Solid ganaxolone formulations and methods for the making and use thereof

1. Solid stabilized 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 being a small organic molecule 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 is 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 particles of the solid.

2. The solid stabilized particles 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 solid particles.

3. The solid stabilized particles 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 solid particles.

4. The solid stabilized particles of claim 1 , wherein the stabilized 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 as compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

5. The solid stabilized particles of claim 1 , wherein the stabilized particles exhibit an increase in volume weighted median diameter (D50) of not more than about 150% when the formulation is dispersed in 15 mL of SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone/mL as compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

6. The solid stabilized particles of claim 3 , wherein the ganaxolone is in an amount from about 10% to about 80% based on the weight of the stabilized particles.

7. The solid stabilized particles of claim 3 , wherein the ganaxolone is present in an amount of from about 50% to about 75%, based on the weight of the particles.

8. The solid stabilized particles of claim 3 , wherein the stabilized 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, as compared to the D50 of the stabilized particles when the particles are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

9. The solid stabilized particles of claim 3 in the form of a powder.

10. The solid stabilized particles of claim 3 , wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule.

11. The solid stabilized particles of claim 3 , wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in distilled water is from about 100 nm to about 350 nm.

12. The solid stabilized particles 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.

13. The solid stabilized particles of claim 12 , wherein the paraben is selected from the group consisting of methylparaben, ethylparaben, propylparaben, pharmaceutically acceptable salts thereof and mixtures thereof.

14. The solid stabilized particles of claim 2 , wherein the hydrophilic polymer is selected from the group consisting of a cellulosic polymer, a vinyl polymer and mixtures thereof.

15. The solid stabilized particles of claim 14 , wherein the cellulosic polymer is a cellulose ether.

16. The solid stabilized particles of claim 15 , wherein the cellulose ether is hydroxypropymethylcellulose.

17. The solid stabilized particles of claim 14 , wherein the vinyl polymer is polyvinyl alcohol.

18. The solid stabilized particles of claim 14 , wherein the vinyl polymer is vinyl pyrrolidone/vinyl acetate copolymer (S630).

19. The solid stabilized particles of claim 3 , wherein the wetting agent is selected from the group consisting of sodium lauryl sulfate, a pharmaceutically acceptable salt of docusate, and mixtures thereof.

20. The solid stabilized particles of claim 3 , wherein the particles are incorporated into a solid dosage form, further comprising at least one pharmaceutically acceptable excipient.

21. The solid stabilized particles of claim 20 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of an ionic dispersion modulator, an water soluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, a lubricant, and any combinations or mixtures thereof.

22. The solid stabilized particles of claim 20 , wherein the pharmaceutically acceptable excipient comprises an ionic dispersion modulator.

23. The solid stabilized particles of claim 22 , wherein the ionic dispersion modulator is in an amount from about 1% to about 50%, w/w, based on the weight of the solid particles.

24. The solid stabilized particles of claim 22 , wherein the ionic dispersion modulator is a salt.

25. The solid stabilized particles of claim 24 , wherein the salt is an inorganic salt.

26. The solid stabilized particles of claim 25 , 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.

27. The solid stabilized particles of claim 26 , wherein the inorganic salt is sodium chloride.

28. The solid stabilized particles of claim 24 , wherein the salt is an organic salt.

29. The solid stabilized particles of claim 28 , 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.

30. The solid stabilized particles of claim 20 , wherein the pharmaceutically acceptable excipient comprises a water soluble spacer.

31. The solid stabilized particles of claim 30 , wherein the water soluble spacer is in an amount from about 2% to about 60%, w/w, based on the weight of the solid particles.

32. The solid stabilized particles of claim 30 , wherein the water soluble spacer is a saccharide or an ammonium salt.

33. The solid stabilized particles of claim 32 , wherein the saccharide is selected from the group consisting of fructose, sucrose, glucose, lactose, mannitol and mixtures thereof.

34. The solid stabilized particles of claim 21 , wherein the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, crospovidone and any combinations or mixtures thereof.

35. The solid stabilized particles of claim 21 , wherein the surfactant is a polysorbate.

36. The solid stabilized particles of claim 21 , wherein the plasticizer is polyethylene glycol.

37. The solid stabilized particles of claim 20 , incorporated into a tablet or capsule, wherein the stabilized particles exhibit an increase in volume weighted median diameter (D50) of from not more than about 150% after the tablets or capsules are dispersed in 15 ml of simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) in a concentration of 0.5 mg ganaxolone/ml and placed in a heated bath at 36° to 38° C. for 1 hour without stirring, as compared to the D50 of the particles when the tablets or capsules are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

38. The solid stabilized particles of claim 20 , incorporated into a tablet or capsule, wherein the stable particles exhibit an increase in volume weighted median diameter (D50) of not more than about 150% when the tablets or capsules are dispersed in SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone/mL at 36° to 38° C. using a Type II dissolution apparatus and a stirring rate of 75 RPM for 1 hour, as compared to the D50 of the particles when the tablets or capsules are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the particles when the tablets or capsules are dispersed in SGF or SIF is less than about 750 nm.

