Solid ganaxolone compositions and methods for the making and use thereof

1. A pharmaceutical composition comprising 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 solid stabilized particles have a volume weighted median diameter (D50) 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 the solid stabilized particles; the pharmaceutical composition further comprising one or more pharmaceutically acceptable additives selected from the group consisting of a diluent, a binder, a disintegrant, a plasticizer, a stabilizer, and mixtures of any of the foregoing, the pharmaceutical composition being an oral solid dosage form.

2. The pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition solid stabilized particles of claim 1 , wherein the ganaxolone is in an amount from about 10% to about 80% based on the weight of the stabilized particles.

6. The pharmaceutical composition solid stabilized particles of claim 5 , wherein the ganaxolone is present in an amount from about 50% to about 80%, based on the weight of the particles.

7. The pharmaceutical composition solid stabilized particles of claim 5 , wherein the complexing agent is selected from the group consisting of one or more parabens, benzoic acid, phenol, methyl anthranilate, pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing.

8. The pharmaceutical composition of claim 7 , wherein the complexing agent is one or more parabens or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 7 , wherein the complexing agent is benzoic acid or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 1 , wherein the complexing agent is methyl anthranilate.

11. The pharmaceutical composition of claim 1 , wherein the complexing agent is phenol.

12. The pharmaceutical composition solid stabilized particles of claim 8 , wherein the paraben is selected from the group consisting of methylparaben, ethylparaben, propylparaben, pharmaceutically acceptable salts thereof and mixtures thereof.

13. The pharmaceutical composition 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 pharmaceutical composition solid stabilized particles of claim 13 , wherein the cellulosic polymer is a cellulose ether.

15. The pharmaceutical composition solid stabilized particles of claim 14 , wherein the cellulose ether is hydroxypropymethylcellulose.

16. The pharmaceutical composition solid stabilized particles of claim 13 , wherein the vinyl polymer is polyvinyl alcohol.

17. The pharmaceutical composition solid stabilized particles of claim 16 , wherein the vinyl polymer is vinyl pyrrolidone/vinyl acetate copolymer (S630).

18. The pharmaceutical composition 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.

19. The pharmaceutical composition of claim 7 , further comprising an ionic dispersion modulator in an amount from about 1% to about 50%, w/w, based on the weight of the solid particles, and 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, or an organic salt 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.

20. The pharmaceutical composition of claim 7 , further comprising a an effective amount of a controlled release material such that the dosage form provides a therapeutic effect for about 8 to about 24 hours after administration.

21. The pharmaceutical composition of claim 20 , which is an oral solid dosage form comprising (i) a controlled release component comprising a first portion of said solid stabilized ganaxolone particles; and a controlled release material, and (ii) an immediate release component comprising a second portion of said solid stabilized ganaxolone particles.

22. The pharmaceutical composition of claim 20 , wherein the controlled release component is in the form of (i) a plurality of pharmaceutically acceptable beads coated with the first portion of said solid stabilized ganaxolone particles and overcoated with the controlled release material, or (ii) a plurality of matrices comprising the first portion of said solid stabilized ganaxolone particles dispersed in the controlled release material, or (iii) a tablet comprising the first portion of ganaxolone particles dispersed in a controlled release material, or (iv) a granulation comprising the first portion of ganaxolone particles and the controlled release material.

23. The pharmaceutical composition of claim 20 , wherein the controlled release component is a tablet and the immediate release component is coated onto the tablet.

24. The pharmaceutical composition of claim 7 , wherein the stable ganaxolone particles are in a form selected from crystalline form, amorphous form, semi-crystalline form, semi-amorphous form, and mixtures thereof.

25. The pharmaceutical composition of claim 20 , further comprising a pH dependent polymer, the pharmaceutical composition providing a delayed release of the ganaxolone from a time period from about 2 to about 12 hours after administration.

26. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is a compressed tablet.

