COMPOSITIONS AND METHODS OF USING (R)-PRAMIPEXOLE

• US 20090042956A1
• Filed: 12/14/2007
• Published: 02/12/2009
• Est. Priority Date: 04/10/2006
• Status: Active Grant

• Current Assignee: Knopp Biosciences LLC
• Original Assignee: Knopp Neurosciences Inc. (Knopp Biosciences LLC)
• Inventors: Gribkoff, Valentin, Petzinger, Thomas JR., Bozik, Michael E.
• Granted Patent: US 8,518,926 B2
• Time in Patent Office: Days
• US Class Current: 514/367
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

Pharmaceutical compositions of (R)-pramipexole and methods and kits of using such compositions for the treatment of neurodegenerative diseases, or those related to mitochondrial dysfunction or increased oxidative stress are disclosed.

Claims

1. A single dose composition comprising at least about 25 milligrams of (R)-pramipexole;

less than about 1.5 milligrams of (S)-pramipexole and a pharmaceutically acceptable carrier.

2. The single dose composition of claim 1, wherein said composition comprises less than about 0.5 dopaminergic activity equivalents.

3. The single dose composition of claim 1, wherein said composition comprises less than about 0.05 dopaminergic activity equivalents.

4. The single dose composition of claim 1, wherein said composition comprises at least about 50 milligrams of (R)-pramipexole.

5. The single dose composition of claim 1, wherein said composition comprises at least about 75 milligrams of (R)-pramipexole.

6. The single dose composition of claim 1, wherein said composition comprises at least about 125 milligrams of (R)-pramipexole.

7. The single dose composition of claim 1, wherein said composition comprises at least about 150 milligrams of (R)-pramipexole.

8. The single dose composition of claim 1, wherein said composition comprises at least about 200 milligrams of (R)-pramipexole.

9. The single dose composition of claim 1, wherein said composition comprises at least about 300 milligrams of (R)-pramipexole.

10. The single dose composition of claim 1, wherein said composition comprises at least about 400 milligrams of (R)-pramipexole.

11. The single dose composition of claim 1, wherein said composition comprises at least about 500 milligrams of (R-pramipexole.

12. The single dose composition of claim 1, wherein said composition comprises at least about 600 milligrams of (R)-pramipexole.

13. The single dose composition of claim 1, wherein said composition comprises at least about 750 milligrams of (R)-pramipexole.

14. The single dose composition of claim 1 wherein said composition has from about 50 to about 5,000 neuroprotective activity equivalents;

and between about 0.0001 and 1.5 dopaminergic activity equivalents.

15. The single dose composition of claim 14, wherein said composition has from about 100 to about 3,000 neuroprotective activity equivalents;

and between about 0.0001 to about 0.5 dopaminergic activity equivalents.

16. The single dose composition of claim 14, wherein said composition has from about 175 to about 2,100 neuroprotective activity equivalents;

and from about 0.0001 to 1.5 dopaminergic activity equivalents.

17. The single dose composition of claim 14, wherein said composition has from about 200 to 1,500 neuroprotective activity equivalents;

and from about 0.0001 to about 0.125 dopaminergic activity equivalents.

18. The single dose composition of claim 14, wherein said composition has from about 50 to about 5,000 neuroprotective activity equivalents;

and less than about 0.125 dopaminergic activity equivalents.

19. The single dose composition of claim 14, wherein said composition has from about 50 to about 5,000 neuroprotective activity equivalents;

and less than about 0.05 dopaminergic activity equivalents.

20. The single dose composition of claim 14, wherein said composition has from about 100 to about 2,000 neuroprotective activity equivalents;

and less than about 0.05 dopaminergic activity equivalents.

21. The single dose composition of claim 14, wherein said composition has from about 200 to about 2,000 neuroprotective activity equivalents;

and less than about 0.05 dopaminergic activity equivalents.

22. Ale single dose composition of claim 14, wherein said composition has from about 300 to about 1,500 neuroprotective activity equivalents;

and less than about 0.05 dopaminergic activity equivalents.

23. The single dose composition of claim 14, wherein said composition has from about 500 to about 1,000 neuroprotective activity equivalents;

and less than about 0.05 dopaminergic activity equivalents.

24. The single dose composition of claim 1, wherein said composition is a solid oral dosage form.

25. The single dose composition of claim 14 wherein said composition is a tablet.

26. The single dose composition of claim 1, wherein said composition is a capsule.

27. A pharmaceutical composition comprising from about 25 milligrams to about 5,000 milligrams of (R)-pramipexole, said composition having therapeutic neuroprotective effects and a no adverse effect level attributable to either the (R)-pramipexole or any (S) pramipexole.

