Patent EA-002223-B1 (EA)
Title: Ziprasidone formulations
Inventor: BUSH FRANK ROBERT
IPC: A61K47/26
Filed: 1999-06-15
Abstract: 1. A composition comprising crystalline (ziprasidone) free base 5-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indole-2-one or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than about 85 μm and a pharmaceutically acceptable diluent or carrier. 2. A composition as defined in Claim 1, wherein said composition comprises ziprasidone hydrochloride monohydrate. 3. A composition as defined in Claim 1, wherein said mean particle size is equal to or less than 50 μm. 4. A composition as defined in Claim 3, wherein said mean particle size is from 5 to 50 μm. 5. A composition as defined in Claim 4, wherein said mean particle size is from 5 to 40 μm. 6. A composition as defined in Claim 5, wherein said mean particle size is from 5 to 30 μm. 7. A composition as defined in Claim 1 which exhibits an AUC and/or Cmax that is at least 80% of the mean AUC and/or Cmax observed for an equivalent formulation differing only in that the ziprasidone hydrochloride mean particle size is 20 μm. 8. A composition as defined in Claim 1, wherein, when an amount of said dosage form equivalent to 100 mgA or less of ziprasidone is placed in a USP-2 apparatus containing 900 ml of aqueous NaH2PO4 buffer, pH 7.5, containing 2% (w/v) sodium dodecylsulfate, and equipped with paddles stirring at 75 r/m, at least 70% of the ziprasidone therein dissolves within 45 minutes. 9. A method of treating a psychosis, comprising administering to a patient in need of such treatment an effective amount of a composition as defined in Claim 1. 10. A method as defined in Claim 9, wherein said composition comprises ziprasidone hydrochloride monohydrate. 11. A method as defined in Claim 9, wherein said mean particle size is equal to or less than 50 μm. 12. A method as defined in Claim 11, wherein said mean particle size is from 5 to 50 μm. 13. A method as defined in Claim 12, wherein said mean particle size is from 5 to 40 μm. 14. A method as defined in Claim 13, wherein said mean particle size is from 5 to 30 μm. 15. A method as defined in Claim 9 wherein said composition exhibits an AUC and/or Cmax that is at least 80% of the mean AUC and/or Cmax observed for an equivalent composition differing only in that the ziprasidone hydrochloride particle size is 20 μm. 16. A method as defined in Claim 9 wherein, when an amount of said composition equivalent to 100 mgA or less of ziprasidone is placed in a USP-2 apparatus containing 900 ml of aqueous NaH2PO4 buffer, pH 7.5, containing 2% (w/v) sodium dodecylsulfate, and equipped with paddles stirring at 75 r/m, at least 70% of the ziprasidone therein dissolves within 45 minutes. 17. A composition comprising crystalline ziprasidone free base or crystalline ziprasidone hydrochloride particles having a mean particle size equal to or less than about 85 μm, as measured by Malvern light scattering, and a pharmaceutically acceptable carrier, said composition exhibiting a mean AUC and/or Cmax which is at least 80% of the mean AUC exhibited by a composition equivalent thereto but differing only in that it has a crystalline ziprasidone hydrochloride mean particle size of 20 μm. 18. A composition as defined in Claim 17, which comprises crystalline ziprasidone hydrochloride monohydrate. 19. A composition as defined in Claim 17, wherein said mean particle size is equal to or less than 50 μm. 20. A composition as defined in Claim 19, wherein said mean particle size is from 5 to 50 μm. 21. A composition as defined in Claim 20, wherein said mean particle size is from 5 to 40 μm. 22. A composition as defined in Claim 21, wherein said mean particle size is from 5 to 30 μm. 23. A composition as defined in Claim 17, wherein, when an amount of said composition equivalent to 100 mgA or less of ziprasidone is placed in a USP-2 apparatus containing 900 ml of aqueous NaH2PO4 buffer, pH 7.5, containing 2% (w/v) sodium dodecylsulfate, and equipped with paddles stirring at 75 r/m, at least 70% of the ziprasidone hydrochloride therein dissolves within 45 minutes. 24. A method of treating a psychosis, comprising administering to a patient in need of such treatment an effective amount of a composition as defined in Claim 17. 25. A method as defined in Claim 24, which comprises ziprasidone hydrochloride monohydrate. 26. A method as defined in Claim 24, wherein said mean particle size is equal to or less than 50 μm. 27. A method as defined in Claim 26, wherein said mean particle size is from 5 to 50 μm. 28. A method as defined in Claim 27, wherein said mean particle size is from 5 to 40 μm. 29. A method as defined in Claim 28, wherein said mean particle size is from 5 to 30 μm. 30. A method as defined in Claim 24, wherein, when an amount of said composition equivalent to 100 mgA or less of ziprasidone is placed in a USP-2 apparatus containing 900 ml of aqueous NaH2PO4, pH 7.5, containing 2% (w/v) sodium dodecylsulfate, and equipped with paddles stirring at 75 r/m, at least 70% of the ziprasidone therein dissolves within 45 minutes. 31. A process of preparing large crystals of ziprasidone hydrochloride monohydrate, having volume mean diameter of 50 μm or more, comprising the steps of: 1) dissolving ziprasidone free base in a solvent comprising THF and water, in a volume ratio of about 22-35 unit volumes of THF to about 1.5-8 volumes of water; 2) heating the solution resulting from step (1); 3) adding HCl to the solution resulting from step (2); and 4) cooling the solution resulting from step (3). 32. A process as defined in Claim 31, wherein the volume ratio of THF to water in said solvent is 24-30 to 2-6. 33. A process as defined in Claim 31, wherein, in said step (3), the temperature of said solution is maintained below reflux. 34. A process as defined in Claim 33, wherein said temperature is 60-64 degree C.