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Claims for Patent: 8,377,474

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Claims for Patent: 8,377,474

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 (Hillsborough, CA)
Assignee: Impax Laboratories, Inc. (Hayward, CA)
Application Number:12/599,668
Patent Claims: 1. A controlled release oral solid formulation of levodopa comprising: a. a 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, and c. an immediate release component comprising levodopa and a decarboxylase inhibitor, wherein the carboxylic acid component of (b) is a distinct component and is coated with an enteric polymer; and wherein the controlled release component (a), the immediate release component (c) and the carboxylic acid component (b) comprise beads or granules.

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, ascorbic 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 or a dicarboxylic acid.

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

5. The controlled release oral solid formulation of claim 4, wherein the carbidopa and levodopa are present in the formulation in a ratio of about 1:1 to about 1:10.

6. The controlled release oral solid formulation of claim 5, wherein the ratio of carbidopa to levodopa is about 1:4.

7. A multiparticulate, controlled release oral solid formulation of levodopa comprising: a. a controlled release component comprising levodopa, carbidopa and one or more rate controlling excipients; b. an immediate release component comprising levodopa and carbidopa, and c. a carboxylic acid component comprising a carboxylic acid that is not levodopa or carbidopa and one or more rate controlling excipients, wherein the carboxylic acid component of (c) is a distinct component and is coated with an enteric polymer and wherein the controlled release component (a), the immediate release component (b) and the carboxylic acid component (c) comprise beads or granules.

8. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the carboxylic acid component comprises a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof.

9. The multiparticulate, controlled release oral solid formulation of claim 7, having a ratio of moles of carboxylic acid to levodopa of greater than 1:4.

10. The multiparticulate, controlled release oral solid formulation of claim 7, having a ratio of moles of carboxylic acid to levodopa of greater than 1:4 and less than 3:2.

11. The multiparticulate, controlled release oral solid formulation of claim 7, comprising from about 25 mg to about 1000 mg levodopa.

12. The multiparticulate, controlled release oral solid formulation of claim 11 comprising about 50 to about 600 mg of levodopa.

13. The controlled release oral solid formulation of levodopa of claim 1 or 7 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.

14. The formulation of claim 13, 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.

15. The controlled release oral solid formulation of levodopa of claim 1 or 7 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.

16. A controlled release oral solid formulation of claim 1 or 7 having a levodopa plasma or serum concentration profile substantially the same as levodopa formulation IPX066 in FIG. 1 for a 380 mg dose of levodopa, or having a levodopa plasma or serum concentration profile substantially proportional to said formulation in FIG. 1 for a dose other than 380 mg.

17. A controlled release oral solid formulation of claim 1 or 7 having a levodopa plasma or serum concentration profile such that the ratio of the maximum concentration of said profile to the concentration at any time between one hour and seven hours after administration of said formulation is less than or equal to 4:1.

18. The controlled release oral solid formulation of levodopa of claim 1 or 7 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.

19. A stable, controlled release oral solid formulation of levodopa of claim 1 comprising levodopa, a decarboxylase inhibitor and a dicarboxylic acid wherein no more than 1% by weight of the degradation product of levodopa is present after being stored for 3 months at 40 degrees Centigrade and 75% relative humidity.

20. 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.

21. 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.

22. 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 or serum concentration of levodopa effective to increase on time in the patient.

23. 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 or serum concentration of levodopa effective to reduce the time to on in the patient.

24. 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.

25. The method of claim 20, wherein the plasma or serum concentration of levodopa comprises: a controlled release oral solid formulation of levodopa 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.

26. 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.

27. The method of claim 26, wherein the blood plasma level does not fluctuate more than 40% between 0.5 hours after administration and six hours after administration.

28. The controlled release oral solid formulation of claim 1 or 2, wherein the carboxylic acid is tartaric acid.

29. The controlled release oral solid formulation of claim 1, wherein the controlled release component is separately coated with an enteric polymer.

30. The controlled release oral solid formulation of claim 1, wherein the component of (a), (b), or (c) is a bead or granule.

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

32. The controlled release oral solid formulation of claim 30, wherein the bead or granules has a size that passes through 12, 14, 16 or 18 mesh but is retained on 18 or 25 mesh screens.

33. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the immediate release and controlled release components have a size that pass through 12, 14, 16 or 18 mesh but are retained on 18 or 25 mesh screens.

34. The controlled release oral solid formulation of claim 30, wherein the bead or granule has a size that passes through 18 mesh but is retained on 25 mesh screens.

35. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the immediate release and controlled release components have a size that pass through 18 mesh but are retained on 25 mesh screens.

36. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa and the amount of carbidopa is about 48.75 mg and the amount of levodopa is about 195 mg.

37. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa and the amount of carbidopa is about 61.25 mg and the amount of levodopa is about 245 mg.

38. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the amount of carbidopa is about 48.75 mg and the amount of levodopa is about 195 mg.

39. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the amount of carbidopa is about 61.25 mg and the amount of levodopa is about 245 mg.

40. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa and the amount of carbidopa is about 47.5 mg and the amount of levodopa is about 190 mg.

41. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the amount of carbidopa is about 47.5 mg and the amount of levodopa is about 190 mg.

42. The controlled release oral solid formulation of levodopa of claim 1, wherein the rate controlling excipient is an enteric polymer or a mixture of more than one type of enteric polymer.

43. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the rate controlling excipient is an enteric polymer or a mixture of more than one type of enteric polymer.

44. The controlled release oral solid formulation of levodopa of claim 1, wherein the controlled release component (a), the immediate release component (c) and the carboxylic acid component are distinct, separable beads or granules; and wherein the carboxylic acid component (b) comprises a carboxylic acid that is not in (a) and (c).

45. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the controlled release component (a), the immediate release component (b) and the carboxylic acid component are distinct, separable beads or granules; and wherein the carboxylic acid component (c) comprises a carboxylic acid that is not in (a) and (b).

46. The multiparticulate, controlled release oral solid formulation of levodopa of claim 7, wherein the carboxylic acid is a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof; and wherein a ratio of carbidopa to levodopa is about 1:4, and a ratio of moles of carboxylic acid to levodopa is greater than 1:4 and less than 3:2.

47. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof; and wherein the decarboxylase inhibitor is carbidopa and a ratio of carbidopa to levodopa is about 1:4, and a ratio of moles of carboxylic acid to levodopa is greater than 1:4 and less than 3:2.

48. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is physically separated from levodopa and the decarboxylase inhibitor.

49. The multiparticulate, controlled release oral solid formulation of claim 7, wherein the carboxylic acid is physically separated from levodopa and carbidopa.

50. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa and a ratio in weight of levodopa:carbidopa:carboxylic acid component is any of: a. 245.00 mg:61.25 mg:132.53 mg; b. 195.00 mg:48.75 mg:105.48 mg; c. 190.00 mg:47.50 mg:88.52 mg; d. 180.00 mg:45.00 mg:82.20 mg; e. 180.00 mg:45.00 mg:54.80 mg; f. 120.00 mg:30.00 mg:103.20 mg; or g. 150.00 mg:37.50 mg:134.50 mg; with each value capable of varying by .+-.10%.

51. The multiparticulate, controlled release oral solid formulation of claim 7, wherein a ratio in weight of levodopa:carbidopa:carboxylic acid component is any of: a. 245.00 mg:61.25 mg:132.53 mg; b. 195.00 mg:48.75 mg:105.48 mg; c. 190.00 mg:47.50 mg:88.52 mg; d. 180.00 mg:45.00 mg:82.20 mg; e. 180.00 mg:45.00 mg:54.80 mg; f. 120.00 mg:30.00 mg:103.20 mg; or g. 150.00 mg:37.50 mg:134.50 mg; with each value capable of varying by .+-.10%.

52. The controlled release oral solid formulation of claim 1, wherein a ratio of moles of carboxylic acid to levodopa is greater than 1:4.

53. The controlled release oral solid formulation of claim 1, wherein a ratio of moles of carboxylic acid to levodopa is less than 3:2.

54. The controlled release oral solid formulation of claim 1, wherein a ratio of moles of carboxylic acid to levodopa is greater than 1:4 and less than 3:2.

55. The multiparticulate, controlled release oral solid formulation of claim 7, wherein a ratio of moles of carboxylic acid to levodopa is greater than 1:4 and less than 3:2 and wherein the controlled release component and carboxylic acid component are separately coated with an enteric polymer.

56. The multiparticulate, controlled release oral solid formulation of claim 7 or 8, wherein the carboxylic acid is tartaric acid.

57. The controlled release oral solid formulation of levodopa of claim 1, wherein the levodopa and decarboxylase inhibitor of (a) and (c) are not in (b).

58. The multiparticulate, controlled release oral solid formulation of levodopa of claim 7, wherein the levodopa and carbidopa of (a) and (b) are not in (c).

