder or one or more clinical symptoms of the disease or disorder; causing regression of the disease or disorder or one or more clinical symptoms of the disease or disorder; and / or stabilizing the disease or disorder or one or more clinical symptoms of the disease or disorder, and "treating" or "treatment" of a disease or disorder means producing a clinically beneficial effect without requiring a cure of the underlying disease or disorder.

[0234] A "therapeutically effective amount" refers to an amount of a compound, such as a pharmaceutical active ingredient, that is sufficient, when administered to a patient to treat a disease or at least one clinical symptom of a disease, to affect such treatment of the disease or its symptoms. A "therapeutically effective amount" may vary depending on, for example, the compound; the disease and / or symptoms of the disease; the severity of the disease and / or symptoms of the disease or disorder; the age, weight, and / or health of the patient to be treated; and the judgment of the prescribing physician. The therapeutically effective amount in any given case may be determined by a person skilled in the art or can be determined by routine experimentation.

[0235] "Therapeutically effective dose" refers to a dose that provides effective treatment for a disease or condition in a patient. Therapeutically effective doses may vary with the compound and the patient, and may depend on factors such as the patient's condition and the route of delivery. Therapeutically effective doses may be determined according to conventional pharmacological procedures known to those skilled in the art.

[0236] "Vehicle" refers to a diluent, excipient, or carrier used to administer a compound to a patient. The vehicle may be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0237] Reference is now made to pharmaceutical particles with functional coatings, methods for preparing coated pharmaceutical particles, and pharmaceutical compositions comprising coated pharmaceutical particles. The disclosed coated pharmaceutical particles, compositions comprising coated pharmaceutical particles, and methods for preparing coated pharmaceutical particles are not intended to limit the claims. On the contrary, the claims are intended to cover all alternatives, modifications, and equivalents.

[0238] 4-((L-valyl)oxy)butyric acid is a prodrug of γ-hydroxybutyric acid. When administered orally, 4-((L-valyl)oxy)butyric acid is absorbed from the gastrointestinal tract and metabolized in the systemic circulation to release γ-hydroxybutyric acid. γ-Hydroxybutyric acid can be used to treat diseases and conditions such as narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0239] The coated drug particles provided by the present disclosure can be used to provide a modified release of 4-((L-valyl)oxy)butyric acid after oral administration to a patient. The coated drug particles contain 4-((L-valyl)oxy)butyric acid, which is a hygroscopic, highly water-soluble and easily hydrolyzed pharmaceutical active ingredient. The coated drug particles can be used to provide a modified release oral pharmaceutical composition. The coated drug particles can be used to orally administer high doses of 4-((L-valyl)oxy)butyric acid.

[0240] The modified release particles provided by the present disclosure can be prepared by coating the pellets containing 4-((L-valyl)oxy)butyric acid with a coating. The pellets containing 4-((L-valyl)oxy)butyric acid may be uncoated or may contain a seal coat.

[0241] The uncoated drug particles provided by the present disclosure may comprise a plurality of granules, wherein the granules may comprise more than 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the granules; and the uncoated drug particles may be characterized by a particle size distribution (PSD) (D50) of 150 μm to 400 μm, 150 μm to 350 μm, 150 μm to 300 μm, 200 μm to 400 μm, 200 μm to 300 μm, 250 μm to 350 μm or 225 μm to 275 μm, wherein the PSD is determined by sieve analysis; and the wt % is based on the total weight of the drug particles.

[0242] The uncoated granules may contain a high loading of 4-((L-valyl)oxy)butyric acid. For example, the granules may contain more than 90 wt%, more than 93 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, or more than 99 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the uncoated granules. The uncoated granules may contain, for example, 90 wt% to 99.5 wt%, 95 wt% to 99.5 wt% of the γ-hydroxybutyric acid derivative, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the uncoated granules.

[0243] 4-((L-valyl)oxy)butyric acid has the structure of formula (1):

[0244]

[0245] 4-((L-valyl)oxy)butyric acid is a prodrug of gamma-hydroxybutyric acid (GHB) having the structure of formula (2):

[0246]

[0247] After administration, such as oral administration, 4-((L-valyl)oxy)butyric acid is metabolized in the systemic circulation to release gamma-hydroxybutyric acid in the patient's plasma. 4-((L-valyl)oxy)butyric acid provides an oral bioavailability of more than 60% F of gamma-hydroxybutyric acid in the patient.

[0248] The pharmaceutical composition provided by the present disclosure comprises pharmaceutical particles, wherein the pharmaceutical particles comprise small particles of 4-((L-valyl)oxy)butyric acid coated with a functional coating.

[0249] Prior to being formed into pellets, 4-((L-valyl)oxy)butyric acid may have a low bulk density.

[0250] 4-((L-valyl)oxy)butyric acid can have a bulk density of, for example, less than 0.20 g / mL, less than 0.30 g / mL, less than 0.40 g / mL, or less than 0.50 g / mL.

[0251] 4-((L-valyl)oxy)butyric acid can have a bulk density of, for example, 0.15 g / mL to 0.33 g / mL, 0.16 g / mL to 0.32 g / mL, 0.17 g / mL to 0.31 g / mL, 0.18 g / mL to 0.30 g / mL, 0.19 g / mL to 0.29 g / mL, or 0.20 g / mL to 0.28 g / mL.

[0252] 4-((L-valyl)oxy)butyric acid can have a particle size distribution characterized, for example, by a D10 of 1 μm to 3 μm, a D50 of 6.5 μm to 8.5 μm, and a D90 of 15 μm to 17 μm, wherein the particle size distribution is measured by laser diffraction.

[0253] 4-((L-valyl)oxy)butyric acid can have a particle size distribution characterized, for example, by a D50 of 5 μm to 15 μm, 6 μm to 14 μm, 7 μm to 13 μm, 8 μm to 12 μm, or 9 μm to 11 μm, wherein the particle size distribution is measured by laser diffraction.

[0254] 4-((L-valyl)oxy)butyric acid can be jet milled to reduce particle size.

[0255] Uncoated particles containing 4-((L-valyl)oxy)butyric acid may be used Prepared by Microgranulation Technology (Glatt GmbH).

[0256] For high-dose pharmaceutical compositions containing 4-((L-valyl)oxy)butyric acid, it may be useful to have uncoated and coated pellets with a smaller average diameter to improve palatability, especially when reconstituted as a suspension prior to administration.

[0257] The uncoated pharmaceutical particles containing 4-((L-valyl)oxy)butyric acid can be characterized by a PSD (D50) of, for example, 75 μm to 450 μm, 100 μm to 400 μm, 150 μm to 350 μm, 200 μm to 350 μm, 200 μm to 300 μm, 250 μm to 350 μm, or 225 μm to 275 μm, wherein the PSD is determined by sieve analysis or by laser diffraction.

[0258] The uncoated granules may comprise a high loading of 4-((L-valyl)oxy)butyric acid. For example, the uncoated granules may comprise more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, or more than 99 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the uncoated granules. The uncoated granules may comprise, for example, 95 wt% to 99.5 wt% of 4-((L-valyl)oxy)butyric acid, 96 wt% to 99 wt%, 97 wt% to 99 wt%, or 98 wt% to 99 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the uncoated granules.

[0259] The uncoated granules or granules provided by the present disclosure may comprise, for example, more than 85% by weight of 4-((L-valyl)oxy)butyric acid; 1% to 10% by weight of an antistatic agent, such as magnesium silicate (talc); and 1% to 10% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose, wherein the % by weight is based on the total weight of the granules or granules. The uncoated granules or granules provided by the present invention may comprise, for example, more than 90% by weight of 4-((L-valyl)oxy)butyric acid; 2% to 8% by weight of an antistatic agent, such as magnesium silicate (talc); and 2% to 8% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose, wherein the % by weight is based on the total weight of the granules or granules. The uncoated granules or particles provided by the present invention may comprise, for example, more than 90% by weight of 4-((L-valyl)oxy)butyric acid; 3% to 7% by weight of an antistatic agent, such as magnesium silicate (talc); and 3% to 7% by weight of a water-soluble polymer, such as hydroxypropylmethylcellulose, wherein the weight % is based on the total weight of the granules or particles.

[0260] The uncoated granules provided by the present disclosure can be characterized by a sphericity of, for example, 0.90 to 1, for example, 0.91 to 0.99 or 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure can be characterized by a sphericity of, for example, greater than 0.90, greater than 0.91, greater than 0.92, greater than 0.93, greater than 0.94 or greater than 0.95.

[0261] The uncoated granules provided by the present disclosure may include a plurality of granules, characterized by a mode sphericity of, for example, 0.90 to 1, for example, 0.91 to 0.99 or 0.92 to 0.98, wherein the sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. The uncoated granules provided by the present disclosure may include a plurality of granules, characterized by an average sphericity of, for example, greater than 0.94, greater than 0.95, greater than 0.96, greater than 0.97, greater than 0.98 or greater than 0.99.

[0262] The uncoated granules provided by the present disclosure are solid and characterized by a substantially homogeneous composition throughout the granule.

[0263] The drug particles provided by the present disclosure may include a seal coating. The drug particles including a seal coating can be used as direct release drug particles.

[0264] The pharmaceutical particles provided by the present disclosure may comprise a seal coating covering the pellets comprising 4-((L-valyl)oxy)butyric acid.

[0265] The seal coat may comprise a water soluble polymer such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or any of the water soluble polymers disclosed herein.

[0266] The seal coat may contain an antistatic agent, such as talc, magnesium stearate, or a combination thereof.

[0267] The seal coat may comprise, for example, 65 wt % to 95 wt % of a water-soluble polymer, such as 70 wt % to 90 wt % or 75 wt % to 85 wt % of a water-soluble polymer; and 5 wt % to 35 wt % of an antistatic agent, such as 10 wt % to 30 wt % or 15 wt % to 25 wt % of an antistatic agent, wherein the wt % are based on the total weight of the seal coat.

[0268] The seal coat may have a thickness of, for example, 0.5 μm to 4 μm, 1 μm to 3.5 μm, 1 μm to 3 μm, or 1 μm to 2.5 μm.

[0269] Examples of methods of coating pellets comprising 4-((L-valyl)oxy)butyric acid with a seal coat are provided in Examples 1 and 2.

[0270] Figure 1 and 3 The particle size distribution of seal coated granules is shown.

[0271] FIG. 2A to FIG. 2D Pellets containing 4-((L-valyl)oxy)butyric acid and having a 1.3 μm (+ / - 0.27 μm) thick seal coating containing hydroxypropylmethylcellulose and talc are shown at various magnifications. Figure 2E Shown is a cross-sectional view of granules containing 4-((L-valyl)oxy)butyric acid and having a seal coat containing hydroxypropylmethylcellulose and talc.

[0272] FIG. 4A to FIG. 4D Pellets containing 4-((L-valyl)oxy)butyric acid and having a 2.23 μm (+ / - 0.34 μm) thick seal coat containing hydroxypropylcellulose and talc are shown at various magnifications. Figure 4E Shown is a cross-sectional view of 4-((L-valyl)oxy)butyric acid pellets having a seal coat containing hydroxypropylmethylcellulose and talc.

[0273] The coated drug particles provided by the present disclosure may include a plurality of functional coated granules. The functional coating may include, for example, a modified release coating, such as a controlled release coating, a sustained release coating, a pH release coating, a pulsed release coating, a timed release coating, or a delayed release coating. The functional coating may be configured to release 4-((L-valyl)oxy)butyric acid from the coated granules, for example, within a predetermined period after ingestion and / or within a predetermined region of the gastrointestinal tract.

[0274] The coated drug particles provided by the present disclosure may include one or more functional coatings.

[0275] Each of the one or more functional coatings may independently have, for example, an average thickness of less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm. Each of the one or more functional coatings may independently have, for example, an average thickness of 5 μm to 50 μm, 5 μm to 40 μm, 5 μm to 30 μm, 5 μm to 20 μm, 5 μm to 15 μm, or 5 μm to 10 μm.

