Claims for Patent: 8,367,651

Summary for Patent: 8,367,651

Title:	Solid ganaxolone formulations and methods for the making and use thereof
Abstract:	In certain embodiments, the invention is directed to composition comprising stable particles comprising ganaxolone, wherein the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm.
Inventor(s):	Shaw; Kenneth (Weston, CT), Zhang; Mingbao (Millwood, NY)
Assignee:	Marinus Pharmaceuticals (Branford, CT)
Application Number:	13/052,798
Patent Claims:	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 and the concentration of ganaxolone in the solid stabilized particles is at least 50% by weight. 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 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.degree. to 38.degree. 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 1, wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles. 7. The solid stabilized particles 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.degree. to 38.degree. 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 solid stabilized particles of claim 1 in the form of a powder. 9. The solid stabilized particles of claim 1, wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule. 10. The solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles of claim 13, wherein the cellulosic polymer is a cellulose ether. 15. The solid stabilized particles of claim 13, wherein the cellulose ether is hydroxypropylmethylcellulose. 16. The solid stabilized particles of claim 13, wherein the vinyl polymer is polyvinyl alcohol. 17. The solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles of claim 18, wherein the pharmaceutically acceptable excipient comprises an ionic dispersion modulator. 20. The solid stabilized particles 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 solid stabilized particles of claim 19, wherein the ionic dispersion modulator is a salt. 22. The solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles of claim 18, wherein the pharmaceutically acceptable excipient comprises a water soluble spacer. 25. The solid stabilized particles 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 solid stabilized particles of claim 18, wherein the water soluble spacer is a saccharide or an ammonium salt. 27. The solid stabilized particles of claim 26, wherein the saccharide is selected from the group consisting of fructose, sucrose, glucose, lactose, mannitol and mixtures thereof. 28. The solid stabilized particles 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 solid stabilized particles of claim 18, wherein the surfactant is a polysorbate. 30. The solid stabilized particles of claim 18, wherein the plasticizer is polyethylene glycol. 31. The solid stabilized particles of claim 1, incorporated into a tablet or capsule, wherein the dosage form provides a ratio of mean blood plasma fed AUC.sub.(0-.tau.) to fasted AUC.sub.(0-.tau.) from about 1:1 to about 4:1. 32. The solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles 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 stabilized particles of claim 1, wherein the solid dosage form is an immediate release dosage form. 39. The stabilized particles of claim 1, wherein the solid dosage form is a controlled release dosage form. 40. The solid stabilized particles 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 solid stabilized particles 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 solid stabilized particles of claim 39, wherein dosage form provides a therapeutic effect for about 8 to about 24 hours after administration. 43. The solid stabilized particles 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 solid stabilized particles of claim 1, wherein the complexing agent comprises methylparaben or a salt thereof. 45. The solid stabilized particles of claim 1, wherein the complexing agent comprises benzoic acid or a salt thereof. 46. The solid stabilized particles of claim 1, wherein the complexing agent comprises methyl anthranilate. 47. The solid stabilized particles of claim 1, which includes from about 200 mg to about 800 mg ganaxolone. 48. 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, the concentration of ganaxolone in the solid stabilized particles being at least 50% by weight. 49. The solid stabilized particles of claim 48, wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles. 50. The solid stabilized particles of claim 1, wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule. 51. The solid stabilized particles of claim 48, wherein the complexing agent is selected from the group consisting of parabens, benzoic acid, methyl anthranilate, and pharmaceutically acceptable salts thereof and mixtures thereof.