59. A controlled release oral solid formulation of levodopa comprising: a. a controlled release component comprising levodopa and a decarboxylase inhibitor, wherein the component is coated with a rate controlling excipient, b. a carboxylic acid component coated with a rate controlling excipient, and c. an immediate release component comprising levodopa and a decarboxylase inhibitor, wherein the carboxylic acid component of (b) is a distinct component and wherein the carboxylic acid component (b) comprises a carboxylic acid that is not in (a) and (c).

60. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa and a ratio in weight of levodopa:carbidopa is any of: a. 245.00 mg:61.25 mg; b. 195.00 mg:48.75 mg; c. 190.00 mg:47.50 mg; d. 180.00 mg:45.00 mg; e. 180.00 mg:45.00 mg; f. 120.00 mg:30.00 mg; or g. 150.00 mg:37.50 mg; with each value capable of varying by .+-.10%.

61. The multiparticulate, controlled release oral solid formulation of claim 7, wherein a ratio in weight of levodopa:carbidopa is any of: a. 245.00 mg:61.25 mg; b. 195.00 mg:48.75 mg; c. 190.00 mg:47.50 mg; d. 180.00 mg:45.00 mg; e. 180.00 mg:45.00 mg; f. 120.00 mg:30.00 mg; or g. 150.00 mg:37.50 mg; with each value capable of varying by .+-.10%.

62. The controlled release oral solid formulation of claim 7, wherein the controlled release component is separately coated with an enteric polymer.

63. The controlled release oral solid formulation of claim 1, wherein the multiparticulate, controlled release oral solid formulation of levodopa is encapsulated in a capsule and the beads or granules therein may be removed from the capsule and sprinkled on food or liquid prior to administration.

64. The controlled release oral solid formulation of claim 7, wherein the multiparticulate, controlled release oral solid formulation of levodopa is encapsulated in a capsule and the beads or granules therein may be removed from the capsule and sprinkled on food or liquid prior to administration.

65. The controlled release oral solid formulation of claim 1, wherein the controlled release oral solid formulation of levodopa comprises two controlled release components that release carbidopa and levodopa at different rates.

66. The controlled release oral solid formulation of claim 1, wherein the controlled release component comprises a carbidopa bead.

67. The controlled release oral solid formulation of claim 1, wherein the controlled release component comprises a levodopa bead.

68. The controlled release oral solid formulation of claim 1, wherein the bead or granule is in a tablet or capsule.

69. The controlled release oral solid formulation of claim 7, wherein the controlled release oral solid formulation of levodopa comprises two controlled release components that release carbidopa and levodopa at different rates.

70. The controlled release oral solid formulation of claim 7, wherein the controlled release component comprises a carbidopa bead.

71. The controlled release oral solid formulation of claim 7, wherein the controlled release component comprises a levodopa bead.

72. The controlled release oral solid formulation of claim 7, wherein the bead or granule is in a tablet or capsule.

73. The controlled release oral solid formulation of claim 1, wherein a single dose of the controlled release oral solid formulation administered to a human provides a levodopa plasma concentration profile comprising: a. a time of administration; b. a first peak concentration at a first time that occurs less than or equal to about two hours from said time of administration; c. a second peak concentration at a second time that occurs between about 4 and about 7 hours after said time of administration.

74. The controlled release oral solid formulation of claim 73, wherein the minimum concentration between the first time and the second time is greater than or equal to 50% of the first peak concentration and greater than or equal to 50% of the second peak concentration.

75. The controlled release oral solid formulation of claim 7, wherein a single dose of the controlled release oral solid formulation administered to a human provides a levodopa plasma concentration profile comprising: a. a time of administration; b. a first peak concentration at a first time that occurs less than or equal to about two hours from said time of administration; c. a second peak concentration at a second time that occurs between about 4 and about 7 hours after said time of administration.

76. The controlled release oral solid formulation of claim 75, wherein the minimum concentration between the first time and the second time is greater than or equal to 50% of the first peak concentration and greater than or equal to 50% of the second peak concentration.

77. The controlled release oral solid formulation of claim 31, wherein the tablet or caplet is a multi-layered or matrix tablet or caplet.

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

79. The controlled release oral solid formulation of claim 78, wherein the multiparticulate formulation is encapsulated or pressed into a tablet.

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

81. The controlled release oral solid formulation of claim 80, wherein the tablet or caplet is a multi-layered or matrix tablet or caplet.

82. The controlled release oral solid formulation of claim 7, wherein the multiparticulate formulation is encapsulated or pressed into a tablet.
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