[0276] The coated pellets or coated granules may contain, for example, more than 50 wt % 4-((L-valyl)oxy)butyric acid, more than 55 wt %, more than 60 wt %, more than 70 wt %, more than 80 wt % or more than 85 wt % 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the coated pellets or coated granules.

[0277] The coated pellets or coated granules comprising a plurality of coated pellets may contain, for example, 50 to 85 wt % of 4-((L-valyl)oxy)butyric acid, 55 to 80 wt %, 60 to 80 wt %, 65 to 80 wt %, or 70 to 75 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the coated pellets or coated granules.

[0278] The coated granules or coated granules may comprise, for example, less than 50% by weight of functional coating, less than 40% by weight of functional coating, less than 30% by weight, less than 20% by weight or less than 10% by weight of functional coating, wherein the weight % is based on the total weight of the coated granules or the coated granules. The coated granules or coated granules may comprise, for example, 10% to 50% by weight of functional coating, 10% to 45% by weight, 15% to 40% by weight or 15% to 35% by weight of functional coating, wherein the weight % is based on the total weight of the coated granules. The coated particles containing 4-((L-valyl)oxy)butyric acid may have a thicker coating to reduce the release rate of 4-((L-valyl)oxy)butyric acid and / or increase the storage stability of 4-((L-valyl)oxy)butyric acid by minimizing or preventing the ingress of moisture.

[0279] The coated pellets or coated granules may contain, for example, more than 50 wt % 4-((L-valyl)oxy)butyric acid, more than 55 wt %, more than 60 wt %, more than 70 wt %, more than 80 wt % or more than 85 wt % 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the coated pellets or coated granules.

[0280] The coated pellets or coated granules comprising a plurality of coated pellets may contain, for example, 50 to 90 wt % of 4-((L-valyl)oxy)butyric acid, 55 to 85 wt %, 60 to 85 wt %, 65 to 85 wt %, or 70 to 80 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the coated pellets or coated granules.

[0281] The functional coating may comprise a matrix polymer or a combination of matrix polymers. The combination of matrix polymers and / or pore-forming polymers may be selected to provide a desired release profile of 4-((L-valyl)oxy)butyric acid in the gastrointestinal tract.

[0282] The functional coating may comprise, for example, 55 to 95 wt % of the matrix polymer, 60 to 90 wt %, 65 to 90 wt %, 70 to 85 wt %, or 75 to 85 wt % of the matrix polymer, wherein the wt % are based on the total weight of the functional coating.

[0283] The functional coating may comprise a matrix polymer or a combination of matrix polymers. The combination of matrix polymers may be selected to provide a desired release profile of 4-((L-valyl)oxy)butyric acid in the gastrointestinal tract.

[0284] The functional coating may comprise, for example, 55 to 95 wt % of the matrix polymer, 60 to 90 wt %, 65 to 90 wt %, 70 to 85 wt %, or 75 to 85 wt % of the matrix polymer, wherein the wt % are based on the total weight of the functional coating.

[0285] The functional coating may comprise, for example, less than 95 wt % of the matrix polymer, less than 90 wt %, less than 85 wt %, less than 80 wt %, less than 75 wt %, less than 70 wt %, or less than 60 wt % of the matrix polymer, wherein the wt % is based on the total weight of the functional coating.

[0286] The functional coating may comprise, for example, greater than 50% matrix polymer, greater than 55 wt%, greater than 60 wt%, greater than 65 wt%, greater than 70 wt%, greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, or greater than 90 wt% matrix polymer, wherein the wt% are based on the total weight of the functional coating.

[0287] The matrix polymer may comprise a water-insoluble polymer or a combination of water-insoluble polymers.

[0288] Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl acetate, polyacrylates, and polymethacrylates.

[0289] The water-insoluble polymer, such as ethylcellulose, can have an average molecular weight of, for example, 25,000 Daltons to 300,000 Daltons, such as 50,000 Daltons to 200,000 Daltons, 50,000 Daltons to 150,000 Daltons, or 50,000 Daltons to 100,000 Daltons.

[0290] A water-insoluble polymer, such as ethyl cellulose, can have a viscosity, for example, of less than 100 mPa×sec, less than 75 mPa×sec, less than 50 mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15 mPa×sec, as measured using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0291] Examples of suitable ethylcellulose polymers include ethylcellulose available from Ashland T10 Pharm, N7 Pharm, N10 Pharm, N14 Pharm, N22 Pharm, N50 Pharm, and N100 Pharm polymers. Other examples of suitable ethylcellulose polymers include TETRAPharm, available from DuPont. Standard 7, Standard 10, Standard 14, Standard 20 polymers.

[0292] The matrix polymer can comprise for example 90 % by weight to 100 % by weight of water-insoluble polymer, 91 % by weight to 99 % by weight or 82 % by weight to 98 % by weight or 93 % by weight to 97 % by weight of water-insoluble polymer, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise for example more than 90 % by weight of water-insoluble polymer, more than 92 % by weight, more than 94 % by weight, more than 96 % by weight or more than 98 % by weight of water-insoluble polymer, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise for example less than 100 % by weight of water-insoluble polymer, less than 98 % by weight, less than 96 % by weight, less than 94 % by weight or less than 92 % by weight of water-insoluble polymer, wherein % by weight is based on the gross weight of the matrix polymer.

[0293] The matrix polymer may include a pore-forming polymer. Examples of pore-forming polymers include water-soluble polymers; swellable or expanding polymers, such as carbomers; and polymers soluble in gastric fluid, such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid-methyl methacrylate copolymers, and polyvinyl acetate phthalate. The pore-forming polymer can increase the permeability of the functional coating under predetermined conditions.

[0294] The matrix polymer may comprise a water-soluble polymer or a combination of water-soluble polymers.

[0295] Examples of suitable water-soluble polymers include hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, crospovidone, and poloxamer.

[0296] Water soluble polymers, such as hydroxypropylcellulose, can have an average molecular weight of, for example, less than 1,000,000 Daltons, less than 800,000 Daltons, less than 600,000 Daltons, less than 400,000 Daltons, less than 200,000 Daltons, less than 100,000 Daltons, or less than 50,0000 Daltons.

[0297] Water-soluble polymers, such as hydroxypropyl cellulose, can have a viscosity, for example, of less than 7,000 mPa×sec, less than 5,000 mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec as measured using a Brookfield viscometer in an 80:20 mixture of toluene / ethanol.

[0298] Examples of suitable hydroxypropyl cellulose polymers include hydroxypropyl cellulose available from Ashland HF Pharm, MFPharm, GF Pharm, JF Pharm, LF Pharm, EF Pharm and ELF Pharm polymers.

[0299] Examples of suitable hydroxypropyl methylcellulose polymers include hydroxypropyl methylcellulose available from Shin-Etsu Chemical Co. 603, 645, 606 and 615 polymers.

[0300] The matrix polymer can comprise, for example, 0 % by weight to 15 % by weight of water-soluble polymer, 0 % by weight to 10 % by weight, 1 % by weight to 8 % by weight or 2 % by weight to 6 % by weight of water-soluble polymer, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise, for example, a water-soluble polymer exceeding 0 % by weight, exceeding 2 % by weight, exceeding 4 % by weight, exceeding 6 % by weight or exceeding 8 % by weight of water-soluble polymer, wherein % by weight is based on the gross weight of the matrix polymer. The matrix polymer can comprise, for example, a water-soluble polymer less than 10 % by weight, less than 8 % by weight, less than 6 % by weight, less than 4 % by weight or less than 2 % by weight of water-soluble polymer, wherein % by weight is based on the gross weight of the matrix polymer.

[0301] The matrix polymer may comprise, for example, 90 wt % to 100 wt % of a water-insoluble polymer and 0 wt % to 10 wt % of a water-soluble polymer; 92 wt % to 98 wt % of a water-insoluble polymer and 2 wt % to 8 wt % of a water-soluble polymer; or 94 wt % to 96 wt % of a water-insoluble polymer and 4 wt % to 6 wt % of a water-soluble polymer, wherein the wt % is based on the total weight of the matrix polymer.

[0302] The functional coating can be applied to the granules provided by the present disclosure by any suitable method, for example by spraying a solution, suspension or dispersion of the functional coating onto the granules in a fluidized bed apparatus.

[0303] In addition to the matrix polymer or combination of matrix polymers, the functional coating may also contain, for example, a plasticizer, an antistatic agent, an anti-adherent agent, a colorant or pigment, a glidant, a viscosity modifier, or a combination of any of the foregoing.

[0304] The functional coating may comprise an antistatic agent or a combination of antistatic agents.

[0305] Antistatic agents may be used to minimize or prevent agglomeration of particles during application of the functional coating.

[0306] Examples of suitable antistatic agents include talc, magnesium stearate and silicon dioxide.

[0307] The functional coating may comprise, for example, 5% to 25% by weight of an antistatic agent, for example, 8% to 22% by weight or 10% to 20% by weight of an antistatic agent, wherein the % by weight is based on the gross weight of the functional coating. The functional coating may comprise, for example, less than 25% by weight of an antistatic agent, less than 23% by weight, less than 18% by weight or less than 15% by weight of an antistatic agent, wherein the % by weight is based on the gross weight of the functional coating. The functional coating may comprise, for example, more than 5% by weight of an antistatic agent, more than 8% by weight, more than 12% by weight, more than 16% by weight or more than 20% by weight of an antistatic agent, wherein the % by weight is based on the gross weight of the functional coating.

[0308] The functional coatings provided by the present disclosure do not include plasticizers, such as dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0309] The functional coating provided by the present disclosure may comprise, for example, 70 wt % to 95 wt % of a matrix polymer and 5 wt % to 30 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0310] The functional coating provided by the present disclosure may comprise, for example, 75 wt % to 90 wt % of a matrix polymer and 10 wt % to 25 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0311] The functional coating provided by the present disclosure may comprise, for example, 80 to 90 wt % of a matrix polymer and 10 to 12 wt % of an antistatic agent, wherein the wt % is based on the total weight of the functional coating.

[0312] In the functional coating provided by the present disclosure, the matrix polymer may include hydroxypropyl cellulose and hydroxypropyl methyl cellulose, and the antistatic agent may include magnesium stearate, talc, or a combination thereof.

[0313] Functional coatings of the present disclosure, such as modified release coatings, may include, for example, 72% to 92% by weight of a water-insoluble polymer, such as ethylcellulose; 0.5% to 4% by weight of a water-soluble polymer, such as hydroxypropylmethylcellulose; and 11% to 22% by weight of an antistatic agent, such as magnesium stearate, wherein the weight % is based on the total weight of the functional coating. Functional coatings of the present disclosure, such as modified release coatings, may include, for example, 74% to 90% by weight of a water-insoluble polymer, such as ethylcellulose; 1% to 3.5% by weight of a water-soluble polymer, such as hydroxypropylmethylcellulose; and 13% to 20% by weight of an antistatic agent, such as magnesium stearate, wherein the weight % is based on the total weight of the functional coating. Functional coatings of the present disclosure, such as modified release coatings, may comprise, for example, 76 wt % to 88 wt % of a water-insoluble polymer, such as ethylcellulose; 1 wt % to 3.0 wt % of a water-soluble polymer, such as hydroxypropyl methylcellulose; and 14 wt % to 18 wt % of an antistatic agent, such as magnesium stearate, wherein the wt % is based on the total weight of the functional coating.

[0314] The modified release granules or particles provided by the present disclosure may include, for example, a core and a modified release coating surrounding the core. The core may include, for example, 85% to 95% by weight of 4-((L-valyl)oxy)butyric acid; 1% to 9% by weight, for example, 3% to 7% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose; and 1% to 9% by weight, for example, 3% to 7% by weight of an antistatic agent, such as magnesium stearate, wherein the weight % is based on the gross weight of the core; and the modified release coating surrounding the core may include, for example, 77% to 87% by weight of a water-insoluble polymer, such as ethylcellulose; 0.1% to 5% by weight of a water-soluble polymer, such as hydroxypropyl methylcellulose; and 11% to 21% by weight, for example, 14% to 18% by weight of an antistatic agent, such as magnesium stearate, wherein the weight % is based on the gross weight of the modified release coating.

