Solid ganaxolone formulations and methods for the making and use thereof

1. A method of treating human patients in need 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 an effective amount of solid stabilized particles comprising ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent which is 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 and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight.

2. 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 solid particles.

3. The method 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 method of claim 2 , 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 method 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 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 6 , 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.

8. The method of claim 1 in the form of a powder.

9. The method of claim 1 , wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule.

10. The method of claim 1 , wherein the volume weighted median diameter (D50) of the stabilized particles dispersed in distilled water is from about 100 nm to about 350 nm.

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 1 , wherein the paraben is selected from the group consisting of methylparaben, ethylparaben, propylparaben, 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 13 , wherein the cellulose ether is hydroxypropymethylcellulose.

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

17. 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, and mixtures thereof.

18. The method of claim 1 , wherein the particles are incorporated into a solid dosage form, further comprising at least one pharmaceutically acceptable excipient 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.

19. The method of claim 18 , wherein the pharmaceutically acceptable excipient comprises an ionic dispersion modulator.

20. The method of claim 19 , 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.

21. The method of claim 19 , wherein the ionic dispersion modulator is a salt.

22. The method of claim 19 , wherein the ionic dispersion modulator is an 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.

23. The method of claim 19 , wherein the ionic dispersion modulator is an 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.

24. The method of claim 18 , wherein the pharmaceutically acceptable excipient comprises a water soluble spacer.

25. The method of claim 24 , 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.

26. The method of claim 24 , wherein the water soluble spacer is a saccharide or an ammonium salt.

27. The method of claim 26 , wherein the saccharide is selected from the group consisting of fructose, sucrose, glucose, lactose, mannitol and mixtures thereof.

28. The method of claim 18 , wherein the disintegrant is selected from the group consisting of cross-linked sodium carboxymethylcellulose, crospovidone and any combinations or mixtures thereof.

29. The method of claim 18 , wherein the surfactant is a polysorbate.

30. The method of claim 18 , wherein the plasticizer is polyethylene glycol.

31. The method of claim 1 , 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.

32. The method of claim 1 , 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.

33. The method of claim 1 , 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.

34. The method of claim 1 , 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.

35. The method of claim 1 , 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.

36. The method of claim 1 , 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.

37. The method of claim 1 , 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.

38. The method of claim 1 , wherein the solid dosage form is an immediate release dosage form.

39. The method of claim 1 , wherein the solid dosage form is a controlled release dosage form.

40. The method of claim 39 , 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.

41. The method of claim 40 , wherein the ratio of ganaxolone in controlled release to immediate release is from about 4:1 to about 1:4.

42. The method of claim 39 , wherein dosage form provides a therapeutic effect for about 8 to about 24 hours after administration.

43. 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.

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

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

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

47. The method of claim 1 , wherein the effective amount of solid stabilized particles include from about 200 mg to about 800 mg ganaxolone.

48. The method of claim 1 , further comprising incorporating the solid stabilized particles into an oral solid dosage form comprising from about 200 mg to about 800 mg ganaxolone prior to administration to said human patients.

49. A method of treating patients, comprising administering to human patients in need 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 an effective amount of solid stabilized particles comprising ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a complexing agent which is 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 and 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.

50. A method of treating patients, comprising administering to human patients in need of treatment for a central nervous system disorder an effective amount of solid stabilized particles comprising 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.

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 48 , wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule.

53. 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.

54. The method of claim 53 , further comprising incorporating the solid stabilized particles into an oral solid dosage form comprising from about 200 mg to about 800 mg ganaxolone prior to administration to said human patients.