Claims for Patent: 10,736,866

Summary for Patent: 10,736,866

Title:	Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Abstract:	Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
Inventor(s):	Mégret Claire, Guillard Hervé, Dubuisson Jean-François
Assignee:	Flamel Ireland Limited
Application Number:	US16281235
Patent Claims:	1. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the suspending or viscosifying agent and the acidifying agent are separate and distinct from the immediate release portion and the modified release portion; andwherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.2. The formulation of claim 1 , wherein the suspending or viscosifying agent is present at 1% to 15% by weight of the formulation claim 1 , and the acidifying agent is present at 1.2% to 15% by weight of the formulation.3. The formulation of claim 2 , wherein:the suspending or viscosifying agent is a mixture of xanthan gum, carrageenan gum, and hydroxyethylcellulose, or a mixture of xanthan gum and carrageenan gum, andthe acidifying agent is malic acid or tartaric acid.4. The formulation of claim 1 , wherein the formulation further comprises a lubricant or glidant selected from the group consisting of magnesium stearate claim 1 , calcium stearate claim 1 , zinc stearate claim 1 , glyceryl monostearate claim 1 , glyceryl palmitostearate claim 1 , glycerol behenate claim 1 , sodium stearyl fumarate claim 1 , talc claim 1 , or colloidal silicon dioxide.5. The formulation of claim 1 , wherein the formulation is a dry particulate formulation or a powdered formulation.6. The formulation of claim 1 , wherein the formulation comprises 4.5 g claim 1 , 6.0 g claim 1 , 7.5 g claim 1 , or 9.0 g of gamma-hydroxybutyrate.7. The formulation of claim 1 , wherein the formulation comprises gamma-hydroxybutyrate in the form of sodium oxybate.8. The formulation of claim 1 , wherein modified release portion comprises a hydrophobic compound having a melting point equal to or greater than 40° C.9. The formulation of claim 1 , wherein a dose of the formulation achieves a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses claim 1 , when administered approximately two hours after a standardized evening meal.10. The formulation of claim 1 , wherein a dose of the formulation achieves a ratio of mean AUCto mean AUCof greater than 0.80 when administered once approximately two hours after a standardized evening meal.11. The formulation of claim 1 , wherein a dose of the formulation achieves a median Twithin 150 minutes of the median Tof half the dose of an immediate release liquid solution of sodium oxybate claim 1 , when administered approximately two hours after a standardized evening meal.12. The formulation of claim 1 , wherein a dose of the formulation achieves a mean Cor mean Cgreater than claim 1 , and a mean Cless than claim 1 , the mean Cof half the dose of an immediate release liquid solution of sodium oxybate claim 1 , when administered approximately two hours after a standardized evening meal.13. The formulation of claim 1 , wherein a dose of the formulation achieves a mean AUCof greater than 80% of the mean AUCprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal claim 1 , and a mean Cless than 95% of the mean Cprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal.214. The formulation of claim 1 , wherein the formulation releases at least 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.215. The formulation of claim 1 , wherein the formulation releases from 10% to 65% claim 1 , of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.216. The formulation of claim 1 , wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.217. The formulation of claim 1 , wherein the modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.18. The formulation of claim 1 , wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.219. The formulation of claim 1 , wherein the immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.20. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the suspending or viscosifying agent and the acidifying agent are separate and distinct from the immediate release portion and the modified release portion;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate; andwherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy.21. The formulation of claim 20 , wherein:the suspending or viscosifying agent is selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andthe acidifying agent is selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid.22. The formulation of claim 20 , wherein:the suspending or viscosifying agent is a mixture of xanthan gum, carrageenan gum, and hydroxyethylcellulose, or a mixture of xanthan gum and carrageenan gum, andthe acidifying agent is malic acid or tartaric acid.23. The formulation of claim 20 , wherein the formulation further comprises a lubricant or glidant selected from the group consisting of magnesium stearate claim 20 , calcium stearate claim 20 , zinc stearate claim 20 , glyceryl monostearate claim 20 , glyceryl palmitostearate claim 20 , glycerol behenate claim 20 , sodium stearyl fumarate claim 20 , talc claim 20 , and colloidal silicon dioxide.24. The formulation of claim 20 , wherein the formulation is a dry particulate formulation or a powdered formulation.25. The formulation of claim 20 , wherein the formulation comprises 4.5 g claim 20 , 6.0 g claim 20 , 7.5 g claim 20 , or 9.0 g of gamma-hydroxybutyrate.26. The formulation of claim 20 , wherein the formulation comprises gamma-hydroxybutyrate in the form of sodium oxybate.27. The formulation of claim 20 , wherein the modified release portion comprises a hydrophobic compound having a melting point equal to or greater than 40° C.28. The formulation of claim 20 , wherein a dose of the formulation achieves a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses claim 20 , when administered approximately two hours after a standardized evening meal.29. The formulation of claim 20 , wherein a dose of the formulation achieves a ratio of mean AUCto mean AUCof greater than 0.80 when administered once approximately two hours after a standardized evening meal.30. The formulation of claim 20 , wherein a dose of the formulation achieves a median Twithin one hundred fifty minutes of the median Tof half the dose of an immediate release liquid solution of sodium oxybate claim 20 , when administered approximately two hours after a standardized evening meal.31. The formulation of claim 20 , wherein a dose of the formulation achieves a mean Cor mean Cgreater than claim 20 , and a mean Cless than claim 20 , the mean Cof half the dose of an immediate release liquid solution of sodium oxybate claim 20 , when administered approximately two hours after a standardized evening