39. The solid stabilized particles of claim 20 , incorporated into a tablet or capsule, wherein the dosage form provides a ratio of mean blood plasma fed AUC (0-τ) to fasted AUC (0-τ) from about 1:1 to about 4:1.

40. The solid stabilized particles of claim 39 , wherein the dosage form provides a ratio of mean blood plasma fed Cmax to fasted Cmax from about 1.5:1 to about 7:1.

41. The solid stabilized particles of claim 39 , wherein the particles have a volume weighted median diameter (D50) from about 50 nm to about 1000 nm, and the dosage form 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.

42. The solid stabilized particles of claim 41 , wherein the dosage form 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.

43. The solid stabilized particles of claim 41 , wherein the dosage form providing 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.

44. The solid stabilized particles of claim 41 , wherein the dosage form providing 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.

45. The solid stabilized particles of claim 41 , wherein the dosage form 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.

46. The stabilized particles of claim 20 , wherein the solid dosage form is an immediate release dosage form.

47. The solid stabilized particles of claim 46 , incorporated into a tablet or capsule, wherein the stabilized particles exhibit an increase in volume weighted median diameter (D50) of not more than about 150% when the tablets or capsules are dispersed in SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone/mL at 36° to 38° C. using a Type II dissolution apparatus and a stirring rate of 75 RPM for 1 hour as compared to the D50 of the stabilized particles when the tablets or capsules are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

48. The stabilized particles of claim 20 , wherein the solid dosage form is a controlled release dosage form.

49. The solid stabilized particles of claim 48 , incorporated into a tablet or capsule, wherein the stabilized particles exhibit a volume weighted median diameter (D50) of less than about 750 nm when the tablets or capsules are dispersed in simulated gastric fluid (SGF) for one hour followed by simulated intestinal fluid (SIF) for three additional hours, at a concentration of 0.5 to 1 mg ganaxolone/mL at a temperature of 36° to 38° C. using a Type II dissolution apparatus and a stirring rate of 75 RPM, as compared to the D50 of the stabilized particles when the tablets or capsules are dispersed in distilled water under the same conditions, wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in SGF or SIF is less than about 750 nm.

50. The solid stabilized particles of claim 3 , wherein the particles are incorporated into an oral solid dosage form comprising (i) a controlled release component comprising a first portion of the stabilized particles; and a controlled release material, and (ii) an immediate release component comprising a second portion of the stabilized particles, the first and second portion of stabilized particles having a volume weighted median diameter (D50) of from about 50 nm to about 500 nm.

51. The solid stabilized particles of claim 50 , wherein the ratio of ganaxolone in controlled release to immediate release is from about 4:1 to about 1:4.

52. The solid stabilized particles of claim 48 , wherein dosage form provides a therapeutic effect for about 8 to about 24 hours after administration.

53. The solid stabilized particles of claim 50 , wherein dosage form provides a therapeutic effect for about 8 to about 24 hours after administration.

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

55. The solid stabilized particles of claim 54 , wherein the complexing agent comprises methylparaben or a salt thereof.

56. The solid stabilized particles of claim 10 , which includes from about 50 mg to about 800 mg ganaxolone.

57. The solid stabilized particles of claim 1 , wherein the complexing agent comprises benzoic acid or a salt thereof.

58. The solid stabilized particles of claim 1 , wherein the complexing agent comprises methyl anthranilate.

59. Solid stabilized 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 consisting of methyl paraben, propyl paraben, and mixtures thereof and being present in an amount from about 0.05% to about 5% w/w based on the weight particles of the solid; wherein the stabilized particles have a volume weighted median diameter (D50) of the particles from about 50 nm to about 500 nm.

60. Solid stabilized 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 consisting of methyl paraben, propyl paraben, and mixtures thereof and being present in an amount from about 0.05% to about 5% w/w based on the weight particles of the solid; the hydrophilic polymer being present in an amount from about 3% to about 50%, w/w, based on the weight of the solid particles and being selected from the group consisting of a cellulosic polymer, a vinyl polymer and mixtures thereof; and the wetting agent being present in an amount from about 0.01% to about 10% w/w based on the weight of the solid particles; wherein the stabilized particles have a volume weighted median diameter (D50) of the particles from about 50 nm to about 500 nm.

61. The solid stabilized particles of claim 60 , wherein the wetting agent is selected from the group consisting of sodium lauryl sulfate, a pharmaceutically acceptable salt of docusate, and mixtures thereof.

62. The solid stabilized particles of claim 61 , wherein the ganaxolone is present in an amount of from about 50% to about 75%, based on the weight of the particles.