Liquid ganaxolone formulations and methods for the making and use thereof

1. An aqueous dispersion of stabilized ganaxolone particles comprising ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent that stabilizes particle growth after an initial particle growth and endpoint is reached, the complexing agent selected from the group of small organic molecules having a molecular weight less than 550 and containing a moiety selected from the group consisting of a phenol moiety, an aromatic ester moiety and an aromatic acid moiety, wherein the stabilized particles have a volume weighted median diameter (D50) of the particles from about 50 nm to about 500 nm, the complexing agent being present in an amount from about 0.05% to about 5%, w/w based on the weight of particles, the particles dispersed in an aqueous solution which further contains at least two preservatives in an amount sufficient to inhibit microbial growth.

2. The aqueous dispersion of claim 1 , wherein the hydrophilic polymer is in an amount from about 3% to about 50%, w/w, based on the weight of the dispersion.

3. The aqueous dispersion of claim 2 , wherein the wetting agent is in an amount from about 0.01% to about 10%, w/w, based on the weight of the dispersion.

4. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% after 10 days of storage at room temperature.

5. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% after 20 days of storage at room temperature.

6. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% after 40 days of storage at room temperature.

7. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% after 60 days of storage at room temperature.

8. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% after 80 days of storage at room temperature.

9. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles is from about 100 nm to about 450 nm.

10. The aqueous dispersion of claim 9 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles is from about 100 nm to about 350 nm.

11. The aqueous dispersion of claim 1 , wherein the complexing agent is selected from the group consisting of parabens, benzoic acid, and pharmaceutically acceptable salts thereof and mixtures thereof.

12. The aqueous dispersion of claim 3 , wherein the ganaxolone is present in an amount from about 10% to about 80%, w/w, based on the weight of the dispersion.

13. The aqueous dispersion of claim 3 , wherein the hydrophilic polymer is selected from the group consisting of a cellulosic polymer, a vinyl polymer and mixtures thereof.

14. The aqueous dispersion of claim 13 , wherein the cellulosic polymer is a cellulose ether.

15. The aqueous dispersion of claim 14 , wherein the cellulose ether is hydroxypropymethylcellulose.

16. The aqueous dispersion of claim 13 , wherein the vinyl polymer is vinyl pyrrolidone/vinyl acetate copolymer (S630).

17. The aqueous dispersion of claim 16 , wherein the vinyl polymer is polyvinyl alcohol.

18. The aqueous dispersion of claim 3 , wherein the ganaxolone is present in an amount of about 5%, w/w, based on the weight of the dispersion.

19. The aqueous dispersion of claim 3 , wherein the wetting agent is selected from the group consisting of sodium lauryl sulfate, a pharmaceutically acceptable salt of docusate, or mixtures thereof.

20. The aqueous dispersion of claim 3 , wherein the aqueous dispersion further comprises from about 1% to about 50% of an ionic dispersion modulator based on the weight of the aqueous dispersion.

21. The aqueous dispersion of claim 20 , wherein the ionic dispersion modulator is a salt.

22. The aqueous dispersion of claim 21 , wherein the salt is an inorganic salt.

23. The aqueous dispersion of claim 22 , wherein the inorganic salt is selected from the group consisting of a magnesium salt, a calcium salt, a lithium salt, a potassium salt, a sodium salt and mixtures thereof.

24. The aqueous dispersion of claim 23 , wherein the inorganic salt is sodium chloride.

25. The aqueous dispersion of claim 21 , wherein the salt is an organic salt.

26. The aqueous dispersion of claim 25 , wherein the organic salt is selected from the group consisting of a citrate salt, a succinate salt, a fumarate salt, a malate salt, maleate salt, a tartrate salt, a glutarate salt, a lactate salt and mixtures thereof.

27. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% when placed in a glass vial and heated in a 100° C. oil bath for 20 minutes.

28. The aqueous dispersion of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles does not change by more than about 15% when placed in a glass vial and heated in a 100° C. oil bath for 4 hours.

29. The aqueous dispersion of claim 3 , wherein the stabilized ganaxolone particles exhibit an increase in volume weighted median diameter (D50) of not more than about 150% when the particles are dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone/mL and placed in a heated bath at 36° to 38° C. for 1 hour.

30. The aqueous dispersion of claim 3 , further comprising a sweetener.

31. The aqueous dispersion of claim 30 , wherein the sweetener is sucralose.

32. The aqueous dispersion of claim 3 , wherein the endpoint ranges from about 5 days to 25 days.

33. The aqueous dispersion wherein the endpoint ranges from about 7 days to 14 days.

34. The aqueous dispersion of claim 3 , wherein the endpoint ranges from about 5 days to 7 days.

35. The aqueous dispersion of claim 3 , wherein the complexing agent is methylparaben and the endpoint ranges from about 5 to 7 days.

36. The aqueous dispersion of claim 3 , wherein the complexing agent is benzoic acid and the endpoint is up to about 3 weeks.

37. The aqueous dispersion of claim 3 , wherein the stabilized ganaxolone particles have a D50 of less than about 250 nm.

38. The aqueous dispersion of claim 3 , wherein the stabilized ganaxolone particles have a D50 of less than about 150 nm.

39. The aqueous dispersion of claim 1 , wherein the complexing agent comprises methylparaben or a salt thereof.

40. The aqueous dispersion of claim 1 , wherein the complexing agent comprises propylparaben or a salt thereof.

41. The aqueous dispersion of claim 1 , wherein the complexing agent comprises benzoic acid or a salt thereof.

42. The aqueous dispersion of claim 1 , wherein the complexing agent comprises methyl anthranilate.

43. The aqueous dispersion of claim 1 , wherein the concentration of ganaxolone in the formulation is about 50 mg/ml.

44. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a ratio of mean blood plasma fed AUC(O-t) to fasted AUC(O-t) from about 1.5:1 to about 5:1.

45. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a ratio of mean blood plasma fed Cmax to fasted Cmax from about 2:1 to about 7:1.

46. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a mean blood plasma AUC 0-24 hours from about 100 to about 375 ng*h/ml when a dose of 200 mg to 500 mg of the ganaxolone is orally administered to adult subjects in the fasted state.

47. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a mean blood plasma Cmax from about 25 to about 70 ng/ml when a dose of 200 mg to 500 mg of the ganaxolone is orally administered to adult subjects in the fasted state.

48. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a mean blood plasma AUC (0-48) hours from about 400 to about 1200 ng*h/ml when a dose of 200 mg to 500 mg of the ganaxolone is orally administered to adult subjects in the fed state.

49. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a mean blood plasma Cmax from about 60 to about 250 ng/ml when a dose of 200 mg to 500 mg of the ganaxolone is orally administered to adult subjects in the fed state.

50. The aqueous dispersion of claim 1 , wherein the aqueous dispersion provides a mean blood plasma Cmax/Cmin ratio of not greater than about 4 to 1 at steady state with a dose of 200 to 500 mg ganaxolone to adult subjects in the fed or fasted state.

51. The aqueous dispersion of claim 1 , wherein the preservative is selected from the group consisting of potassium sorbate, methylparaben, propylparaben, benzoic acid, butylparaben, ethyl alcohol, benzyl alcohol, phenol, benzalkonium chloride, and mixtures of any of the foregoing.