[0315] The modified release particles provided by the present disclosure can be configured to provide overnight dosing, once-a-day dosing (QD), twice-a-day dosing (BID), three-a-day dosing (TID), or four-a-day dosing (QID). For example, the modified release particles can release substantially 100% of 4-((L-valyl)oxy)butyric acid over a 24-hour duration, a 12-hour duration, an 8-hour duration, or a 4-hour duration.

[0316] For example, a modified release particle may exhibit substantially as e.g. Figure 6 , Fig. 9 , Fig.12and the dissolution profiles shown in Figure 16. For example, modified release particles may exhibit dissolution profiles similar to, for example Figure 6 , Fig. 9 , Fig.12 and any one of the dissolution profiles shown in Figure 16 that is bioequivalent.

[0317] The modified release particles can exhibit a dissolution profile, for example, wherein less than 80% of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 2 hours, less than 70% by weight, less than 60% by weight, less than 50% by weight, or less than 40% by weight of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 2 hours, and more than 60% by weight, more than 70% by weight, or more than 80% by weight of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 6 hours, as measured using a Type 2 USP dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0318] The modified release particles can exhibit a dissolution profile wherein 30 to 80 wt%, e.g., 35 to 75 wt% or 40 to 70 wt% of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 2 hours as measured using a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 100 rpm, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0319] The modified release particles can exhibit a dissolution profile wherein 50 to 90 wt%, e.g., 65 to 85 wt% or 70 to 80 wt% of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 4 hours as measured using a Type 2 USP dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0320] The modified release particles can exhibit a dissolution profile wherein 60 to 100 wt%, e.g., 65 to 95 wt% or 70 to 90 wt% of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 6 hours as measured using a Type 2 USP dissolution apparatus in a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 100 rpm, wherein the wt% is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0321] The modified release particles can exhibit a dissolution profile wherein 30% to 80% of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 2 hours, 50% to 90% by weight of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 4 hours, and 60% to 100% by weight of 4-((L-valyl)oxy)butyric acid is released from the composition within 6 hours, as measured using a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0322] The modified release particles can exhibit a dissolution profile wherein 25 to 70 weight percent of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 2 hours, 50 to 85 weight percent of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 4 hours, and 60 to 85 weight percent of 4-((L-valyl)oxy)butyric acid is released from the modified release particles within 6 hours, as measured using a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, wherein the weight percent is based on the total weight of 4-((L-valyl)oxy)butyric acid in the particles.

[0323] Modified release particles can exhibit Fig. 9 and Fig.12 Any of the dissolution profiles shown in is bioequivalent to the dissolution profile.

[0324] The coated particles provided by the present disclosure may have a moisture content of, for example, less than 2 wt%, less than 1.5 wt%, less than 1 wt%, less than 0.5 wt%, or less than 0.25 wt%, wherein the wt% is based on the total weight of the coated particles.

[0325] The coated particles provided by the present disclosure may have a moisture content of, for example, 0.1 wt % to 2 wt %, 0.1 wt % to 1 wt %, or 0.2 wt % to 0.6 wt %, wherein the wt % is based on the total weight of the coated particles.

[0326] The coated drug particles can have a bulk density of, for example, greater than 0.55 g / mL, greater than 0.60 g / mL, greater than 0.65 g / mL, greater than 0.70 g / mL, or greater than 0.75 g / mL.

[0327] The coated drug particles may have a bulk density of, for example, 0.55 g / mL to 0.80 g / mL, 0.60 g / mL to 75 g / mL, 0.60 g / mL to 0.70 g / mL.

[0328] Bulk density can be measured using a bulk density measuring cylinder.

[0329] The coated drug particles provided by the present disclosure may be characterized by a PSD (D50) of, for example, 150 to 400 μm, such as 150 to 350 μm, 175 to 325 μm, 200 to 300 μm, 250 to 350 μm, or 225 to 275 μm.

[0330] Examples of particle size distributions of coated particles provided by the present disclosure are shown in Figure 5 , Figure 8 , Fig.11 and Fig.15 middle.

[0331] The particle size distribution can be determined by laser diffraction or by sieve analysis.

[0332] The functional coating provided by the present disclosure can be coated onto the particles using any suitable equipment and method. Examples of suitable coating methods include Wurster fluidized bed film coating, compression coating, and phase inversion.

[0333] The functional coating can be applied to uncoated particles or particles comprising a seal coating provided by the present disclosure.

[0334] Examples of coating compositions are provided in the Experimental Examples.Coating compositions refer to compositions that are applied to uncoated particles or to included seal-coated particles to provide coated particles.

[0335] The functional coating composition may comprise greater than 70 wt %, greater than 75 wt %, greater than 80 wt %, greater than 85 wt % or greater than 90 wt % of a non-aqueous solvent, such as ethanol or acetone, wherein the wt % is based on the total weight of the functional coating solution / suspension composition used to coat the particles.

[0336] The functional coating composition may contain, for example, less than 20 wt % water, less than 15 wt %, less than 10 wt % or less than 5 wt % water, wherein the wt % is based on the functional coating solution / suspension composition used to coat the particles.

[0337] For highly water soluble and hygroscopic pharmaceutical active ingredients, such as 4-((L-valyl)oxy)butyric acid, it may be useful to minimize the amount of water in the functional coating composition. Reducing the water content in the functional coating solution / suspension composition may generate static electricity, which may cause problems in the coating process.

[0338] The functional coating solution / suspension composition may comprise, for example, a solids content of less than 20 wt %, less than 18 wt %, less than 16 wt %, less than 14 wt %, less than 12 wt %, less than 10 wt %, less than 8 wt %, or less than 6 wt %, wherein the wt % is based on the functional coating solution / suspension composition.

[0339] The functional coating composition may comprise, for example, a solids content of 2 to 20 wt%, 4 to 16 wt%, 4 to 12 wt%, 6 to 14 wt%, or 6 to 10 wt%, wherein the wt% is based on the functional coating composition.

[0340] An example of coating procedure conditions using a Wurster column inserted into a fluidized bed coating apparatus is provided in the Experimental Examples.

[0341] The particles provided by the present disclosure may comprise direct release particles.

[0342] The immediate release granules may comprise a plurality of uncoated granules or a plurality of granules comprising a seal coat.

[0343] Direct-release granules comprising a plurality of uncoated granules or seal-coated granules may comprise greater than 90% by weight of 4-((L-valyloxy)butyric acid, e.g., 4-((L-valyl)oxy)butyric acid, provided by the present disclosure. When tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, the direct-release granules comprising uncoated granules or seal-coated granules may be completely dissolved, e.g., in less than 10 minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes, or less than 4 minutes.

[0344] The direct release granules may comprise a plurality of coated or seal coated granules having a direct release functional coating. The direct release granules comprising a plurality of coated granules may comprise more than 80% by weight of 4-((L-valyl)oxy)butyric acid. When tested in a USP dissolution apparatus type 2, in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 100 rpm, the direct release granules comprising coated granules may be completely dissolved, for example, in less than 25 minutes, less than 20 minutes, less than 18 minutes, less than 16 minutes, less than 14 minutes, or less than 12 minutes. When tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, direct release particles comprising coated granules can release more than 80% of 4-((L-valyl)oxy)butyric acid in, for example, less than 10 minutes, less than 8 minutes, less than 6 minutes, or less than 4 minutes. The coated direct release particles can comprise a coating comprising a water-soluble polymer, such as hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, polyvinylpyrrolidone, or polyethylene glycol. The coated direct release particles can comprise a coating comprising an antistatic agent, such as talc, magnesium stearate, or silicon dioxide.

[0345] The pharmaceutical composition provided by the present disclosure may include a combination of direct release particles and modified release particles. The pharmaceutical composition may include 4-((L-valyl)oxy)butyric acid as direct release particles and 4-((L-valyl)oxy)butyric acid as modified release particles in a weight % ratio of, for example, 1:1 to 1:4, 1:1 to 1:3, 1:1 to 1:2, or 1:2 to 1:3.

[0346] The pharmaceutical composition provided by the present disclosure may include the coated particles provided by the present disclosure.

[0347] The pharmaceutical composition may comprise any dosage form suitable for oral administration.

[0348] Examples of suitable oral dosage forms include tablets, capsules, caplets, sachets, bottles, stick packs, dispersions and suspensions.

[0349] The oral dosage forms provided by the present disclosure can include, for example, 0.1 g to 20 g of 4-((L-valyl)oxy)butyric acid, 0.1 g to 15 g, 0.1 g to 12 g, 0.1 g to 10 g, 0.2 g to 8 g, 0.5 g to 5 g, 1 g to 4.5 g, or 1.5 g to 4 g of 4-((L-valyl)oxy)butyric acid. The oral dosage forms can include, for example, more than 0.5 g, more than 1 g, more than 2 g, more than 3 g, more than 4 g, more than 6 g, or more than 8 g, more than 10 g, more than 14 g, or more than 18 g of 4-((L-valyl)oxy)butyric acid.

[0350] The oral formulation provided by the present disclosure may include an oral suspension of coated small particles with a modified release functional coating provided by the present disclosure. The oral composition may include modified release particles and direct release particles provided by the present disclosure.

[0351] Oral compositions may comprise a combination of immediate release particles and modified release particles provided by the present disclosure.

[0352] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a period of time.

[0353] For example, the oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0354] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid over a period of 4 hours to 12 hours, 4 hours to 10 hours, or 4 hours to 8 hours.

[0355] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid for a duration of 1 hour to 12 hours after oral administration, 2 hours to 10 hours, or 4 hours to 8 hours after oral administration.

[0356] The oral composition provided by the present disclosure can be a once-nightly composition. For a once-nightly composition, a patient can take a dose of 4-((L-valyl)oxy)butyric acid before bedtime and a full night's sleep of, for example, 6 or 8 hours, without having to take a second dose at night.

[0357] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma.

[0358] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate in the patient's plasma within a period of 4 hours, 6 hours, 8 hours, or 10 hours following oral administration of the modified release oral composition.

[0359] The oral compositions provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 10 μg / mL for greater than 4 hours, greater than 6 hours, greater than 8 hours, or greater than 10 hours following oral administration of the modified release oral composition.

[0360] The oral compositions provided by the present disclosure can provide a plasma concentration of gamma-hydroxybutyrate greater than 15 μg / mL for greater than 4 hours, greater than 6 hours, greater than 8 hours, or greater than 10 hours following oral administration of the modified release oral composition.

[0361] The oral compositions provided by the present disclosure can provide a therapeutically effective amount of C in the patient's plasma for a duration of 4 hours, 6 hours, 8 hours, or 10 hours after oral administration of the modified release oral composition. max Than C min A ratio of less than 3 or less than 2 gamma-hydroxybutyrate.

[0362] The oral composition provided by the present disclosure may include the γ-hydroxybutyric acid derivative of formula (2), and may include, for example, 0.5 gram equivalents, 1 gram equivalents, 2 gram equivalents, 3 gram equivalents, 4 gram equivalents, 5 gram equivalents, 6 gram equivalents, 7 gram equivalents, 8 gram equivalents, 9 gram equivalents, 10 gram equivalents, 11 gram equivalents, or 12 gram equivalents of γ-hydroxybutyric acid.

[0363] The pharmaceutical composition provided by the present disclosure may be included in a kit, which can be used to administer the compound to a patient to achieve a therapeutic purpose. The kit may include a pharmaceutical composition comprising a direct release component and a modified release component suitable for administration to a patient, and instructions for administering the pharmaceutical composition to the patient. The kit may be used, for example, to treat sleep disorders. The kit may include a direct release component and a modified release component, a pharmaceutically acceptable vehicle for administering the direct release component and the modified release component, and instructions for administering the pharmaceutical composition to a patient.

