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 pharmaceutical formulation for the treatment of narcolepsy or a symptom thereof, comprising:
an immediate release portion comprising gamma-hydroxybutyrate;
a modified release portion comprising gamma-hydroxybutyrate, a polymer carrying free carboxylic groups, and a hydrophobic compound having a melting point equal or greater than 40° C., wherein the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.6 to 2.5; and
an acidifying agent,
wherein the formulation is designed to be administered orally only once nightly, and
wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12 g of sodium oxybate.
2. The pharmaceutical formulation of claim 1 , wherein the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.6 to 2.33.
3. The pharmaceutical formulation of claim 1 , wherein the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is about 1.5.
4. The pharmaceutical formulation of claim 1 , wherein the modified release portion comprises a pH triggering release from 5.5 up to 6.97.
5. The pharmaceutical formulation of claim 1 , wherein the modified release portion comprises a pH triggering release from 6.5 up to 6.97.
6. The pharmaceutical formulation of claim 1 , further comprising hydrogenated vegetable oil.
7. A pharmaceutical formulation for the treatment of narcolepsy or a symptom thereof, comprising:
an immediate release portion comprising gamma-hydroxybutyrate;
a modified release portion comprising gamma-hydroxybutyrate and a coating, the coating comprising a methacrylic acid copolymer carrying free carboxylic groups having a pH trigger of from 5.5 to 6.97, and a hydrophobic compound having a melting point equal or greater than 40° C., wherein the weight ratio of the hydrophobic compound to the polymer carrying free carboxylic groups is from 0.4 to 4, wherein the coating is from 10 to 50% of the weight of the particles, and wherein the ratio of gamma-hydroxybutyrate in the immediate release portion and the modified release portion is from 10/90 to 65/35; and
an acidifying agent,
wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to 12 g of sodium oxybate.
8. The pharmaceutical formulation of claim 7 , wherein the coating further comprises hydrogenated vegetable oil.
9. The pharmaceutical formulation of claim 7 , wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to 4.5 g of sodium oxybate and achieves a ratio of AUC 8h to AUC inf of 0.83.
10. The pharmaceutical formulation of claim 7 , wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to 6.0 g of sodium oxybate and achieves a ratio of AUC 8h to AUC inf of 0.93.
11. The pharmaceutical formulation of claim 7 , wherein the formulation comprises an amount of gamma-hydroxybutyrate equivalent to 7.5 g of sodium oxybate and achieves a ratio of AUC 8h to AUC inf of 0.89.
12. The pharmaceutical formulation of claim 7 , wherein the immediate release portion comprises immediate release particles comprising gamma-hydroxybutyrate, the modified release portion comprises modified release particles comprising gamma-hydroxybutyrate and the coating.
13. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 7.2% to 58.2%.
14. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 11.0% to 52.9%.
15. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 14.9% to 47.8%.
16. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 18.9% to 47.8%.
17. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 23.1% to 47.8%.
18. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 27.4% to 47.8%.
19. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 31.8% to 47.8%.
20. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 31.8% to 52.9%.
21. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 36.4% to 47.8%.
22. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 5.9% to 63.2%.
23. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 9.1% to 58.1%.
24. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 12.4% to 53.1%.
25. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 19.9% to 53.1%.
26. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 19.6% to 53.1%.
27. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 23.4% to 53.1%.
28. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 27.4% to 53.1%.
29. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 27.4% to 58.1%.
30. The pharmaceutical formulation of claim 12 , wherein the weight percentage of the immediate release particles relative to the total weight of immediate release particles and modified release particles ranges from 31.7% to 53.1%.