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 composition comprising an immediate release portion and a modified release portion, wherein the immediate release portion and the modified release portion each comprise one or more pharmaceutically acceptable salts of gamma-hydroxybutyric acid, including their hydrate, solvate, complex or tautomer forms in an amount equivalent to 3.0 to 12.0 grams of sodium oxybate, wherein the composition is designed to be administered only once per day to a human subject, and wherein the composition achieves a relative bioavailability (RBA) of greater than 80% relative to a comparable amount of an immediate release liquid solution of sodium oxybate administered at to and to in equally divided doses, when administered approximately two hours after a standardized evening meal.
2. The pharmaceutical composition of claim 1 , wherein the composition yields a plasma concentration versus time curve, when administered only once per day in a human subject at a dose equivalent to 4.5 g or 6.0 g of sodium oxybate approximately two hours after a standardized evening meal, that is bioequivalent to the plasma concentration versus time curve depicted in FIG. 12 for the corresponding dose.
3. The pharmaceutical composition of claim 1 , wherein the composition yields a plasma concentration versus time curve, when administered only once per day in a human subject at a dose equivalent to 4.5 g of sodium oxybate approximately two hours after a standardized evening meal, that is bioequivalent to the plasma concentration versus time curve depicted in FIG. 22 .
4. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the profile as depicted in FIG. 7 and FIG. 8 .
5. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the profile as depicted in FIG. 20 and FIG. 21 .
6. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the profile as depicted in FIG. 3 .
7. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the profile as depicted in FIG. 16 .
8. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the profile as depicted in any one of FIGS. 29 through 31 .
9. The pharmaceutical composition of claim 1 , wherein the composition yields a plasma concentration versus time curve, when administered only once per day in a human subject at a dose equivalent to 4.5_g, 7.5_g or 9.0_g of sodium oxybate approximately two hours after a standardized evening meal, that is bioequivalent to the plasma concentration versus time curve depicted in FIG. 90 for the corresponding dose.
10. The pharmaceutical composition of claim 1 , wherein the composition yields a plasma concentration versus time curve, when administered only once per day in a human subject at a dose equivalent to 4.5_g, 6.0_g or 7.5_g of sodium oxybate approximately two hours after a standardized evening meal, that is bioequivalent to the plasma concentration versus time curve depicted in FIG. 13 for the corresponding dose.
11. The pharmaceutical composition of claim 1 , wherein the one or more pharmaceutically acceptable salts of gamma-hydroxybutyric acid of the immediate release portion and/or the modified release portion is selected from a sodium salt of gammahydroxybutyric acid, a potassium salt of gamma-hydroxybutyric acid, a magnesium salt of gamma-hydroxybutyric acid, a calcium salt of gamma-hydroxybutyric acid, a lithium salt of gamma-hydroxybutyric, or a tetra ammonium salt of gamma-hydroxybutyric acid.