Liquid ganaxolone formulations and methods for the making and use thereof

1. A method of treatment for a central nervous system disorder selected from the group consisting of epileptic seizures, infantile spasms, anxiety, stress, panic, depression, postpartum depression, insomnia, premenstrual syndrome, post-traumatic stress disorder, substance abuse withdrawal, hypertension, pain, migraine headache, headache associated with pre- and peri-menstrual period, Neimann Pick disease Type-C and Mucolipidosis type IV lipid accumulation, mucolipidosis Type IV lipid accumulation, AIDS-related dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease, comprising administering to a human patient an oral liquid dosage form of aqueous dispersion of stabilized ganaxolone particles comprising a therapeutically effective amount of ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a 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, the stabilized particles having a volume weighted median diameter (D50) of the particles from about 50 nm to about 500 nm, wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment to the human patient suffering from a central nervous system disorder.

2. The method of claim 1 , wherein the stabilized ganaxolone particles are dispersed in an aqueous solution which further contains at least two preservatives in an amount sufficient to inhibit microbial growth.

3. The method of claim 1 , wherein the complexing agent stabilizes particle growth after an initial particle growth and endpoint is reached.

4. The method 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.

5. The method of claim 1 , wherein the wetting agent is in an amount from about 0.01% to about 10%, w/w, based on the weight of the dispersion.

6. The method of claim 1 , wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles.

7. The method of claim 1 , 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.

8. The method of claim 1 , 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.

9. The method of claim 1 , wherein the volume weighted median diameter (D50) of the stabilized ganaxolone particles is from about 100 nm to about 450 nm.

10. The method of claim 1 , wherein the complexing agent is in an amount from about 0.05% to about 5%, w/w, based on the weight of the solid particles.

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

12. The method of claim 10 , wherein the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate and pharmaceutically acceptable salts thereof and mixtures thereof.

13. The method of claim 1 , wherein the hydrophilic polymer is selected from the group consisting of a cellulosic polymer, a vinyl polymer and mixtures thereof.

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

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

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

17. The method of claim 13 , wherein the vinyl polymer is polyvinyl alcohol.

18. The method of claim 1 , wherein the ganaxolone is present in an amount of about 5%, w/w, based on the weight of the dispersion.

19. The method of claim 1 , 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 method of claim 1 , 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 method of claim 1 , 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.

22. The method of claim 1 , 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.

23. The method of claim 1 , further comprising incorporating an effective amount of a sweetener into the oral liquid dosage form.

24. The method of claim 23 , wherein the sweetener is sucralose.

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

26. The method of claim 1 , wherein the complexing agent comprises methylparaben or a salt thereof.

27. The method of claim 1 , wherein the complexing agent comprises propylparaben or a salt thereof.

28. The method of claim 1 , wherein the complexing agent comprises benzoic acid or a salt thereof.

29. The method of claim 1 , wherein the complexing agent comprises methyl anthranilate.

30. The method of claim 1 , wherein the concentration of ganaxolone in the dispersion is from about 20 mg/ml to about 150 mg/ml.

31. The method of claim 1 , wherein the concentration of ganaxolone in the dispersion is from about 25 mg/ml to about 75 mg/ml.

32. The method of claim 1 , wherein the aqueous dispersion provides a ratio of mean blood plasma fed AUC(0-τ) to fasted AUC(0-τ) from about 1:1 to about 7:1.

33. The method 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.

34. The method 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.

35. The method 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.

36. The method 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.

37. The method 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.

38. The method 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.

39. The method 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.

40. The method of claim 30 , wherein the liquid oral dosage form contains from about 200 mg to about 500 mg ganaxolone.

41. The method of claim 1 , wherein the complexing agent is one or more parabens.

42. A method of treatment for a central nervous system disorder selected from the group consisting of epileptic seizures, infantile spasms, anxiety, stress, panic, depression, postpartum depression, insomnia, premenstrual syndrome, post-traumatic stress disorder, substance abuse withdrawal, hypertension, pain, migraine headache, headache associated with pre- and peri-menstrual period, Neimann Pick disease Type-C and Mucolipidosis type IV lipid accumulation, mucolipidosis Type IV lipid accumulation, AIDS-related dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease”, comprising administering to a human patient a therapeutically effective amount of an liquid dosage form comprising an aqueous solution of stabilized ganaxolone particles comprising ganaxolone, a hydrophilic polymer, a wetting agent, and a 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 and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight, the particles dispersed in an aqueous solution which further contains at least two preservatives in an amount sufficient to inhibit microbial growth, wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment to the human patient suffering from a central nervous system disorder.

43. The method of claim 42 , wherein the complexing agent is in an amount from about 0.05% to about 5%, w/w, based on the weight of the solid particles.

44. The method of claim 43 , wherein the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate and pharmaceutically acceptable salts thereof and mixtures thereof.

45. The method of claim 44 , 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.

46. The method of claim 43 , wherein the hydrophilic polymer is in an amount from about 3% to about 50%, w/w and the wetting agent is in an amount from about 0.01% to about 10%, w/w, based on the weight of the dispersion.

47. The method of claim 43 , wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles.

48. The method of claim 43 , wherein the liquid oral dosage form contains from about 200 mg to about 500 mg ganaxolone.

49. The method of claim 43 , wherein the complexing agent is one or more parabens.

50. A method of treatment for a central nervous system disorder selected from the group consisting of epileptic seizures, infantile spasms, anxiety, stress, panic, depression, postpartum depression, insomnia, premenstrual syndrome, post-traumatic stress disorder, substance abuse withdrawal, hypertension, pain, migraine headache, headache associated with pre- and peri-menstrual period, Neimann Pick disease Type-C and Mucolipidosis type IV lipid accumulation, mucolipidosis Type IV lipid accumulation, AIDS-related dementia, Alzheimer's disease, Huntington's disease, and Parkinson's disease”, comprising administering to a human patient a therapeutically effective amount of an liquid dosage form comprising 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 a preservative in an amount sufficient to inhibit microbial growth, wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment to the human patient suffering from a central nervous system disorder.

51. The method of claim 50 , wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles.

52. The method of claim 50 , wherein the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate and pharmaceutically acceptable salts thereof and mixtures thereof.

53. The method of claim 50 , 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.

54. The method of claim 50 , wherein the hydrophilic polymer is in an amount from about 3% to about 50%, w/w and the wetting agent is in an amount from about 0.01% to about 10%, w/w, based on the weight of the dispersion.

55. The method of claim 50 , wherein the liquid oral dosage form contains from about 200 mg to about 500 mg ganaxolone.

56. The method of claim 50 , wherein the complexing agent is one or more parabens.

57. The method of claim 1 , wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment to a human patient suffering from a condition selected from the group consisting of anxiety, stress, panic, depression and depression related disorders, insomnia, premenstrual syndrome, Post Traumatic Stress Disorder, substance abuse withdrawal, and hypertension.

58. The method of claim 1 , wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment of pain in a human patient.

59. The method of claim 1 , wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment of a neurodegenerative disease.

60. The method of claim 1 , wherein the therapeutically effective amount of ganaxolone is sufficient to provide treatment of a sphingolipid storage disease.