28. The pharmaceutical composition of claim 27, wherein said no adverse effect levels is a non observable adverse effect level in humans.

29. The pharmaceutical composition of claim 27 wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

30. The pharmaceutical composition of claim 27, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

31. The pharmaceutical composition of claim 27, wherein the chiral purity for the (R)-pramipexole is 100% within detectable limits.

32. The pharmaceutical composition of claim 27, comprising from about 50 milligrams to about 5,000 milligrams of (R)-pramipexole.

33. The pharmaceutical composition of claim 32, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

34. The pharmaceutical composition of claim 32, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

35. The pharmaceutical composition of claim 32, wherein the chiral purity for the (R)-pramipexole is 99.995% or greater.

36. The pharmaceutical composition of claim 27, comprising from about 100 milligrams to about 2,000 milligrams of (R)-pramipexole.

37. The pharmaceutical composition of claim 36, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

38. The pharmaceutical composition of claim 36, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

39. The pharmaceutical composition of claim 27, comprising from about 175 milligrams to about 3,000 milligrams of (R)-pramipexole.

40. The pharmaceutical composition of claim 39, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

41. The pharmaceutical composition of claim 39, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

42. The pharmaceutical composition of claim 27, comprising from about 300 milligrams to about 1,500 milligrams of (R)-pramipexole.

43. The pharmaceutical composition of claim 42, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

44. The pharmaceutical composition of claim 42, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

45. The pharmaceutical composition of claim 27, comprising from about 500 milligrams to about 1,000 milligrams of (R)-pramipexole.

46. The pharmaceutical composition of claim 45, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

47. The pharmaceutical composition of claim 45, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

48. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is a solid oral dosage form.

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

50. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is a capsule.

51. A starting daily dose of (R)-pramipexole, comprising at least about 25 milligrams of (R)-pramipexole in a pharmaceutical composition.

52. The starting daily dose of claim 51, comprising at least about 50 milligrams of (R)-pramipexole.

53. The starting daily dose of claim 51, comprising at least about 75 milligrams of (R)-pramipexole.

54. The starting daily dose of claim 51, comprising at least about 125 milligrams of (R)-pramipexole.

55. The starting daily dose of claim 51, comprising at least about 150 milligrams of (R)-pramipexole.

56. The starting daily dose of claim 51, comprising at least about 200 milligrams of (R)-pramipexole.

57. The starting daily dose of claim 51, comprising at least about 300 milligrams of (R)-pramipexole.

58. The starting daily dose of claim 51, comprising at least about 500 milligrams of (R)-pramipexole.

59. The starting daily dose of claim 51, comprising at least about 600 milligrams of (R)-pramipexole.

60. The starting daily dose of claim 51, comprising at least about 750 milligrams of (R)-pramipexole.

61. The starting daily dose of claim 51, comprising at least about 1000 milligrams of (R)-pramipexole.

62. A method of treating an acute disease in a patient in need thereof, comprising administering to said patient a daily dose amount of about 25 milligrams to about 5,000 milligrams of (R)-pramipexole in a pharmaceutical composition.

63. The method of claim 62, wherein said disorder is an acute neurodegenerative disease.

64. The method of claim 63, wherein said acute neurodegenerative disease is selected from stroke, neurotrauma, acute metabolic dysfunction, sequelae from cerebral seizure, status epilepticus, and acute encephalitis.

65. The method of claim 63, wherein said patient is a naï

ve patient.

66. The method of claim 62, wherein said daily dose amount is from about 50 milligrams to about 5,000 milligrams of (R)-pramipexole.

67. The method of claim 62, wherein said daily dose amount is from about 100 milligrams to about 3,000 milligrams of (R)-pramipexole.

68. The method of claim 62, wherein said daily dose amount is from about 200 milligrams to about 3,000 milligrams of (R)-pramipexole.

69. The method of claim 62, wherein said daily dose amount is from about 300 milligrams to about 1,500 milligrams of (R)-pramipexole.

70. The method of claim 62, wherein said daily dose amount is from about 500 milligrams to about 1,000 milligrams of (R)-pramipexole.