[0364] The oral compositions provided by the present disclosure can be provided, for example, in the form of sachets containing the coated particles provided by the present disclosure. The sachets can provide different doses of 4-((L-valyl)oxy)butyric acid, for example, 0.5g, 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 11g, 10g, 12g, 15g or 20g of 4-((L-valyl)oxy)butyric acid. The coated particles can be combined, for example, with water to provide a dosage form that can be orally ingested.

[0365] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0366] The instructions supplied with the kit may be printed and / or supplied, for example, on an electronically readable medium, videocassette, audiotape, flash memory device, or may be published on an Internet website or sent to the patient and / or health care provider in the form of an electronic communication.

[0367] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 0.9 hours average T max , an average C of 16 μg / mL max , 16h×μg / mL average AUC 0-6 , 16h×AUC of μg / mL 0-inf and CL / F of 48 L / h.

[0368] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 0.8 hours to 1.0 hours average T max , 14μg / mL to 18μg / mL average C max , average AUC from 14h×μg / mL to 18h×μg / mL 0-6 , AUC from 14h×μg / mL to 18h×μg / mL 0-inf and CL / F of 44L / h to 52L / h.

[0369] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 0.85 hours to 0.95 hours average T max , 15μg / mL to 17μg / mL average C max , average AUC from 15h×μg / mL to 17h×μg / mL 0-6 , AUC from 15h×μg / mL to 17h×μg / mL 0-inf and CL / F of 446L / h to 50L / h.

[0370] Following oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.6 hours average T max , an average C of 4 μg / mLmax , 9h×μg / mL average AUC 0-6 , 9h×AUC of μg / mL 0-inf and an average CL / F of 838 L / h.

[0371] After oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.4 hours to 1.8 hours average T max , 2μg / mL to 6μg / mL average C max , average AUC from 7h×μg / mL to 11h×μg / mL 0-6 , AUC from 7h×μg / mL to 11h×μg / mL 0-inf and an average CL / F of 818 L / h to 858 L / h.

[0372] Following oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 1.5 hours to 1.7 hours average T max , 3μg / mL to 5μg / mL average C max , average AUC from 8h×μg / mL to 10h×μg / mL 0-6 , AUC from 8h×μg / mL to 10h×μg / mL 0-inf and an average CL / F of 828L / h to 848L / h.

[0373] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.4 hours average T max , 6μg / mL average C max , 10h×μg / mL average AUC 0-6 , 10h×AUC of μg / mL 0-inf and an average CL / F of 762 L / h.

[0374] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 1.2 hours to 1.6 hours average T max, 4μg / mL to 8μg / mL average C max , average AUC from 8h×μg / mL to 12h×μg / mL 0-6 , AUC from 8h×μg / mL to 12h×μg / mL 0-inf and an average CL / F of 720L / h to 800L / h.

[0375] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 1.3 hours to 1.5 hours average T max , 5μg / mL to 7μg / mL average C max , average AUC from 9h×μg / mL to 11h×μg / mL 0-6 , AUC from 9h×μg / mL to 11h×μg / mL 0-inf and an average CL / F of 740L / h to 780L / h.

[0376] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.1 hours average T max , 5μg / mL average C max , 10h×μg / mL average AUC 0-6 , 10h×AUC of μg / mL 0-inf and an average CL / F of 801 L / h.

[0377] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t 1 / 2 , 0.9 hours to 1.3 hours average T max , 3μg / mL to 7μg / mL average C max , average AUC from 8h×μg / mL to 12h×μg / mL 0-6 , AUC from 8h×μg / mL to 12h×μg / mL 0-inf and an average CL / F of 760L / h to 840L / h.

[0378] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of compound (1) may be characterized by an average t1 / 2 , 1.0 hours to 1.2 hours average T max , 4μg / mL to 6μg / mL average C max , average AUC from 9h×μg / mL to 11h×μg / mL 0-6 , AUC from 9h×μg / mL to 11h×μg / mL 0-inf and an average CL / F of 780L / h to 820L / h.

[0379] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by a mean t 1 / 2 , 1.3 hours average T max , an average C of 86 μg / mL max , 239h×mean AUC of μg / mL 0-6 , 246h×AUC of μg / mL 0-inf and an average CL / F of 31 L / h.

[0380] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 1.1 hours to 1.5 hours average T max , 76μg / mL to 96μg / mL average C max , average AUC from 219h×μg / mL to 259h×μg / mL 0-6 , AUC from 226h×μg / mL to 266h×μg / mL 0-inf and an average CL / F of 21 L / h to 41 L / h.

[0381] Following oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 0.5 to 0.7 hours. 1 / 2 , 1.2 hours to 1.4 hours average T max , 81μg / mL to 91μg / mL average C max , average AUC from 229h×μg / mL to 249h×μg / mL 0-6 , AUC from 236h×μg / mL to 256h×μg / mL 0-inf and an average CL / F of 26 L / h to 36 L / h.

[0382] Following oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 2.4 hours average T max , an average C of 27 μg / mL max , average AUC of 86h×μg / mL 0-6 , AUC at 95h×μg / mL 0-inf and an average CL / F of 95 L / h.

[0383] Following oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , average T of 2.2 hours to 2.6 hours max , 17μg / mL to 37μg / mL average C max , average AUC from 76h×μg / mL to 96h×μg / mL 0-6 , AUC from 75h×μg / mL to 115h×μg / mL 0-inf and an average CL / F of 85 L / h to 105 L / h.

[0384] Following oral administration of an MR1 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 2.3 hours to 2.5 hours average T max , 22μg / mL to 32μg / mL average C max , average AUC from 81h×μg / mL to 91h×μg / mL 0-6 , AUC from 85h×μg / mL to 105h×μg / mL 0-inf and an average CL / F of 90L / h to 100L / h.

[0385] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 2.4 hours average T max , an average C of 36 μg / mL max , 112h×mean AUC of μg / mL 0-6 , 120h×AUC of μg / mL 0-inf and an average CL / F of 72 L / h.

[0386] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , average T of 2.2 hours to 2.6 hours max , 34μg / mL to 38μg / mL average C max , average AUC from 102h×μg / mL to 122h×μg / mL 0-6 , AUC from 110h×μg / mL to 130h×μg / mL 0-inf and an average CL / F of 62 L / h to 82 L / h.

[0387] Following oral administration of an MR2 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 0.85 to 0.95 hours. 1 / 2 , 2.3 hours to 2.5 hours average T max , 35μg / mL to 37μg / mL average C max , average AUC from 107h×μg / mL to 117h×μg / mL 0-6 , AUC of 125h×μg / mL to 135h×μg / mL 0-inf and an average CL / F of 67 L / h to 77 L / h.

[0388] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 1.9 hours average T max , 30μg / mL average C max , average AUC of 102h×μg / mL 0-6 , AUC of 110h×μg / mL 0-inf and an average CL / F of 79 L / h.

[0389] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 0.9 to 1.1 hours. 1 / 2 , 1.7 hours to 2.1 hours average T max , 26μg / mL to 34μg / mL average C max , average AUC from 82h×μg / mL to 122h×μg / mL 0-6, AUC from 90h×μg / mL to 130h×μg / mL 0-inf and an average CL / F of 69 L / h to 89 L / h.

[0390] Following oral administration of an MR3 composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t 1 / 2 , 1.8 hours to 2.0 hours average T max , 28μg / mL to 32μg / mL average C max , average AUC from 92h×μg / mL to 112h×μg / mL 0-6 , AUC from 100h×μg / mL to 120h×μg / mL 0-inf and an average CL / F of 74 L / h to 84 L / h.

[0391] After oral administration of an IR composition containing 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile was characterized by a mean C of 5.9. max ratio, average AUC of 15.0 0-inf ratio and an average AUC of 16.2 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile can be characterized by: a mean C of 4.9 to 6.9 max ratio, mean AUC from 14.0 to 16.0 0-inf ratio and an average AUC of 15.2 to 17.2 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of an IR composition comprising 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile can be characterized by an average C of 5.4 to 6.4. max ratio, average AUC of 14.5 to 15.5 0-inf ratio and an average AUC of 15.7 to 16.7 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0392] Following oral administration of MR1 composition containing 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile was characterized by a mean C of 6.6. max ratio, average AUC of 10.0 0-inf ratio and an average AUC of 9.8 0-6Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR1 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 6.2 to 7.0 max ratio, average AUC from 9.0 to 11.0 0-inf ratio and an average AUC of 9.4 to 10.2 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR1 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 6.4 to 6.8 max ratio, average AUC of 9.5 to 10.5 0-inf ratio and an average AUC of 9.6 to 10.0 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0393] Following oral administration of MR2 composition containing 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile was characterized by a mean C of 6.3. max ratio, average AUC of 11.9 0-inf ratio and an average AUC of 11.5 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR2 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 5.9 to 6.7 max ratio, average AUC from 11.5 to 12.3 0-inf ratio and an average AUC of 11.1 to 11.9 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR2 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 6.1 to 6.5 max ratio, average AUC from 11.7 to 12.1 0-inf ratio and an average AUC of 11.3 to 11.7 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0394] After oral administration of MR3 composition containing 7.25 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile was characterized by a mean C of 6.5. max ratio, average AUC of 11.40-inf ratio and an average AUC of 11.4 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR3 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 6.1 to 6.9 max ratio, average AUC from 11.0 to 11.8 0-inf ratio and an average AUC of 11.0 to 11.8 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value. After oral administration of the MR3 composition containing 7.25 g of compound (1) to a group of fasting healthy individuals, the plasma pharmacokinetic profile is characterized by: a mean C of 6.3 to 6.7 max ratio, average AUC of 11.2 to 11.6 0-inf ratio and an average AUC of 11.2 to 11.6 0-6 Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0395] The pharmaceutical composition may comprise an immediate release component and a modifying component.

[0396] The immediate release component may comprise any of the immediate release microparticles disclosed herein.

[0397] The modified component may comprise any of the modified microparticles or a combination of modified microparticles disclosed herein.

[0398] The pharmaceutical composition provided by the present disclosure may contain, for example, 10% to 50% by weight of compound (1) in the IR component and 50% to 90% by weight in the MR component, 20% to 40% by weight of compound (1) in the IR component and 60% to 80% by weight of γ-hydroxybutyrate in the MR component, or 25% to 35% by weight of compound (1) in the IR component and 65% to 75% by weight of compound (1) in the MR component, wherein the weight % is based on the total weight of compound (1) in the pharmaceutical composition.

[0399] The pharmaceutical composition provided by the present disclosure may contain, for example, more than 10 wt % of compound (1) in the IR component and less than 90 wt % of compound (1) in the MR component, more than 20 wt % of compound (1) in the IR component and less than 80 wt % of compound (1) in the MR component, more than 30 wt % of compound (1) in the IR component and less than 70 wt % of compound (1) in the MR component, or more than 40 wt % of compound (1) in the IR component and less than 60 wt % of compound (1) in the MR component, wherein the wt % is based on the total weight of compound (1) in the pharmaceutical composition.

[0400] The weight ratio of compound (1) in the IR component to compound (1) in the MR component in the pharmaceutical compositions provided by the present disclosure can be, for example, 1:1.4 to 1:3.4, 1:1.6 to 1.3.2, 1.1.8 to 1:3.0, 1:2.0 to 1:2.8 or 1.22 to 1:2.6.

[0401] The weight ratio of compound (1) in the IR component to compound (1) in the MR component in the pharmaceutical compositions provided by the present disclosure may be, for example, greater than 1:1.4, greater than 1:1.6, greater than 1:1.8, greater than 1:2.0, greater than 1:2.2, greater than 1:2.4 or greater than 1:2.6.

