Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
1. A composition comprising a blend of granules for suspension in water, the blend of granules comprising an immediate release portion and a modified release portion, the granules comprising sodium oxybate, wherein the composition;
is provided in a single dose packet,
comprises 3.0 g, 4.5 g, 6 g, 7.5 g, or 9 g of sodium oxybate,
is for the treatment of narcolepsy or a symptom thereof,
is administered orally only once nightly,
is effective to induce sleep in a human subject in need thereof for at least six hours, and
provides a C max which increases approximately 2-fold, and more than dose proportionally for AUC increasing approximately 2.3-fold, as a total daily dose is doubled.
2. The composition of claim 1 , further comprising carrageenan, hydrogenated vegetable oil, hydroxyethyl cellulose, magnesium stearate, malic acid, methacrylic acid copolymer, microcrystalline cellulose, povidone, and/or xanthan gum.
3. A composition comprising a blend of granules for suspension in water, the blend of granules comprising an immediate release portion and a modified release portion, the granules comprising sodium oxybate, wherein the composition:
is packaged in a once-nightly dose packet,
comprises 3.0 g, 4.5 g, 6 g, 7.5 g, or 9 g of sodium oxybate,
is for the treatment of narcolepsy or a symptom thereof,
is administered orally only once nightly,
is effective to induce sleep in a human subject in need thereof for at least six hours, and
provides a C max which increases approximately 2-fold, and more than dose proportionally for AUC increasing approximately 2.3-fold as a total daily dose is doubled.
4. The composition of claim 1 , wherein the single dose packet is provided as part of a total of 7 or 30 single dose packets per package.
5. The composition of claim 1 , wherein the composition is provided with a prepackaged mixing cup.
6. The composition of claim 1 , further comprising approximately one-third of a cup of water to be used in forming a suspension with the composition.
7. The composition of claim 1 , further comprising approximately 80 mL of water.
8. The composition of claim 7 , wherein the water temperature is 50° C. or less.
9. The composition of claim 1 , wherein the granules of the modified release portion are coated with a coating comprising:
a polymer carrying free carboxylic groups, and
a hydrophobic compound having a melting point equal or greater than 40° C.
10. The composition of claim 1 , wherein the amount of sodium oxybate in the immediate release portion is equal to the amount of sodium oxybate in the modified release portion.
11. The composition of claim 9 , wherein the polymer carrying free carboxylic groups has a pH trigger from 5.5 to 6.97.
12. The composition of claim 9 , wherein the free carboxylic groups are ionized at pH 7.5.
13. The composition of claim 1 in an amount effective to treat narcolepsy Type 1 or Type 2, wherein said treatment of narcolepsy or a symptom thereof comprises reducing excessive daytime sleepiness, reducing the frequency of cataplectic attacks, or a combination thereof.
14. The composition of claim 1 in an amount effective to induce sleep for at least eight consecutive hours.
15. The composition of claim 1 , wherein the ratio of sodium oxybate in the immediate release portion and the modified release portion is from 10/90 to 65/35.
16. The composition of claim 1 , wherein the ratio of sodium oxybate in the immediate release portion and the modified release portion is from 40/60 to 60/40.
17. The composition of claim 1 , wherein the granules of the immediate release portion have a mean diameter from 10 to 1000 microns, and the granules of the modified release portion have a mean diameter from 100 to 1200 microns.
18. The composition of claim 1 , wherein the granules comprising sodium oxybate in the immediate release portion have a mean diameter from 150 to 400 microns, and the particles granules comprising sodium oxybate in the modified release portion have a mean diameter from 200 to 800 microns.
19. The composition of claim 3 , wherein the composition provides a lower risk of causing a confusional state in a patient as compared to a twice-nightly oxybate composition.
20. The composition of claim 3 , wherein the composition provides a 50% lower risk of causing a confusional state in a patient as compared to a twice-nightly oxybate composition.
21. The composition of claim 3 , further comprising hydroxyethyl cellulose, malic acid, methacrylic acid copolymer, microcrystalline cellulose, and povidone.
22. The composition of claim 3 , further comprising carrageenan, hydrogenated vegetable oil, hydroxyethyl cellulose, malic acid, methacrylic acid copolymer, microcrystalline cellulose, povidone, and/or xanthan gum.
23. The composition of claim 1 , further comprising a suspending agent that prevents the granules from settling in less than 1 minute when suspended in water.
24. A composition comprising a blend of granules for suspension in water, the granules comprising from 3.0 to 9.0 g sodium oxybate, wherein the composition:
is packaged in a once-nightly dose packet,
is for the treatment of narcolepsy or a symptom thereof,
is effective to induce sleep in a human subject in need thereof,
is administered orally only once nightly, and
produces a dose-proportional C max .
25. A composition comprising a blend of granules for suspension in water, the granules comprising from 3.0 to 9.0 g sodium oxybate, wherein the composition:
is packaged in a once-nightly dose packet,
is for the treatment of narcolepsy or a symptom thereof,
is effective to induce sleep in a human subject in need thereof,
is administered orally only once nightly, and
produces a more than dose-proportional in AUC inf .