27. The pharmaceutical composition of claim 20 , wherein the pharmaceutical composition is a compressed tablet.

28. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is contained inside a capsule.

29. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition is contained inside a capsule.

30. The pharmaceutical composition of claim 5 , 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.

31. The pharmaceutical composition of claim 5 , which provides a ratio of mean blood plasma fed Cmax to fasted Cmax from about 1.5:1to about 7:1.

32. The pharmaceutical composition of claim 30 , 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.

33. The pharmaceutical composition of claim 5 , which 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.

34. The pharmaceutical composition of claim 30 , which provides a mean blood plasma AUC (0-48) hours from about 400 to about 1200ng*h/ml when a dose of 200 mg to 500 mg of the ganaxolone is orally administered to adult subjects in the fed state.

35. The pharmaceutical composition of claim 5 , which 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.

36. The pharmaceutical composition of claim 5 , which 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.

37. A pharmaceutical composition comprising solid stabilized particles comprising ganaxolone, a hydrophilic polymer, a wetting agent, and an effective amount of a 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 pharmaceutical composition further comprising one or more pharmaceutically acceptable additives selected from the group consisting of a diluent, a binder, a disintegrant, a plasticizer, a stabilizer, and mixtures of any of the foregoing, wherein the stabilized particles have a volume weighted median diameter (D50) from about 50 nm to about 500nm, the pharmaceutical composition being an oral solid dosage form and including from about 50 mg to about 800 mg ganaxolone.

38. The pharmaceutical composition of claim 37 , wherein the solid dosage form is an immediate release dosage form.

39. The pharmaceutical composition of claim 37 , further comprising a an effective amount of a controlled release material such that the dosage form provides a therapeutic effect for about 8 to about 24 hours after administration.

40. The pharmaceutical composition of claim 37 , which is an oral solid dosage form comprising (i) a controlled release component comprising a first portion of said solid stabilized ganaxolone particles; and a controlled release material, and (ii) an immediate release component comprising a second portion of said solid stabilized ganaxolone particles.

41. The pharmaceutical composition of claim 40 , wherein the controlled release component is in the form of (i) a plurality of pharmaceutically acceptable beads coated with the first portion of said solid stabilized ganaxolone particles and overcoated with the controlled release material, or (ii) a plurality of matrices comprising the first portion of said solid stabilized ganaxolone particles dispersed in the controlled release material, or (iii) a tablet comprising the first portion of ganaxolone particles dispersed in a controlled release material, or (iv) a granulation comprising the first portion of ganaxolone particles and the controlled release material.

42. The pharmaceutical composition of claim 41 , wherein the controlled release component is in the form of (i) a plurality of pharmaceutically acceptable beads coated with the first portion of said solid stabilized ganaxolone particles and overcoated with the controlled release material, or (ii) a plurality of matrices comprising the first portion of said solid stabilized ganaxolone particles dispersed in the controlled release material or (iii) a granulation comprising the first portion of ganaxolone particles and the controlled release material; wherein the pharmaceutical composition is contained inside a capsule.

43. The pharmaceutical composition of claim 39 , wherein the pharmaceutical composition is a compressed tablet.

44. A pharmaceutical composition comprising 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 pharmaceutical composition further comprising one or more pharmaceutically acceptable additives selected from the group consisting of a diluent, a binder, a disintegrant, a plasticizer, a stabilizer, and mixtures of any of the foregoing, the solid stabilized particles having a volume weighted median diameter (D50) from about 50 nm to about 500 nm, the concentration of ganaxolone in the solid stabilized particles being at least 50% by weight and the composition including from about 50 mg to about 800 mg ganaxolone, wherein the pharmaceutical composition is an oral solid dosage form.

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

46. The pharmaceutical composition of claim 44 , wherein the ganaxolone is present in an amount greater than 50% to about 80%, based on the weight of the particles.

47. The pharmaceutical composition of claim 44 , wherein the particles are incorporated into a dosage form selected from the group consisting of a tablet or capsule.