[0402] The pharmaceutical compositions provided by the present disclosure may contain, for example, 2.0 g to 6.0 g of compound (1) in the IR fraction, 2.25 g to 5.75 g, 2.5 g to 5.5 g, 2.75 g to 5.25 g, 3.0 g to 5.0 g, 3.25 g to 4.75 g, or 3.5 g to 4.5 g of compound (1) in the IR fraction.

[0403] The pharmaceutical composition may contain, for example, 8 g to 12 g of compound (1) in the MR fraction, 8.5 g to 11.5 g, 9 g to 11 g, 9.25 g to 10.75 g, or 9.5 g to 10.5 g of compound (1) in the MR fraction.

[0404] The pharmaceutical composition may contain, for example, 2.0 g to 6.0 g of compound (1) in the IR component, 2.25 g to 5.75 g, 2.5 g to 5.5 g, 2.75 g to 5.25 g, 3.0 g to 5.0 g, 3.25 g to 4.75 g, or 3.5 g to 4.5 g of compound (1) in the IR component; and 8 g to 12 g of compound (1) in the MR component, 8.5 g to 11.5 g, 9 g to 11 g, 9.25 g to 10.75 g, or 9.5 g to 10.5 g of compound (1) in the MR component.

[0405] The pharmaceutical composition provided by the present disclosure may contain, for example, 9.5 g to 22 g of compound (1), 10 g to 20 g of compound (1), 12 g to 18 g of compound (1), or 14 g to 16 g of compound (1). The pharmaceutical composition provided by the present disclosure may contain, for example, more than 9 g of compound (1), more than 10 g, more than 12 g, more than 14 g, more than 16 g, more than 18 g, or more than 20 g of compound (1).

[0406] The pharmaceutical compositions provided by the present disclosure may include, for example, 10 wt % to 50 wt % of γ-hydroxybutyrate equivalents in the IR component and 50 wt % to 90 wt % in the MR component, 20 wt % to 40 wt % of γ-hydroxybutyrate equivalents in the IR component and 60 wt % to 80 wt % of γ-hydroxybutyrate in the MR component, or 25 wt % to 35 wt % of γ-hydroxybutyrate equivalents in the IR component and 65 wt % to 75 wt % of γ-hydroxybutyrate equivalents in the MR component, wherein the weight % equivalents are based on the total weight percentage of γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0407] The pharmaceutical compositions provided by the present disclosure may comprise, for example, greater than 10 wt % of γ-hydroxybutyrate equivalents in the IR component and less than 90 wt % of γ-hydroxybutyrate equivalents in the MR component, greater than 20 wt % of γ-hydroxybutyrate equivalents in the IR component and less than 80 wt % of γ-hydroxybutyrate equivalents in the MR component, greater than 30 wt % of γ-hydroxybutyrate equivalents in the IR component and less than 70 wt % of γ-hydroxybutyrate equivalents in the MR component, or greater than 40 wt % of γ-hydroxybutyrate in the IR component and less than 60 wt % of γ-hydroxybutyrate in the MR component, wherein the wt % equivalents are based on the total γ-hydroxybutyrate equivalents in the pharmaceutical composition.

[0408] The weight ratio of γ-hydroxybutyrate equivalents in the IR component to γ-hydroxybutyrate in the MR component in the pharmaceutical compositions provided by the present disclosure can be, for example, 1:1.5 to 1:3.5, 1:1.7 to 1.3.3, 1.1.9 to 1:3.1, 1:2.1 to 1:2.9, or 1.23 to 1:2.7.

[0409] The weight ratio of γ-hydroxybutyrate equivalents in the IR component to the γ-hydroxybutyrate equivalents in the MR component of the pharmaceutical compositions provided by the present disclosure can be, for example, greater than 1:1.5, greater than 1:1.7, greater than 1:1.9, greater than 1:2.1, greater than 1:2.3, greater than 1:2.5, or greater than 1:2.7.

[0410] The pharmaceutical compositions provided by the present disclosure can include, for example, 1.1 g to 3.1 g of γ-hydroxybutyrate equivalents in the IR component, 1.2 g to 3.0 g, 1.3 g to 2.9 g, or 1.4 g to 2.8 g of γ-hydroxybutyrate equivalents in the IR component.

[0411] The pharmaceutical composition may comprise, for example, 4.1 g to 6.1 g of gamma-hydroxybutyrate equivalents in the MR component, 4.2 g to 6.0 g, 4.3 g to 5.9 g, 4.4 g to 6.8 g, or 4.5 g to 6.7 g of gamma-hydroxybutyrate equivalents in the MR component.

[0412] The pharmaceutical composition may comprise, for example, 1.1 g to 3.1 g of γ-hydroxybutyrate equivalents in the IR component and 4.1 g to 6.1 g of γ-hydroxybutyrate equivalents in the MR component; 1.4 g to 2.8 g of γ-hydroxybutyrate equivalents in the IR component and 4.3 g to 5.9 g of γ-hydroxybutyrate equivalents in the MR component; 1.6 g to 2.6 g of γ-hydroxybutyrate equivalents in the IR component and 4.5 g to 5.7 g of γ-hydroxybutyrate equivalents in the MR component; or 1.8 g to 2.2 g of γ-hydroxybutyrate equivalents in the IR component and 4.7 g to 5.5 g of γ-hydroxybutyrate equivalents in the MR component.

[0413] The pharmaceutical composition provided by the present disclosure may contain, for example, 6.5 g to 18 g of compound (1), 8 g to 16 g of γ-hydroxybutyrate equivalents, 10 g to 14 g of compound (1), or 11 g to 13 g of γ-hydroxybutyrate equivalents. The pharmaceutical composition provided by the present disclosure may contain, for example, more than 9 g of γ-hydroxybutyrate equivalents, more than 6.5 g, more than 8 g, more than 10 g, more than 12 g, more than 14 g, or more than 16 g of γ-hydroxybutyrate equivalents.

[0414] Methods for determining the plasma pharmacokinetic profiles of gamma-hydroxybutyrate and 4-((L-valyl)oxy)butyric acid (1) following administration of 4-((L-valyl)oxy)butyric acid (1) to fasting healthy subjects are provided in an Experimental Example.

[0415] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.4 hours average T max , 15μg / mL average C max , average AUC of 25h×μg / mL 0-6 , average AUC of 27h×μg / mL 0-inf and an average CL / F of 556 L / h.

[0416] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t of 1.0 to 1.2 hours. 1 / 2 , 1.3 hours to 1.5 hours average T max , 12μg / mL to 18μg / mL average C max, average AUC from 20h×μg / mL to 30h×μg / mL 0-6 , average AUC from 22h×μg / mL to 32h×μg / mL 0-inf and an average CL / F of 536L / h to 576L / h.

[0417] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t of 1.05 to 1.15 hours. 1 / 2 , 1.35 hours to 1.45 hours average T max , 14μg / mL to 16μg / mL average C max , average AUC from 22h×μg / mL to 28h×μg / mL 0-6 , average AUC from 24h×μg / mL to 30h×μg / mL 0-inf and an average CL / F of 546 L / h to 566 L / h.

[0418] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by a mean t 1 / 2 , 2.7 hours average T max , an average C of 108 μg / mL max , average AUC of 400h×μg / mL 0-6 , 534h×mean AUC of μg / mL 0-inf and an average CL / F of 32 L / h.

[0419] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 1.0 to 1.2 hours. 1 / 2 , 2.5 hours to 2.9 hours average T max , 88μg / mL to 128μg / mL average C max , average AUC from 380h×μg / mL to 420h×μg / mL 0-6 , average AUC from 514h×μg / mL to 554h×μg / mL 0-inf and an average CL / F of 22 L / h to 42 L / h.

[0420] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 1.05 to 1.15 hours. 1 / 2 , 2.6 hours to 2.8 hours average T max , 98μg / mL to 118μg / mL average C max , average AUC from 390h×μg / mL to 410h×μg / mL 0-6 , average AUC from 524h×μg / mL to 544h×μg / mL 0-inf and an average CL / F of 27 L / h to 37 L / h.

[0421] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 8.0. max ratio and an average AUC of 19.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0422] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 7.0 to 9.0. max ratio and an average AUC of 18.3 to 20.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0423] Following oral administration of a combined release composition (CR1) comprising an IR composition containing 4.11 g of compound (1) and an MR1 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 7.5 to 8.5. max ratio and an average AUC of 18.8 to 19.8 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0424] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.3 hours average T max , 12μg / mL average C max , average AUC of 20h×μg / mL 0-6 , average AUC of 21h×μg / mL 0-inf and an average CL / F of 700L / h.

[0425] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t 1 / 2 , 1.1 hours to 1.5 hours average T max , 10μg / mL to 14μg / mL average C max , average AUC from 16h×μg / mL to 24h×μg / mL 0-6 , average AUC from 11h×μg / mL to 31h×μg / mL 0-inf and an average CL / F of 660L / h to 740L / h.

[0426] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of compound (1) can be characterized by an average t of 0.95 hours to 1.05 hours. 1 / 2 , 1.2 hours to 1.4 hours average T max , 11μg / mL to 13μg / mL average C max , average AUC from 18h×μg / mL to 22h×μg / mL 0-6 , average AUC from 16h×μg / mL to 26h×μg / mL 0-inf and an average CL / F of 680L / h to 720L / h.

[0427] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by a mean t of 0.9 hours. 1 / 2 , 2.2 hours average Tmax , an average C of 83 μg / mL max , 322h×mean AUC of μg / mL 0-6 , mean AUC of 386h×μg / mL 0-inf and an average CL / F of 43 L / h.

[0428] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 0.8 to 1.0 hours. 1 / 2 , 2.0 hours to 2.4 hours average T max , 73μg / mL to 93μg / mL average C max , average AUC from 302h×μg / mL to 342h×μg / mL 0-6 , average AUC from 366h×μg / mL to 406h×μg / mL 0-inf and an average CL / F of 33 L / h to 53 L / h.

[0429] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile of γ-hydroxybutyrate can be characterized by an average t of 0.85 to 0.95 hours. 1 / 2 , average T of 2.1 hours to 2.3 hours max , 78μg / mL to 88μg / mL average C max , average AUC from 312h×μg / mL to 332h×μg / mL 0-6 , average AUC from 376h×μg / mL to 396h×μg / mL 0-inf and an average CL / F of 38 L / h to 48 L / h.

[0430] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 7.8. max ratio and an average AUC of 18.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the compound (1) value.

[0431] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 6.8 to 8.8. max ratio and an average AUC of 17.3 to 19.3 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0432] Following oral administration of a combined release composition (CR2) comprising an IR composition containing 4.11 g of compound (1) and an MR2 composition containing 10 g of compound (1) to a group of fasting healthy subjects, the plasma pharmacokinetic profile can be characterized by a mean C of 7.3 to 8.3. max ratio and an average AUC of 17.8 to 18.8 0-inf Ratio, wherein the ratio refers to the ratio of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0433] For the combined release compositions provided by the present disclosure, 8 hours after oral administration of a combined release composition comprising 10 g to 20 g of compound (1) to a group of fasting healthy individuals, the concentration of γ-hydroxybutyrate in the plasma of the individuals is less than 40 μg / mL, less than 30 μg / mL, or less than 20 μg / mL.

[0434] For the combined release composition provided by the present disclosure, after oral administration of a combined release composition comprising 10 g to 20 g of compound (1) to a group of fasting healthy individuals, the AUC of γ-hydroxybutyrate in the plasma of the individuals was inf Greater than the sum of: (a) the AUC of γ-hydroxybutyrate following oral administration of the immediate release component inf ; and (b) the AUC of γ-hydroxybutyrate after oral administration of the modified release component to this group of fasting healthy subjects inf .

[0435] For the combined release compositions provided by the present disclosure, between 6 hours and 8 hours after oral administration of a combined release composition comprising 10 g to 20 g of compound (1) to a group of fasting healthy individuals, the γ-hydroxybutyrate concentration in the individual's plasma is greater than the sum of: (a) the γ-hydroxybutyrate concentration at a time between 6 hours and 8 hours after oral administration of the immediate release component; and (b) the γ-hydroxybutyrate concentration at a time between 6 hours and 8 hours after oral administration of the modified release component to the group of fasting healthy individuals.

