Sustained release dosage forms of ziprasidone

• US 20070190129A1
• Filed: 08/31/2004
• Published: 08/16/2007
• Est. Priority Date: 09/02/2003
• Status: Abandoned Application

• Current Assignee: Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Ahmed, Imran, Smithey, Daniel, Lyon, David, Herbig, Scott, Shanker, Ravi, Appel, Leah, Babcock, Walter, Thombre, Avinash, Friesen, Dwayne, Shamblin, Sheri, Sutton, Steven, Waterman, Kenneth
• Application Number:
  US10/931,143
• Publication Number:
  US 20070190129A1
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

A sustained release solid oral dosage form for treatment of a psychotic disorder, for example schizophrenia, in a mammal is provided, which oral dosage form comprises ziprasidone in an amount effective in treating said psychotic disorder and a pharmaceutically acceptable carrier.

Claims

1. A sustained release oral dosage form comprising a pharmaceutically effective amount of ziprasidone and a sustained release means for releasing at least a portion of said ziprasidone, wherein following administration to achieve steady state, said dosage form provides a steady state minimum blood ziprasidone concentration (C_min) of at least 20 ng/ml, and a steady state maximum blood ziprasidone concentration (C_max) of less than 330 ng/ml.

4. The dosage form of claim 1 or 3 wherein said dosage form releases no greater than 90 wt % of said ziprasidone from said dosage form during the first 2 hours after administration to an in vitro use environment, wherein said dosage form comprises at least 30 mgA of ziprasidone, and said in vitro use environment is 900 mL of a dissolution medium of a simulated intestinal buffer solution consisting of 50 mM NaH₂PO₄ with 2 wt % sodium lauryl sulfate at pH 7.5 and 37°

C.

5. The dosage form of claim 4 wherein said dosage form releases no greater than 80 wt % of said ziprasidone during the first 2 hours after administration to said use environment.

6. The dosage form of claim 5 wherein said dosage form releases no greater than 70 wt % of said ziprasidone during the first 2 hours after administration to said use environment.

8. The dosage form of any one of claims 1-3 wherein the time to release at least about 80 wt % of said ziprasidone in said dosage form is at least 4 hours.

9. The dosage form of any one of claims 1-3 wherein the time to release at least about 80 wt % of said ziprasidone in said dosage form is at least 6 hours.

10. The dosage form of claim 9 wherein no greater than 70 wt % of said ziprasidone is released into said use environment during the first 2 hours after administration.

11. The dosage form of claim 1 wherein, following administration to a patient twice per day, said dosage form provides a steady state ratio of said C_max to said C_min that is less than 2.6.

12. The dosage form of claim 11 wherein said steady state ratio of said C_max to said C_min is less than 2.4.

13. The dosage form of claim 12 wherein said steady state ratio of said C_max to said C_min is less than 2.2.

14. The dosage form of claim 1 wherein, following administration to a patient once per day, said dosage form provides a steady state ratio of said C_max to said C_min that is less than 12.

15. The dosage form of claim 14 wherein said steady state ratio of said C_max to said C_min is less than 10.

16. The dosage form of claim 15 wherein said steady state ratio of said C_max to said C_min is less than 8.

18. The dosage form of claim 1 or 17 wherein said C_min is at least 35 ng/ml.

19. The dosage form of claim 18 wherein said C_min is at least 50 ng/ml.

21. The dosage form of claim 1 or 20 wherein said C_max is less than 265 ng/ml.

22. The dosage form of claim 21 wherein said C_max is less than 200 ng/ml.

23. The dosage form of any one of claims 1-3 wherein said dosage form provides a steady state area under the concentration of ziprasidone in the blood versus time curve over twelve hours after administration in the fed state that is at least 240 ng-hr/ml when administered twice a day.

24. The dosage form of claim 1 wherein a ratio of said C_max to said C_min is less than the ratio of the steady state maximum blood ziprasidone concentration to the steady state minimum blood ziprasidone concentration provided by a control immediate release oral capsule administered at the same dosing frequency, said control immediate release oral capsule consisting essentially of ziprasidone hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate, and said control immediate release oral capsule containing the same amount of ziprasidone as said dosage form.

26. The dosage form of any one of claims 1-3 wherein said dosage form provides a relative bioavailability of at least 50% relative to a control immediate release oral capsule, said control immediate release oral capsule consisting essentially of an equivalent amount of active ziprasidone in the form of ziprasidone hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate.

