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Claims for Patent: 9,089,607

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Claims for Patent: 9,089,607

Title:Controlled release formulations of levodopa and uses thereof
Abstract: The current invention provides a controlled release oral solid formulation of levodopa comprising levodopa, a decarboxylase inhibitor, and a carboxylic acid. Also provided by this invention is multiparticulate, controlled release oral solid formulations of levodopa comprising: i) a controlled release component comprising a mixture of levodopa, a decarboxylase inhibitor and a rate controlling excipient; ii) a carboxylic acid component; and iii) an immediate release component comprising a mixture of levodopa and a decarboxylase inhibitor.
Inventor(s): Hsu; Ann (Los Altos Hills, CA), Kou; Jim H. (San Jose, CA), Alani; Laman Lynn (Fort Worth, TX)
Assignee: Impax Laboratories, Inc. (Hayward, CA)
Application Number:13/900,408
Patent Claims: 1. A controlled release oral solid formulation of levodopa comprising: a. a first controlled release component comprising levodopa, a decarboxylase inhibitor and one or more rate controlling excipients, b. a carboxylic acid component comprising a carboxylic acid that is not levodopa or the decarboxylase inhibitor and one or more rate controlling excipients, c. an immediate release component comprising levodopa and a decarboxylase inhibitor, and d. a second controlled release component comprising levodopa, a decarboxylase inhibitor and one or more rate controlling excipients, the second controlled release component (d) being in a separate bead or granule from (a) and having less levodopa and decarboxylase inhibitor than (a), wherein the carboxylic acid component of (b) is in a distinct component and is coated with an enteric polymer; and wherein the first controlled release component (a), the second release component (d), the immediate release component (c) and the carboxylic acid component (b) comprise beads or granules and wherein the first and second controlled release components release decarboxylase inhibitor and levodopa at different rates.

2. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is selected from a group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbid acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof.

3. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is a polycarboxylic acid.

4. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is a dicarboxylic acid.

5. The controlled release oral solid formulation of claim 4, wherein the dicarboxylic acid is tartaric acid.

6. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa.

7. The controlled release oral solid formulation of claim 1, wherein the formulation is a tablet or a caplet.

8. The controlled release oral solid formulation of claim 7, wherein the tablet or caplet is multi-layered.

9. The controlled release oral solid formulation of claim 7, wherein the tablet or caplet is a matrix tablet or caplet.

10. The controlled release oral solid formulation of claim 1, wherein the formulation is a multiparticulate formulation.

11. The controlled release oral solid formulation of claim 10, wherein the multiparticulates are encapsulated.

12. The controlled release oral solid formulation of claim 10, wherein the multiparticulates are pressed into a tablet.

13. The controlled release oral solid formulation of claim 1, wherein the formulation reduces intrasubject variability in levodopa absorption.

14. The controlled release oral solid formulation of claim 13, wherein the intrasubject variability; calculated as the standard deviation of the levodopa concentration divided by the mean levodopa concentration determined over the range of 0.5 hours after administration to six hours after administration for a single dose of said formulation to an individual subject, and averaged over at least 12 subjects; is less than or equal to 0.40.

15. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa, and wherein the carbidopa and levodopa are present in the formulation in a ratio of about 1:1 to about 1:10.

16. The controlled release oral solid formulation of claim 15, wherein the ratio of carbidopa to levodopa is about 1:4.

17. The controlled release oral solid formulation of claim 4, having a ratio of moles of dicarboxylic acid to levodopa of less than 4:1.

18. The controlled release oral solid formulation of claim 4, having a ratio of moles of dicarboxylic acid to levodopa of greater than 1:4 and less than 3:2.

19. The controlled release oral solid formulation of claim 4, having a ratio of moles of dicarboxylic acid to levodopa of greater than 1:2 and less than 4:3.

20. The controlled release oral solid formulation of claim 4, having a ratio of moles of dicarboxylic acid to levodopa of greater than 2:3 and less than 5:4.

21. The controlled release oral solid formulation of claim 4, having a ratio of moles of dicarboxylic acid to levodopa of greater than 1:1 and less than 4:3.

22. The controlled release oral solid formulation of claim 1, comprising from about 25 mg to about 2000 mg levodopa.

23. The controlled release oral solid formulation of claim 22 comprising 50 mg to 600 mg of levodopa.

24. The controlled release oral solid formulation of claim 6, comprising from about 10 mg to about 300 mg levodopa.

25. The controlled release oral solid formulation of claim 24 comprising 10 mg to 80 mg levodopa.

26. The controlled release oral solid formulation of claim 4, wherein the dicarboxylic acid is physically separated from the levodopa and the decarboxylase inhibitor.