[0436] For the combined release compositions provided by the present disclosure, after oral administration of a combined release composition comprising 10 g to 20 g of compound (1) to a group of healthy fasting individuals, the concentration 6 to 8 hours after administration is greater than the concentration of γ-hydroxybutyrate in the plasma of the individuals after administration of the modified release component alone.

[0437] For the combined release compositions provided by the present disclosure, the average γ-hydroxybutyrate AUC after oral administration of the immediate release component and the modified release component to a group of fasting healthy subjects 0-inf Greater than the mean gamma-hydroxybutyrate AUC following oral administration of the immediate release component alone 0-inf and mean γ-hydroxybutyrate AUC after oral administration of the modified release component alone 0-inf The sum of the sum.

[0438] For the combined release compositions provided by the present disclosure, the average Compound (1) AUC after oral administration of the immediate release component and the modified release component to a group of subjects 0-inf Compared to the mean Compound (1) AUC after oral administration of the immediate release component alone 0-inf and the mean Compound (1) AUC after oral administration of the modified release component alone 0-inf The sum of is essentially the same.

[0439] For the combined release compositions provided by the present disclosure, the average γ-hydroxybutyrate AUC after oral administration of a combined release composition comprising an immediate release component containing 4.11 g of compound (1) and a modified release component containing 10 g of compound (1) to a group of fasting healthy subjects 0-inf Greater than the mean γ-hydroxybutyrate AUC after oral administration of the immediate release component containing 7.25 g of compound (1) alone 0-inf and the mean γ-hydroxybutyrate AUC after oral administration of the modified release component containing 7.25 g of compound (1) alone 0-inf sum.

[0440] For the combined release composition provided by the present disclosure, the average compound (1) AUC after oral administration of a combined release composition comprising a direct release component containing 4.52 g of compound (1) and a modified release component containing 10 g of compound (1) to a group of fasting healthy subjects was: 0-inf Compared with the average compound (1) AUC after oral administration of only the immediate release component containing 7.25 g of compound (1) 0-inf and the average compound (1) AUC after oral administration of only the modified release component containing 7.25 g of compound (1) 0-inf The sum is essentially the same.

[0441] The immediate release components provided by the present disclosure may exhibit similar Fig.17 The compound (1) shown in Fig.18 The direct release components provided by the present disclosure may exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile of γ-hydroxybutyrate as provided in Table 6 or the plasma pharmacokinetic profile of γ-hydroxybutyrate as provided in Table 7.

[0442] The modified release components provided by the present disclosure can exhibit Fig.17 The compound (1) shown in Fig.18 The modified release components provided by the present disclosure can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile of γ-hydroxybutyrate as shown in Table 6 or the plasma pharmacokinetic profile of γ-hydroxybutyrate as provided in Table 7.

[0443] The pharmaceutical compositions provided by the present disclosure, such as combined release compositions, can exhibit Fig.19 The compound (1) shown in Fig. 20 The plasma pharmacokinetic profile of γ-hydroxybutyrate shown in Table 10 is bioequivalent to the plasma pharmacokinetic profile of γ-hydroxybutyrate. The pharmaceutical compositions provided by the present disclosure, such as combined release compositions, can exhibit a plasma pharmacokinetic profile that is bioequivalent to the plasma pharmacokinetic profile of compound (1) as provided in Table 10 or the plasma pharmacokinetic profile of γ-hydroxybutyrate as provided in Table 11.

[0444] The pharmaceutical compositions provided by the present disclosure can be used, for example, to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and fibromyalgia.

[0445] The pharmaceutical compositions provided by the present disclosure can be used, for example, to treat REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headaches, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety disorders.

[0446] The pharmaceutical compositions provided by the present disclosure can be used, for example, to enhance cognitive function in neurodegenerative disorders. For example, the pharmaceutical compositions provided by the present disclosure can be used to enhance cognitive function in patients with Parkinson's disease or patients with Alzheimer's disease.

[0447] The pharmaceutical composition provided by the present disclosure can be used to treat narcolepsy, such as type 1 or type 2 narcolepsy. The treatment of narcolepsy is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplexy attacks. In various embodiments, the composition is sufficient to be administered once a day. For example, the composition may be sufficient to be administered less than 2 hours after eating in the morning or at night. The pharmaceutical composition can also effectively induce sleep for at least 6 to 8 consecutive hours. Applying the pharmaceutical composition less than two hours after eating will effectively induce sleep for at least 8 consecutive hours. The pharmaceutical composition can effectively induce sleep for at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours. The pharmaceutical composition can effectively induce sleep for up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, or up to 10 hours.

[0448] The pharmaceutical compositions and compositions provided by the present disclosure can be used to treat sleep disorders, drug abuse, alcohol and opioid withdrawal, decreased growth hormone levels, anxiety disorders, analgesia, symptoms associated with neurological disorders such as Parkinson's disease, Alzheimer's disease and depression, endocrine disorders, tissue hypoxia or anoxia caused by, for example, stroke or myocardial infarction, or increased intracranial pressure levels.

[0449] The pharmaceutical compositions provided by the present disclosure can be used to treat diseases or conditions that can be treated by administering gamma-hydroxybutyric acid, such as fibromyalgia and sleep disorders, such as apnea, sleep-time disturbances, narcolepsy, cataplexy, excessive daytime sleepiness (EDS), sleep paralysis, hypnagogic hallucinations, sleep arousals, insomnia, and nocturnal myoclonus.

[0450] The pharmaceutical compositions provided by the present disclosure can be used to treat sleep disorders associated with viral diseases such as COVID-19 infection.

[0451] The pharmaceutical compositions provided by the present disclosure can be used to relieve pain and improve function in patients with fibromyalgia syndrome, and relieve excessive daytime sleepiness and fatigue, improve myoclonus and essential tremor, and reduce tardive dyskinesia and bipolar disorder in patients with Parkinson's disease.

[0452] The pharmaceutical compositions provided by the present disclosure can be used to improve cognitive function in patients suffering from neurological disorders such as Parkinson's disease and Alzheimer's disease.

[0453] The pharmaceutical compositions and compositions provided by the present disclosure can be used to treat a neurodegenerative disease or condition or disorder associated with a neurotrophic disease in a patient, wherein the neurodegenerative disease is selected from, for example, Alzheimer's disease, amyotrophic lateral sclerosis, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy, motor neuron disease, Creutzfeldt Jakob disease, primary progressive aphasia, progressive supranuclear palsy. Other examples of neurodegenerative diseases include Alper's disease, Batten disease, cerebro-oculo-facial-skeletal syndrome, corticobasal degeneration, Gerstmann-Straussler-Scheinker disease, kuru, Leigh's disease, monomelic muscular dystrophy, multiple system atrophy, opsoclonus-myoclonus, prion diseases, progressive multifocal leukoencephalopathy, leukoencephalopathy striatonigral degeneration, and transmissible spongiform encephalopathy.

[0454] 4-((L-valyl)oxy)butyric acid is metabolized in the systemic circulation after administration to provide gamma-hydroxybutyric acid, which can be used, for example, to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and fibromyalgia.

[0455] 4-((L-valyl)oxy)butyric acid can be used to treat REM sleep behavior disorder, spastic dystonia, symptoms of schizophrenia, insomnia, insomnia associated with schizophrenia, essential hypersomnia, chronic fatigue syndrome, cluster headaches, symptoms of Alzheimer's disease, symptoms of Parkinson's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety disorders.

[0456] 4-((L-valyl)oxy)butyric acid is a prodrug of gamma-hydroxybutyric acid that provides oral bioavailability of gamma-hydroxybutyric acid in the circulation of a patient following oral administration.

[0457] 4-((L-valyl)oxy)butyric acid and pharmaceutical compositions thereof can be used to treat diseases known or determined to be treatable by administration of gamma-hydroxybutyric acid.

[0458] 4-((Valyl)oxy)butyric acid and pharmaceutical compositions thereof can be used to treat diseases known or determined to be treatable by administering gamma-hydroxybutyric acid and one or more additional therapeutic agents.

[0459] 4-((L-valyl)oxy)butyric acid and pharmaceutical compositions can be used to treat excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0460] The methods provided by the present disclosure include providing a therapeutically effective amount of γ-hydroxybutyrate in the systemic circulation of a patient, comprising administering to the patient 4-((L-valyl)oxy)butyric acid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0461] In addition to 4-((L-valyl)oxy)butyric acid, the pharmaceutical compositions provided by the present disclosure may further comprise one or more pharmaceutically active compounds. Such compounds may provide for the treatment of diseases treated with 4-((L-valyl)oxy)butyric acid, or for the treatment of diseases, disorders or conditions other than those treated with 4-((L-valyl)oxy)butyric acid.

[0462] 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be used in combination with at least one other therapeutic agent. 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof can be administered to a patient together with another compound for treating a bacterial infection in the patient. 4-((L-valyl)oxy)butyric acid and the at least one other therapeutic agent can act additively or synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle comprising 4-((L-valyl)oxy)butyric acid, or can be in a separate pharmaceutical composition or vehicle. Thus, in addition to administering 4-((L-valyl)oxy)butyric acid, the methods provided by the present disclosure further include administering one or more therapeutic agents effective to treat a disease, disorder, or condition other than the disease treated with gamma-hydroxybutyric acid. The methods provided by the present disclosure include administering 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof and one or more other therapeutic agents, as long as the combined administration does not inhibit the therapeutic efficacy of 4-((L-valyl)oxy)butyric acid and / or γ-hydroxybutyric acid and / or does not produce adverse combination effects.

[0463] A pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid may be administered concurrently with the administration of another therapeutic agent, which may be part of the same pharmaceutical composition as the pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid, or in a different pharmaceutical composition than the pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid. 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition thereof may be administered before or after the administration of the other therapeutic agent. In certain embodiments of the combination therapy, the combination therapy may comprise alternating administration of 4-((L-valyl)oxy)butyric acid with a pharmaceutical composition comprising another therapeutic agent, e.g., to minimize adverse drug effects associated with a particular drug. When 4-((L-valyl)oxy)butyric acid is administered concurrently with another therapeutic agent that may potentially produce adverse drug effects, including, e.g., toxicity, the administered dose of the other therapeutic agent may be reduced to below a threshold that causes an adverse drug reaction.

[0464] The pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid may be administered with one or more substances, for example, to enhance, regulate and / or control the release, bioavailability, therapeutic efficacy, therapeutic effectiveness and / or stability of 4-((L-valyl)oxy)butyric acid. For example, to enhance the therapeutic efficacy of 4-((L-valyl)oxy)butyric acid or a pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid, one or more active agents may be co-administered to increase the absorption or diffusion and / or transport of 4-((L-valyl)oxy)butyric acid from the gastrointestinal tract to the systemic circulation, or to inhibit the degradation of 4-((L-valyl)oxy)butyric acid in the patient's blood. The pharmaceutical composition comprising 4-((L-valyl)oxy)butyric acid may be co-administered with an active agent having a pharmacological effect that enhances the therapeutic efficacy of 4-((L-valyl)oxy)butyric acid or γ-hydroxybutyric acid.

[0465] Aspects of the Invention

[0466] The following aspects will further define the present invention.

[0467] Aspect 1. A pharmaceutical particle comprising a plurality of coated granules, wherein the granules comprise a core and a functional coating surrounding the core; the pharmaceutical particles are characterized by a particle size distribution (PSD) (D50) of 200 μm to 400 μm, wherein the PSD is determined by sieve analysis; and the core comprises more than 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the core.

[0468] Aspect 2. The pharmaceutical particle according to aspect 1, wherein the pharmaceutical particle comprises 60 wt % to 90 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the pharmaceutical particle.

[0469] Aspect 3. The pharmaceutical particle according to any one of aspects 1 to 2, wherein the functional coating comprises a modified release coating.