27. The dosage form of any one of claims 1-3 wherein said ziprasidone is crystalline.

28. The dosage form of claim 27 wherein a volume weighted mean particle diameter of said crystalline ziprasidone is less than about 10 μ

m.

29. The dosage form of any one of claims 1-3 wherein said ziprasidone is in a solubility improved form.

30. The dosage form of claim 29 wherein said ziprasidone is a high solubility salt form.

31. The dosage form of claim 29 further comprising a cyclodextrin.

32. The dosage form of any one of claims 1-3 further comprising a solubilizing agent.

33. The dosage form of claim 32 wherein said solubilizing agent is a cyclodextrin.

34. The dosage form of any one of claims 1-3 further comprising a precipitation inhibitor.

35. The dosage form of claim 34 wherein said precipitation inhibitor is a polymer.

36. The dosage form of claim 35 wherein said precipitation inhibitor is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and carboxy methyl ethyl cellulose.

37. The dosage form of claim 36 wherein said precipitation inhibitor is hydroxypropylmethyl cellulose acetate succinate.

38. The dosage form of claim 35 wherein said precipitation inhibitor is present as a coating on said ziprasidone.

39. The dosage form of any one of claims 1-3 comprising at least a portion of said ziprasidone in a solubility-improved form and a precipitation inhibitor.

40. The dosage form of claim 1 or 3 comprising at least 30 mgA of said ziprasidone.

41. The dosage form of any one of claims 1-3 wherein at least 5 wt % of said dosage form is ziprasidone.

42. The dosage form of any one of claims 1-3 wherein at least 10 wt % of said ziprasidone is released within the first hour after administration to said use environment.

43. The dosage form of claim 42 further comprising an immediate release portion.

44. The dosage form of any one of claims 1-3 wherein said dosage form is an osmotic tablet or a matrix tablet.

45. A method for treating a patient in need of ziprasidone, comprising administering the dosage form of any one of claims 1-3.

46. The method of claim 45 wherein said dosage form is administered only once per day.

47. The method of claim 45 wherein said dosage form is administered at least two times per day.

48. The method of claim 47 wherein said dosage form is administered twice per day.

49. The method of claim 48 wherein the daily dose is at least 40 mgA of ziprasidone.

50. The dosage form of claim 37 wherein said hydroxypropylmethyl cellulose acetate succinate comprises the H grade and the M grade of said hydroxypropylmethyl cellulose acetate succinate.

2. A sustained release oral dosage form comprising a pharmaceutically effective amount of ziprasidone, said dosage form releasing no greater than 90 wt % of said ziprasidone from said dosage form during the first 2 hours after administration to an in vitro use environment, wherein said dosage form comprises at least 30 mgA of ziprasidone, and said in vitro use environment is 900 mL of a dissolution medium of a simulated intestinal buffer solution.

7. The dosage form of claim 2 wherein said dosage form releases no greater than 80 wt % of said ziprasidone during the first 2 hours after administration to said use environment.

17. The dosage form of claim 2, wherein following administration to a patient in the fed state, said dosage form provides a steady state minimum blood ziprasidone concentration (C_min) of at least 20 ng/ml.

20. The dosage form of claim 2, wherein following administration to a patient in the fed state, said dosage form provides a steady state maximum blood ziprasidone concentration (C_min) of less than 330 ng/ml.

25. The dosage form of claim 2 or 3 wherein said dosage form provides a ratio of a steady state maximum blood ziprasidone concentration (C_max) to a steady state minimum blood ziprasidone concentration (C_min) that is no greater than the ratio of the steady state maximum blood ziprasidone concentration to the steady state minimum blood ziprasidone concentration provided by a control immediate release oral capsule administered at the same dosing frequency, said control immediate release capsule consisting essentially of ziprasidone hydrochloride monohydrate, lactose, pregelatinized starch, and magnesium stearate, and said control immediate release oral capsule containing the same amount of ziprasidone as said dosage form.

3. A sustained release oral dosage form comprising a pharmaceutically effective amount of ziprasidone and a sustained release means for releasing at least a portion of said ziprasidone, wherein said at least a portion of said ziprasidone in said sustained release means is at least one of crystalline ziprasidone and ziprasidone combined with a cyclodextrin.