71. The method of claim 62, wherein the chiral purity for the (R)-pramipexole is 99.9%, or greater.

72. The method of claim 62, wherein the chiral purity for the (R)-pramipexole is 99.95%, or greater.

73. The method of claim 62, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

74. A method of treating a chronic disorder in a patient in need thereof comprising administering a daily dose of about 25 milligrams to about 5000 milligrams of (R)-pramipexole in a pharmaceutical composition.

75. The method of claim 74, wherein said chronic disorder is a chronic neurodegenerative disease.

76. The method of claim 74, wherein said patient is a naï

ve patient.

77. The method of claim 74, wherein said chronic neurodegenerative disease is selected from primary neurodegenerative disease, Huntington'"'"'s Chorea, metabolically induced neurological damage, senile dementia of Alzheimer'"'"'s type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich'"'"'s ataxia, multiple sclerosis, spinal muscular atrophy primary lateral sclerosis, seizure disorders, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, hepatic encephalopathy, and chronic encephalitis.

78. The method of claim 74, wherein said chronic neurodegenerative disease is selected from neurodegenerative movement disorder, ataxia, seizure disorder, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, and amyotrophic lateral sclerosis.

79. The method of claim 74, wherein said chronic neurodegenerative disease is amyotrophic lateral sclerosis.

80. The method of claim 74, wherein said daily dose amount is from about 50 milligrams to about 5,000 milligrams of (R)-pramipexole.

81. The method of claim 74, wherein said daily dose amount is from about 100 milligrams to about 3,000 milligrams of (R)-pramipexole.

82. The method of claim 74, wherein said daily dose amount is from about 200 milligrams to about 3,000 milligrams of (R)-pramipexole.

83. The method of claim 74, wherein said daily dose amount is from about 300 milligrams to about 1,500 milligrams of (R)-pramipexole.

84. The method of claim 74, wherein said daily dose amount is from about 500 milligrams to about 1000 milligrams of (R)-pramipexole.

85. The method of claim 74, wherein the chiral purity for the (R)-pramipexole is 99.9% or greater.

86. The method of claim 74, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

87. The method of claim 74, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

88. A tablet comprising from about 50 milligrams to about 500 milligrams of (R)-pramipexole and a pharmaceutically acceptable carrier.

89. The tablet of claim 88, wherein said (R)-pramipexole is about 50 milligrams.

90. The tablet of claim 88, wherein said tablet has greater than about 25 neuroprotective activity equivalents and less than about 0.125 dopaminergic activity equivalents.

91. The tablet of claim 88, wherein said tablet has less than about 0.05 dopaminergic activity equivalents.

92. The tablet of 88, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, or combination thereof.

93. A tablet comprising from about 100 milligrams to about 500 milligrams of (R)-pramipexole and a pharmaceutically acceptable carrier.

94. The tablet of claim 93, wherein said (R)-pramipexole is about 100 milligrams.

95. The tablet of claim 93, wherein the tablet has greater than about 25 neuroprotective activity equivalents and less than about 0.125 dopaminergic activity equivalents.

96. The tablet of claim 93, wherein said tablet has less than about 0.05 dopaminergic activity equivalents.

97. The tablet of 93, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, or combination thereof.

98. A tablet comprising from about 150 milligrams to about 500 milligrams of (R)-pramipexole and a pharmaceutically acceptable carrier.

99. The tablet of claim 98, wherein said (R)-pramipexole is about 150 milligrams.

100. The tablet of claim 98, wherein said tablet has greater than about 25 neuroprotective activity equivalents and less than about 0.125 dopaminergic activity equivalents.

101. The tablet of claim 98, wherein said tablet has less than about 0.05 dopaminergic activity equivalents.

102. The tablet of 98, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, or combination thereof.

103. A tablet comprising greater than about 168 milligrams and less than about 2000 milligrams of (R)-pramipexole and a pharmaceutically acceptable carrier.

104. The tablet of claim 103, wherein said (R)-pramipexole is about 200 milligrams.

105. The tablet of claim 103, wherein said tablet has greater than about 25 neuroprotective activity equivalents and less than about 0.125 dopaminergic activity equivalents.

106. The tablet of claim 103, wherein said tablet has less than about 0.05 dopaminergic activity equivalents.

107. The tablet of 103, wherein said pharmaceutically acceptable carrier comprises microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, or combination thereof.

108. A kit comprising:

one or more pharmaceutical compositions comprising (R)-pramipexole; and

instructions for administering or prescribing said one or more pharmaceutical compositions comprising a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of at least about 50 milligrams to about 5,000 milligrams of (R)-pramipexole to a patient.