meal.32. The formulation of claim 20 , wherein a dose of the formulation achieves a mean AUCof greater than 80% of the mean AUCprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal claim 20 , and a mean Cless than 95% of the mean Cprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal.233. The formulation of claim 20 , wherein the formulation releases at least 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.234. The formulation of claim 20 , wherein the formulation releases from 10% to 65% claim 20 , of its gamma-hydroxybutyrate at one hour and three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.235. The formulation of claim 20 , wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.236. The formulation of claim 20 , wherein the modified release portion releases less than 20% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.37. The formulation of claim 20 , wherein the modified release portion releases greater than 80% of its gamma-hydroxybutyrate at three hours in a dissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75 rpm.238. The formulation of claim 20 , wherein the immediate release portion releases greater than 80% of its gamma-hydroxybutyrate at one hour when tested in a dissolution apparatus according to USP 38 <711> in 900 mL of 0.1 N hydrochloric acid at a temperature of 37° C. and a paddle speed of 75 rpm.39. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent for improving the formulation's viscosity and pourabilty after mixing with a liquid, the suspending or viscosifying agent being selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent for ensuring that the formulation's release profile remains unchanged for at least 15 minutes after mixing with a liquid, the acidifying agent being selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.40. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent for improving the formulation's viscosity and pourabilty after mixing with a liquid; andfrom 1.2% to 15% of an acidifying agent for ensuring that the formulation's release profile remains unchanged for at least 15 minutes after mixing with a liquid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate; andwherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy.41. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate and a coating comprising a hydrophobic compound having a melting point equal to or greater than 40° C.;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35.42. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate and a coating comprising a hydrophobic compound having a melting point equal to or greater than 40° C.;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate; andwherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy.43. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and{'sub': 0', '4h, 'wherein a dose of the formulation achieves a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses, when administered approximately two hours after a standardized evening meal.'}44. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate;wherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy; and{'sub': 0', '4h, 'wherein a dose of the formulation achieves a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses, when administered approximately two hours after a standardized evening meal.'}45. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and{'sub': 8h', 'inf, 'wherein a dose of the formulation achieves a ratio of mean AUCto mean AUCof greater than 0.80 when administered once approximately two hours after a standardized evening meal.'}46. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate;wherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy; and{'sub': 8h', 'inf, 'wherein a dose of the formulation achieves a ratio of mean AUCto mean AUCof greater than 0.80 when administered once approximately two hours after a standardized evening meal.'}47. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and{'sub': max', 'max, 'wherein a dose of the formulation achieves a median Twithin 150 minutes of the median Tof half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.'}48. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate;wherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy; and{'sub': max', 'max, 'wherein a dose of the formulation achieves a median Twithin 150 minutes of the median Tof half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.'}49. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and{'sub': 6h', '7h', '10h, 'wherein a dose of the formulation achieves a mean Cor mean Cgreater than, and a mean Cless than, the mean Co of half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.'}50. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate;wherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy; and{'sub': 6h', '7h', '10h, 'wherein a dose of the formulation achieves a mean Cor mean Cgreater than, and a mean Cless than, the mean Co of half the dose of an immediate release liquid solution of sodium oxybate, when administered approximately two hours after a standardized evening meal.'}51. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;a suspending or viscosifying agent selected from the group consisting of xanthan gum, carrageenan gum, gellan gum, guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof; andan acidifying agent selected from the group consisting of malic acid, citric acid, tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and{'sub': inf', 'inf', '0', '4h', '8h', '8h', '0', '4h, 'wherein a dose of the formulation achieves a mean AUCof greater than 80% of the mean AUCprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal, and a mean Cless than 95% of the mean Cprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal.'}52. A formulation of gamma-hydroxybutyrate comprising:an immediate release portion comprising gamma-hydroxybutyrate;a modified release portion comprising gamma-hydroxybutyrate;from 1% to 15% of a suspending or viscosifying agent; andfrom 1.2% to 15% of an acidifying agent;wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35;wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12.0 g of sodium oxybate;wherein the formulation is designed to be orally administered once-nightly to treat cataplexy in narcolepsy or excessive daytime sleepiness (“EDS”) in narcolepsy; and{'sub': inf', 'inf', '0', '4h', '8h', '8h', '0', '4h, 'wherein a dose of the formulation achieves a mean AUCof greater than 80% of the mean AUCprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal, and a mean Cless than 95% of the mean Cprovided by an equal dose of immediate release liquid solution of sodium oxybate administered at tand tin equally divided doses approximately two hours after a standardized evening meal.'}