[0470] Aspect 4. The pharmaceutical particle according to any one of aspects 1 to 3, wherein the functional coating comprises 50 wt% to 85 wt% of the matrix polymer, wherein the wt% is based on the total weight of the functional coating.

[0471] Aspect 5. The drug particle according to aspect 4, wherein the matrix polymer comprises a water-insoluble polymer.

[0472] Aspect 6. The pharmaceutical particle according to aspect 5, wherein the water-insoluble polymer comprises ethylcellulose.

[0473] Aspect 7. The pharmaceutical particle according to any one of aspects 1 to 6, wherein the functional coating comprises 0 wt% to 10 wt% of the pore-forming polymer, wherein the wt% is based on the total weight of the matrix polymer.

[0474] Aspect 8. The pharmaceutical particle according to aspect 7, wherein the pore-forming polymer comprises a water-soluble polymer.

[0475] Aspect 9. The pharmaceutical particle according to aspect 8, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0476] Aspect 10. The pharmaceutical particle according to any one of aspects 1 to 9, wherein the functional coating comprises 10 wt% to 20 wt% of an antistatic agent, wherein the wt% is based on the total weight of the functional coating.

[0477] Aspect 11. The pharmaceutical particle according to aspect 10, wherein the antistatic agent comprises talc, magnesium stearate or a combination thereof.

[0478] Aspect 12. The pharmaceutical particle according to any one of aspects 1 to 11, wherein the functional coating comprises: 50 wt% to 85 wt% of a matrix polymer; and 10 wt% to 20 wt% of an antistatic agent; wherein the wt% is based on the total weight of the functional coating.

[0479] Aspect 13. The pharmaceutical particle of any one of Aspects 1 to 12, wherein the core accounts for 65% to 85% by weight of the total weight of the coated particle; and the functional coating accounts for 15% to 40% by weight of the total weight of the coated particle.

[0480] Aspect 14. The pharmaceutical particle according to any one of aspects 1 to 13, wherein the thickness of the functional coating is 5 μm to 30 μm.

[0481] Aspect 15. The pharmaceutical particle according to any one of aspects 1 to 14, wherein the pharmaceutical particle has a water content of less than 2 wt%, wherein the wt% is based on the total weight of the pharmaceutical particle.

[0482] Aspect 16. The pharmaceutical particle according to any one of aspects 1 to 15, further comprising a seal coat surrounding the core, and wherein the functional coat surrounds the seal coat.

[0483] Aspect 17. The pharmaceutical granules according to aspect 16, wherein the seal coating comprises: hydroxypropyl cellulose; hydroxypropyl methyl cellulose; hydroxypropyl cellulose and talc; or hydroxypropyl methyl cellulose and talc.

[0484] Aspect 18. The pharmaceutical granule according to aspect 17, wherein the pharmaceutical granule comprises 2 wt% to 15 wt% of the seal coating.

[0485] Aspect 19. The pharmaceutical granules according to any one of Aspects 1 to 18, wherein when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, 30 wt % to 80 wt % of the 4-((L-valyl)oxy)butyric acid is released from the granules within 2 hours, wherein the wt % is based on the total weight of the 4-((L-valyl)oxy)butyric acid in the granules.

[0486] Aspect 20. The pharmaceutical granules according to any one of aspects 1 to 19, wherein when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5 at a temperature of 37° C. and a paddle speed of 100 rpm, 50 wt % to 90 wt % of the 4-((L-valyl)oxy)butyric acid is released from the granules within 4 hours, wherein the wt % is based on the total weight of the 4-((L-valyl)oxy)butyric acid in the granules.

[0487] Aspect 21. The pharmaceutical granules according to any one of Aspects 1 to 20, wherein when tested in a Type 2 USP dissolution apparatus in a buffer solution of pH 4.5, at a temperature of 37° C. and a paddle speed of 100 rpm, 60 wt % to 100 wt % of the 4-((L-valyl)oxy)butyric acid is released from the granules within 6 hours, wherein the wt % is based on the total weight of the 4-((L-valyl)oxy)butyric acid in the granules.

[0488] Aspect 22. A pharmaceutical composition comprising the pharmaceutical particles according to any one of aspects 1 to 21.

[0489] Aspect 23. The pharmaceutical composition according to aspect 22, wherein the pharmaceutical composition is an oral composition.

[0490] Aspect 24. The pharmaceutical composition according to aspect 23, wherein the oral composition comprises a modified release composition.

[0491] Aspect 25. The pharmaceutical composition according to any one of aspects 23 to 24, wherein the oral composition comprises: a modified release portion, wherein the modified release portion comprises the drug particles; and the pharmaceutical composition further comprises a direct release portion.

[0492] Aspect 26. The pharmaceutical composition of Aspect 25, wherein the immediate release portion dissolves in water in less than 5 minutes.

[0493] Aspect 27. The pharmaceutical composition according to any one of aspects 23 to 26, wherein the oral composition is a BID composition.

[0494] Aspect 28. The pharmaceutical composition according to any one of aspects 23 to 27, wherein the oral composition is a QD composition.

[0495] Aspect 29. The pharmaceutical composition according to any one of aspects 22 to 28, wherein the pharmaceutical composition comprises 500 milliequivalents to 12 gramequivalents of 4-((L-valyl)oxy)butyric acid.

[0496] Aspect 30. The pharmaceutical composition according to any one of aspects 22 to 29, wherein the pharmaceutical composition comprises a sustained release oral composition, a delayed release composition, an immediate release composition, or a combination of any of the foregoing.

[0497] Aspect 31. The pharmaceutical composition of any one of Aspects 22 to 30, wherein the pharmaceutical composition comprises a therapeutically effective amount of 4-((L-valyl)oxy)butyric acid to treat a disease in a patient, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue, and tardive dyskinesia.

[0498] Aspect 32. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to any one of aspects 22 to 31, wherein the disease is selected from narcolepsy, cataplexy, excessive daytime sleepiness, fibromyalgia, chronic fatigue and tardive dyskinesia.

[0499] Aspect 33. The method of aspect 32, wherein the disease is cataplexy associated with narcolepsy.

[0500] Aspect 34. The method of aspect 32, wherein the disease is excessive daytime sleepiness associated with narcolepsy.

[0501] Aspect 35. The method of aspect 32, wherein the disease is excessive daytime sleepiness in a patient suffering from Parkinson's disease.

[0502] Aspect 36. The method of aspect 32, wherein the disease is chronic fatigue in a patient suffering from Parkinson's disease.

[0503] Aspect 37. The method of any one of aspects 32 to 36, wherein administering comprises oral administration.

[0504] Aspect 38. A method of coating particles with a coating, comprising applying a coating composition to drug particles, the drug particles comprising a plurality of granules comprising 4-((L-valyl)oxy)butyric acid, wherein the coating composition comprises: 6 wt % to 14 wt % solids; 0 wt % to 20 wt % water; and 70 wt % to 95 wt % ethanol, wherein the wt % is based on the total weight of the coating composition.

[0505] Aspect 39. The method of aspect 38, wherein the solid comprises: a matrix polymer selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a combination thereof; and an antistatic agent selected from talc, magnesium stearate, or a combination thereof.

[0506] Aspect 40. The method of any one of aspects 38 to 39, wherein applying comprises spraying.

[0507] Example

[0508] The embodiments provided by the present disclosure will be further illustrated with reference to the following examples, which describe coated drug particles comprising 4-((L-valyl)oxy)butyric acid, coated drug pellets comprising 4-((L-valyl)oxy)butyric acid, oral modified release pharmaceutical compositions, and methods for preparing coated drug particles and pellets provided by the present disclosure. It will be apparent to those skilled in the art that many modifications may be made to the materials and methods without departing from the scope of the present disclosure.

[0509] General approach

[0510] Pharmacokinetic analysis

[0511] Plasma concentrations of compound (1) and gamma-hydroxybutyrate in plasma of healthy human subjects were measured using liquid chromatography-tandem mass spectrometry and the Phoenix TM Version 8.1 (Pharsight Corporation, USA) and 2016 (Microsoft Corporation, USA) for evaluation.

[0512] Dissolution curve

[0513] The dissolution profile of the modified release microparticles was measured using a USP dissolution apparatus type 2 using a sodium acetate buffer solution at pH 4.5 at a temperature of 37°C and a paddle speed of 75 rpm. The dissolution profile of compound (1) released from the modified release microparticles is shown in Figure 1 middle.

[0514] Example 1

[0515] Direct release granules containing 4-((L-valyl)oxy)butyric acid coated with a water-based seal coat

[0516] Seal coated IR granules were prepared by spray coating uncoated IR granules containing 4-((L-valyl)oxy)butyric acid pellets.

[0517] use Uncoated IR granules containing 4-((L-valyl)oxy)butyric acid were prepared using Microgranulation Technology (Glatte Group). The uncoated IR granules had an average particle diameter (D50) of 225 μm to 275 μm. The uncoated IR granules contained 90 wt% 4-((L-valyl)oxy)butyric acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose (hydroxypropyl methylcellulose), wherein the wt% are based on the total weight of the IR granules.

[0518] The composition used to provide the seal coat contained 14.2 wt% hydroxypropyl methylcellulose ( 603), 2.1 wt% talc and 85.6 wt% water, wherein the wt% are based on the total weight of the seal coat composition.

[0519] The composition was sprayed onto the uncoated IR granules to provide a seal coat with a thickness of 2.23 (+ / - 0.34) μm.

[0520] The particle size distribution is shown in Figure 1 The SEM images of the seal-coated particles are shown in FIG. 2A to FIG. 2D The SEM image of the cross-section of the seal-coated pellets is shown in Figure 2E middle.

[0521] Example 2

[0522] Direct release granules containing 4-((L-valyl)oxy)butyric acid coated with an acetone-based seal coat

[0523] The seal coated IR granules were prepared by spray coating the uncoated granules containing 4-((L-valyl)oxy)butyric acid pellets.

[0524] use Uncoated IR granules containing 4-((L-valyl)oxy)butyric acid were prepared using microgranulation technology (Glatte Group). The uncoated IR granules had an average particle diameter (D50) of 225 μm to 275 μm. The uncoated IR granules had a 4-((L-valyl)oxy)butyric acid content of more than 90% by weight.

[0525] The composition used to provide the seal coat contained 5.4% by weight hydroxypropylcellulose ( EF), 2.1 wt% talc and 92.5 wt% acetone, wherein the wt% are based on the total weight of the seal coat composition.

[0526] The composition was sprayed onto the uncoated granules to provide a seal coat with a thickness of 1.30 (+ / - 0.27) μm.

[0527] The particle size distribution of the seal-coated IR particles is shown in Figure 3 The SEM images of the seal-coated particles are shown in FIG. 4A to FIG. 4D The SEM image of the cross-section of the seal-coated pellets is shown in Figure 4E middle.

[0528] Example 3

[0529] Granules of 4-((L-valyl)oxy)butyric acid having a modified release coating (1)

[0530] Granules with a modified release (MR) coating were prepared using granules containing pellets having 98.5 wt% 4-((L-valyl)oxy)butyric acid and characterized by an average pellet diameter (D50) of 225 to 275 μm.

[0531] The ingredients of the modified release coat are provided in Table 1.

[0532] Table 1. Modified release coatings (1).

[0533]

[0534] Modified release coatings of 20% wg and 40% wg were applied.

[0535] For the coated granules with 40% wg, the bulk density was 0.70 g / mL and the (loss on drying) LOD was 0.55%. The thickness of the 40 wg% modified release coating was 10.26 μm + / - 1.46 μm (std).

[0536] The particle size distribution is shown in Figure 5 The dissolution curve is shown in Figure 6 The SEM images of the coated granules at 40% wg at different magnifications are shown in FIG. 7A to FIG. 7D and the cross-sectional view of the coating is shown in Fig. 7E middle.