109. The kit of claim 108, wherein the chiral purity for the (R)-pramipexole is 99.9% or greater.

110. The kit of claim 108, wherein the chiral purity for the (R)-pramipexole is 99.95% or greater.

111. The kit of claim 108, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.

112. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 milligrams to about 3,000 milligrams of (R)-pramipexole to a patient.

113. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 milligrams to about 3,000 milligrams of (R)-pramipexole to a patient.

114. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of from about 300 to about 1,500 milligrams of (R)-pramipexole to a patient.

115. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 to about 1,000 milligrams of (R)-pramipexole to a patient.

116. The kit of claim 108, wherein said direction further results in administration of less than about 1.5 dopaminergic activity equivalents to said patient.

117. The kit of claim 108, wherein said direction further results in administration of less than about 0.5 dopaminergic activity equivalents to said patient.

118. The kit of claim 108, wherein said direction further results in administration of less than about 0.05 dopaminergic activity equivalents to said patient.

119. The kit of claim 108, wherein:

said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 milligrams to 3,000 milligrams of (R)-pramipexole to a patient; and

the chiral purity for the (R)-pramipexole is 99.95% or greater.

120. The kit of claim 108, wherein:

said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 milligrams to about 3,000 milligrams of (R)-pramipexole to a patient; and

the chiral purity for the (R)-pramipexole is 99.95% or greater.

121. The kit of claim 108, wherein:

said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 300 milligrams to about 1.500 milligrams of (R)-pramipexole to a patient; and

the chiral purity for the (R)-pramipexole is 99.95% or greater.

122. The kit of claim 108, wherein:

said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 milligrams to about 1,000 milligrams of (R)-pramipexole to a patient; and

the chiral purity for the (R)-pramipexole is 99.95% or greater.

123. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 100 milligrams to 3,000 milligrams of (R)-pramipexole and less than about 0.05 milligrams of (S)-pramipexole to a patient.

124. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 200 milligrams to 3,000 milligrams of (R)-pramipexole and less than about 0.05 milligrams of (S)-pramipexole to a patient.

125. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 300 milligrams to 1,500 milligrams of (R)-pramipexole and less than about 0.05 milligrams of (S)-pramipexole to a patient.

126. The kit of claim 108, wherein said instructions comprise a direction to administer or prescribe said one or more pharmaceutical compositions in an amount sufficient to result in administration of a starting daily dose of from about 500 milligrams to 1,000 of (R)-pramipexole and less than about 0.05 milligrams of (S)-pramipexole to a patient.

127. A method of treating a neurodegenerative disease in a patient in need thereof comprising administering to said patient a starting dose of about 25 milligrams to about 5,000 milligrams of (R)-pramipexole in a pharmaceutical composition.

128. The method of claim 127, wherein said neurodegenerative disease is selected from stroke, neurotrauma, acute metabolic dysfunction, sequelae from cerebral seizure, status epilepticus, acute encephalitis, primary neurodegenerative disease, Huntington'"'"'s Chorea, metabolically induced neurological damage, senile dementia of Alzheimer'"'"'s type, age associated cognitive dysfunction, vascular dementia, multi-infarct dementia, Lewy body dementia, neurodegenerative dementia, neurodegenerative movement disorder, ataxia, Friedreich'"'"'s ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorder or disease, inflammatory demyelinating disorder, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, hepatic encephalopathy, and chronic encephalitis.

129. The method of claim 127, wherein said neurodegenerative disease is amyotrophic lateral sclerosis.

130. The method of claim 127, wherein said patient is a naï

ve patient.

131. The method of claim 127, wherein said starting dose is from about 50 milligrams to about 5,000 milligrams of (R)-pramipexole.

132. The method of claim 127, wherein said starting dose is from about 100 milligrams to about 3,000 milligrams of (R)-pramipexole.

133. The method of claim 127, wherein said starting dose is from about 200 milligrams to about 3,000 milligrams of (R)-pramipexole.

134. The method of claim 127, wherein said starting dose is from about 300 milligrams to about 1,500 milligrams of (R)-pramipexole.

135. The method of claim 127, wherein said starting dose is from about 500 milligrams to about 1,000 milligrams of (R)-pramipexole.

136. The method of claim 127, wherein the chiral purity for the (R)-pramipexole is 99.9%, or greater.

137. The method of claim 127, wherein the chiral purity for the (R)-pramipexole is 99.95%, or greater.

138. The method of claim 127, wherein the chiral purity for the (R)-pramipexole is 99.99% or greater.