27. The controlled release oral solid formulation of levodopa of claim 1 having a levodopa plasma or serum concentration profile comprising: a. a time of administration, b. a first concentration, and c. a second concentration, wherein, said first concentration is equal to the maximum concentration of said profile; said second concentration is the minimum concentration occurring at a time later than said first concentration and earlier than or equal to about six hours following said time of administration; and wherein said second concentration is greater than or equal to about fifty percent of said first concentration.

28. The formulation of claim 27, wherein said concentration profile is the median plasma or serum concentration profile.

29. The formulation of claim 27, wherein said concentration profile is the mean plasma or serum concentration profile.

30. The formulation of claim 27, wherein said concentration profile further comprises a third concentration, wherein said third concentration is greater than or equal to fifty percent of said first concentration and said third concentration occurs at a time earlier than said first concentration and within about ninety minutes of said time of administration.

31. The formulation of claim 30, wherein said third concentration is greater than or equal to sixty percent of said first concentration and said second concentration is greater than or equal to sixty percent of said first concentration.

32. The formulation of claim 27, wherein said second concentration is the minimum concentration occurring between one hour after said time of administration and said second time.

33. The formulation of claim 27, having a ratio of mean AUC in said profile, where said AUC is measured in units of ng h/mL, to the mass of levodopa in the formulation, where said mass is measured in mg, is between 11:1 and 25:1.

34. The formulation of claim 33, wherein said ratio is between 14:1 and 19:1.

35. The formulation of claim 27, having a mean AUC in said profile of between 4330 and 8000 ng h/mL for a 380 mg dose of levodopa.

36. The formulation of claim 35, wherein said mean AUC in said profile is between 5000 and 7000 ng h/mL for a 380 mg dose of levodopa.

37. The formulation of claim 27, having a ratio of said first concentration, where said concentration is measured in units of ng/mL, to the mass of levodopa in the formulation, where said mass is measured in mg, of between 3:1 and 5:1.

38. The formulation of claim 37, wherein said ratio is between 5:2 and 7:2.

39. The formulation of claim 37, wherein said ratio is greater than or equal to about 3:1.

40. The formulation of claim 27, wherein said first concentration is between 825 and 1505 ng/mL for a 380 mg dose of levodopa.

41. The formulation of claim 27, having a ratio of mean AUC in said profile, where said AUC is measured in units of ng h/mL, to said first concentration, where said concentration is measured in units of ng/mL, of between 9:2 and 6:1.

42. The controlled release oral solid formulation of levodopa of claim 1 having a median levodopa plasma or serum concentration profile comprising: a. a time of administration; b. a first concentration at a first time, that occurs within one hour of said time of administration; c. a second concentration at a second time, that occurs after said first time; d. a third concentration at a third time, that occurs at least four hours after said second time; wherein said second concentration is equal to the maximum concentration of said profile; said first concentration is equal to about fifty percent of said second concentration; said third concentration is equal to about fifty percent of said second concentration.

43. The controlled release oral solid formulation of levodopa of claim 1 having a median levodopa plasma or serum concentration profile comprising: a. a first concentration at a first time; b. a second concentration at a second time, that occurs within about one hour after said first time; c. a third concentration at a third time, that occurs at least four hours after said second time; and d. a maximum concentration, wherein said second concentration is equal to the maximum concentration of said profile; said first concentration is equal to fifty percent of said second concentration; said third concentration is equal to fifty percent of said second concentration.

44. A method of reducing motor fluctuations in a patient suffering from Parkinson's disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma concentration of levodopa effective to reduce motor fluctuations in the patient.

45. A method of reducing off time in a patient suffering from Parkinson's disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to reduce off time in the patient.

46. A method of increasing on time in a patient suffering from Parkinson's disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma concentration of levodopa effective to increase on time in the patient.

47. A method of reducing time to `on` in a patient suffering from Parkinson's disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma concentration of levodopa effective to reduce the time to on in the patient.

48. A method of enhancing dopamine levels in a subject suffering from a disease associated with reduced or impaired dopamine levels comprising; administering to a subject an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to enhance dopamine levels in the subject suffering from a disease associated with reduced or impaired dopamine levels.

49. The method of claim 48, wherein the disease is Alzheimer's disease, dystonia, schizophrenia or Parkinson's disease.

50. The method of claim 49, wherein the disease is Parkinson's disease.

51. A method of providing a therapeutically effective and stable median blood plasma level of levodopa in a subject comprising administering to the subject a therapeutically effective amount of any of the formulations of claim 1.

52. The method of claim 51, wherein the blood plasma level does not fluctuate more than 40% between 0.5 hours after administration and six hours after administration.

53. The method of claim 48 wherein the disease is secondary Parkinsonism.

54. The method of claim 48 wherein the disease is a condition resulting from brain injury.

55. The method of claim 54 wherein the brain injury is caused by carbon monoxide intoxication.

56. The method of claim 54 wherein the brain injury is caused by manganese intoxication.
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