[0537] Example 4

[0538] Granules of 4-((L-valyl)oxy)butyric acid having a modified release coating (2)

[0539] Granules containing particles having 98.5% by weight of 4-((L-valyl)oxy)butyric acid and characterized by a particle diameter of 225 to 275 μm were used.

[0540] The ingredients of the modified release coating composition are provided in Table 2.

[0541] Table 2. Modified release coatings (2).

[0542]

[0543] The processing conditions for applying the modified release coating are provided in Table 3.

[0544] Table 3. Program conditions.

[0545] parameter value Spraying time (min) - Spraying rate (g / min) 8-13 Spraying pressure (bar) 2.5 Exhaust temperature(℃) - Inlet air temperature (℃) 35-38 Atomizing air flow (psi) - <![CDATA[Program air flow rate (m 3 / h)]]> 110 Intake air moisture (g / kg) 7.7-8.2 Accelerator Air (psi) - Dew point(℃) -

[0546] Modified release coatings of 20% wg and 40% wg were applied.

[0547] For the coated particles with 40% wg, the bulk density was 0.63 g / mL and the LOD was 0.37%.The thickness of the modified release coating at 40% wg was 10.16 μm + / - 2.80 μm (std).

[0548] The particle size distribution is shown in Figure 8 The dissolution curve is shown in Fig. 9 The SEM images of the coated granules at 40% wg at different magnifications are shown in FIG. 10A to FIG. 10D and the cross-sectional view of the coating is shown in Fig.10E middle.

[0549] Example 5

[0550] Granules of 4-((L-valyl)oxy)butyric acid having a modified release coating (3)

[0551] Granules containing particles having 98.5% by weight of 4-((L-valyl)oxy)butyric acid and characterized by a particle diameter of 200 to 425 μm were used.

[0552] The procedure conditions for applying the modified release coating were the same as those of Example 3.

[0553] The ingredients of the modified release coat are provided in Table 4.

[0554] Table 4. Modified release coatings (3).

[0555]

[0556]

[0557] Modified release coatings of 20% wg, 30% wg, 35% wg and 40% wg were applied.

[0558] For the coated granules with 40% wg, the bulk density was 0.68 g / mL and the LOD was 0.69%.The thickness of the modified release coating at 40% wg was 11.58 μm + / - 1.45 μm (std).

[0559] The particle size distribution is shown in Fig.11 The dissolution curve is shown in Fig.12 The SEM images of the coated granules at 40% wg at different magnifications are shown in FIG. 13A to FIG. 13D and the cross-sectional view of the coating is shown in Fig.13E middle.

[0560] Example 6

[0561] Coated granules (4)

[0562] The seal-coated granules of Example 1 were used as starting material.

[0563] The procedure conditions for applying the modified release coat were the same as those of Examples 3-5.

[0564] The ingredients of the modified release coating composition are provided in Table 5.

[0565] Table 5. Modified release coating (4).

[0566]

[0567] Modified release coatings of 20% wg and 40% wg were applied.

[0568] For the coated drug particles with 40% wg, the bulk density was 0.64 g / mL and the LOD was 0.45%. The thickness of the functional coating at 40% wg was 15.03 μm + / - 2.24 μm (std).

[0569] The particle size distribution is shown in Fig.14 The dissolution curve is shown in Fig.15 The SEM images of the coated granules at 40% wg at different magnifications are shown in FIG. 16A to FIG. 16D and the cross-sectional view of the coating is shown in Fig.16E middle.

[0570] Example 7

[0571] Pharmacokinetics of immediate and modified release compositions

[0572] The pharmacokinetics of compound (1) and gamma-hydroxybutyrate following oral administration of an immediate release component or a modified release component to fasting healthy subjects were determined.

[0573] To prepare the immediate release component, the immediate release microparticles prepared according to Example 1 were added to 30 mL of water and gently swirled to dissolve the immediate release microparticles. The uncoated IR microparticles had an average particle diameter (D50) of 225 μm to 275 μm. The IR microparticles contained 90 wt% 4-((L-valyl)oxy)butyric acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose, wherein the wt% is based on the total weight of the IR microparticles. Water was added to bring the total volume to 250 mL, thereby providing the immediate release component for ingestion by an individual.

[0574] To prepare the modified release composition, the modified release microparticles prepared according to Example 5 were added to 30 mL of water and swirled gently. (30 mL), the contents were gently swirled, and consumed by the subject. Additional water was added to a total volume of 250 mL for rinsing the container and ingestion by the subject. The MR1 granules had a 60% wg coating, the MR2 granules had a 40 wg% coating, and the MR3 granules had a 50% wg coating. The modified release coating contained 81.7 wt% ethylcellulose, 2.0 wt% hypromellose, and 16.3 wt% magnesium stearate, wherein the wt% are based on the total weight of the coating.

[0575] Each fraction contained 7.25 g of compound (1) (3.172 g equivalent of gamma-hydroxybutyrate).

[0576] The plasma pharmacokinetic profiles of compound (1) and gamma-hydroxybutyrate following oral administration of an immediate release (IR) composition or a modified release (MR1-MR3) composition to fasting healthy subjects are shown for compound (1) Fig.17 and for γ-hydroxybutyrate is shown in Fig.18 The results represent the mean and standard deviation based on the results from 7 to 8 individuals.

[0577] The pharmacokinetic parameters of compound (1) and gamma-hydroxybutyrate after oral administration of the composition comprising IR and MR microparticles are provided in Table 6 and Table 7, respectively. The results represent the mean and standard deviation based on the results from 7 to 8 individuals.

[0578] Table 6. Pharmacokinetic parameters of compound (1) after oral administration of an immediate release composition or a modified release composition.

[0579]

[0580] Table 7. Pharmacokinetic parameters of gamma-hydroxybutyrate after oral administration of immediate release compositions or modified release compositions.

[0581]

[0582]

[0583] C max Ratio, AUC 0-inf Ratio and AUC 0-8 The ratios are shown in Table 8, wherein the ratios refer to the ratios of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0584] Table 8. Pharmacokinetic ratios of immediate release and modified release compositions.

[0585]

[0586] Example 8

[0587] Pharmacokinetics of combined release compositions

[0588] The pharmacokinetics of combined release (CR) compositions comprising immediate release microparticles (IR component) and modified release microparticles (MR component) were determined.

[0589] The amounts of microparticles used to prepare the combined release compositions (CR1 and CR2) are summarized in Table 9.

[0590] Table 9. Composition of combined release compositions.

[0591]

[0592] To prepare the combined release composition, dissolve the specified amount of direct release microparticles in 30 mL of water. Next, add the specified amount of modified release microparticles and swirl gently. Add thirty (30) mL of oral suspension vehicle. The mixture is swirled gently. The subject then drinks the solution. The subject repeatedly rinses the cup with up to 250 mL of water and drinks the solution.

[0593] The plasma pharmacokinetic profiles of compound (1) and gamma-hydroxybutyrate after oral administration of combined release compositions (CR1 and CR2) to fasting healthy subjects are shown in Fig.19 and Fig. 20 The results represent the mean and standard deviation based on 12 individuals.

[0594] A summary of the pharmacokinetic parameters of Compound (1) and gamma-hydroxybutyrate following oral administration of the combined release composition to fasting healthy subjects is provided in Tables 10 and 11. The results reflect the average values ​​obtained for 12 subjects.

[0595] Table 10. Pharmacokinetic parameters of compound (1) after oral administration of combined release composition.

[0596]

[0597] Table 11. Pharmacokinetic parameters of gamma-hydroxybutyrate after oral administration of combined release compositions.

[0598]

[0599] Combined release composition C max Ratio, AUC 0-inf Ratio and AUC 0-8 The ratios are shown in Table 12, wherein the ratios refer to the ratios of the γ-hydroxybutyrate value to the corresponding compound (1) value.

[0600] Table 12. Pharmacokinetic ratios of combined release compositions.

[0601]

[0602] It should be noted that there are alternative ways to implement the embodiments disclosed herein. Therefore, the embodiments of the present invention should be considered illustrative rather than restrictive. In addition, the claims are not limited to the details provided herein, but are entitled to their full scope and equivalents.

Claims

1. A pharmaceutical composition comprising: (a) an immediate release component, wherein the immediate release component comprises a plurality of immediate release particles, wherein the immediate release particles comprise greater than 80 wt % of 4-((L-valyl)oxy)butyric acid, wherein the wt % is based on the total weight of the immediate release particles; and (b) a modified release component, wherein the modified release component comprises a plurality of modified release particles, wherein: The modified release particle comprises a core and a modified release coating surrounding the core; and The core comprises more than 80 wt% of 4-((L-valyl)oxy)butyric acid, wherein the wt% is based on the total weight of the core.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 0.1 g to 20 g of 4-((L-valyl)oxy)butyric acid.

3. The pharmaceutical composition according to claim 1, wherein The immediate release component includes 2 g to 4 g of 4-((L-valyl)oxy)butyric acid; and The modified release component includes 8 g to 16 g of 4-((L-valyl)oxy)butyric acid.

4. The pharmaceutical composition of claim 1, wherein the average diameter of the direct release particles is 75 μm to 450 μm, wherein the average diameter is determined by sieve analysis or laser diffraction. 5 . The pharmaceutical composition of claim 1 , wherein the modified release particles have an average diameter of 150 μm to 400 μm, wherein the average diameter is determined by sieve analysis or laser diffraction.

6. The pharmaceutical composition according to claim 1, wherein The immediate release component comprises 10% to 50% by weight of 4-((L-valyl)oxy)butyric acid; and The modified release component comprises 50% to 90% by weight of 4-((L-valyl)oxy)butyric acid, The weight % is based on the total weight of 4-((L-valyl)oxy)butyric acid in the pharmaceutical composition.

7. The pharmaceutical composition of claim 1, wherein the weight ratio of 4-((L-valyl)oxy)butyric acid in the immediate release component to 4-((L-valyl)oxy)butyric acid in the modified release component is 1:1 to 1:

4.

8. The pharmaceutical composition of claim 1, wherein the modified release granules comprise 10 wt% to 50 wt% of the modified release coating, wherein the wt% is based on the total weight of the modified release granules.

9. The pharmaceutical composition of claim 1, wherein the core comprises, 1 to 10 wt % of an antistatic agent; and 1 to 10 wt. % of a water-soluble polymer, The weight % are based on the total weight of the core.

10. The pharmaceutical composition according to claim 9, wherein The antistatic agent comprises talc; and The water-soluble polymer includes hydroxypropyl methylcellulose.

11. The pharmaceutical composition of claim 1, wherein the modified release coating comprises, 70 wt % to 95 wt % of a matrix polymer; and 5 to 30% by weight of an antistatic agent, The weight % are based on the total weight of the modified release coat.

12. The pharmaceutical composition of claim 11, wherein the matrix polymer comprises, 92 to 98 weight percent of a water-insoluble polymer; and 2 to 8 wt% of a water-soluble polymer, The weight % is based on the total weight of the matrix polymer.

13. The pharmaceutical composition according to claim 12, wherein The water-insoluble polymer comprises ethyl cellulose; and The water-soluble polymer includes hydroxypropyl cellulose.

14. The pharmaceutical composition of claim 9, wherein the antistatic agent comprises talc.

15. The pharmaceutical composition of claim 1, wherein the immediate release component comprises a solution comprising 4-((L-valyl)oxy)butyric acid.

16. The pharmaceutical composition of claim 1, wherein the modified release component comprises a plurality of modified release particles suspended in a solution.

17. A kit comprising the pharmaceutical composition of claim 1.

18. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia in a patient.

19. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating a symptom associated with the following diseases in a patient: narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia.

20. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome or anxiety in a patient.

21. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating symptoms associated with the following diseases in a patient: REM sleep behavior disorder, spastic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety.

22. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating sleep disorders associated with bacterial infection in a patient.

23. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating sleep disorders associated with COVID-19 infection.

24. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for enhancing cognitive function in patients with neurological disorders.

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