Method and Composition for Administering an NMDA Receptor Antagonist to a Subject

• US 20100047342A1
• Filed: 07/30/2009
• Published: 02/25/2010
• Est. Priority Date: 11/23/2004
• Status: Active Grant

• Current Assignee: Adamas Pharma, LLC (Supernus Pharmaceuticals, Inc.)
• Original Assignee: Adamas Pharmaceuticals, Inc. (Supernus Pharmaceuticals, Inc.)
• Inventors: Went, Gregory T., Fultz, Timothy J., Burkoth, Timothy S., Porter, Seth, Meyerson, Laurence R.
• Granted Patent: US 8,168,209 B2
• Time in Patent Office: Days
• US Class Current: 424/462
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence

Abstract

The invention provides methods and compositions for administering an NMDA receptor antagonist (e.g., memantine) to a subject.

Claims

1-58. -58. (canceled)

59. A solid pharmaceutical composition in a unit dosage form for oral administration comprising a therapeutically effective amount of an extended release formulation of memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine.

60. The composition of claim 59 wherein the concentration profile is further characterized by a memantine Tmax of at least 19 hours.

61. The composition of claim 59 or 60 wherein the concentration profile is further characterized by a maximum memantine plasma concentration to mean memantine plasma concentration ratio (Cmax/Cmean) of about 2.5 to 2 at 1 hour to at least 6 hours after administration.

62. The composition of claim 61 wherein the Cmax/Cmean is about 2.5 to 2 at 1 hour to at least 9 hours after administration.

63. The composition of claim 59, wherein at least 98% of the memantine is in an extended release form.

64. The composition of claim 59, wherein the unit dosage form is a capsule and wherein the memantine is formulated as pellets.

65. The composition of claim 64, wherein the pellets comprise an extended release coating.

66. The composition of claim 65, wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

67. The composition of claim 66, wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone.

68. The composition of claim 59 or 64 comprising 25 mg memantine.

69. The composition of claim 59 or 64 comprising 12.5 mg memantine.

70. The composition of claim 59 having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50 to 90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in 500 ml water.

71. The composition of claim 70 in which the dissolution profile is at least 70% in 10 hours and at least 90% in 12 hours.

72. The composition of claim 70 or 71 having the in vitro dissolution profile in an acidic dissolution medium.

73. A method of treating a subject in need of memantine therapy comprising administering to the subject the composition of claim 59.

74. A solid pharmaceutical composition in a unit dosage form for oral administration comprising a therapeutically effective amount of an extended release formulation of memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile characterized by a maximum memantine plasma concentration to mean memantine plasma concentration ratio (Cmax/Cmean) of about 2.5 to 2 at 1 hour to at least 6 hours after administration.

75. The composition of claim 74 wherein the Cmax/Cmean is about 2.5 to 2 at 1 hour to at least 9 hours after administration.

76. The composition of claim 74 wherein the concentration profile is further characterized by a memantine Tmax of at least 19 hours.

77. The composition of claim 74 wherein the concentration profile is further characterized by a dC/dT that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine.

78. The composition of claim 74, wherein at least 98% of the memantine is in an extended release form.

79. The composition of claim 74, wherein the unit dosage form is a capsule and wherein the memantine is formulated as pellets.

80. The composition of claim 78, wherein the pellets comprise an extended release coating.

81. The composition of claim 80, wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

82. The composition of claim 81, wherein the insoluble matrix polymer comprises ethyl cellulose and the water soluble material comprises polyvinylpyrrolidone.

83. The composition of claim 74 or 79 comprising 25 mg memantine.

84. The composition of claim 74 or 79 comprising 12.5 mg memantine.

85. The composition of claim 74 having a memantine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50 to 90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in 500 ml water.

86. The composition of claim 85 in which the dissolution profile is at least 70% in 10 hours and at least 90% in 12 hours.

87. The composition of claim 85 or 86 having the in vitro dissolution profile in an acidic dissolution medium.

88. A method of treating a subject in need of memantine therapy comprising administering to the subject the composition of claim 74.

92. The composition of claim 84 wherein all the amantadine is in an extended release form.

89. A solid pharmaceutical composition in a unit dosage form for oral administration comprising amantadine or pharmaceutically acceptable salt thereof, wherein at least 98% of the amantadine is in an extended release form, and wherein the composition has an amantadine in vitro dissolution profile ranging between 0.1-20% in one hour, 5-30% in two hours, 40-80% in six hours, and 50 to 90% in 10 hours, wherein the dissolution profile is determined using a USP type 2 (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C., in 500 ml water.

90. The composition of claim 89 in which the dissolution profile is at least 70% in 10 hours.

91. The composition of claim 90 in which the dissolution profile is at least 90% in 12 hours.

93. The composition of claim 89 wherein administration of a dose of the composition to a human subject provides a plasma amantadine concentration profile characterized by an amantadine Tmax of at least 7 hours.

94. The composition of claim 89 wherein the Tmax is at least 11 hours.

95. The composition of claim 89 wherein the dosage form is a capsule.

96. The composition of claim 89 wherein the dosage form is a capsule comprising pellets, wherein each pellet comprises a core comprising the amantadine and an extended release coating.

97. The composition of claim 96 wherein the extended release coating comprises an insoluble matrix polymer and a water soluble material.

98. The composition of claim 97 wherein the extended release coating comprises ethyl cellulose and polyvinylpyrrolidone.

99. The composition of claim 89 wherein administration of the composition to a human subject provides a change in amantadine concentration as a function of time (dC/dT) that is less than 75% that of an immediate release dosage form comprising the same amount of amantadine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of amantadine.

100. A method of treating a subject in need of amantadine therapy comprising administering to the subject the composition of claim 89.

101. The method of claim 100 wherein the amantadine is administered at a daily dose of 200 mg/day to 500 mg/day.

102. The method of claim 101 wherein the dose is administered to the subject once daily.

103. The method of claim 101 wherein the dose is greater than 300 mg/day.

104. The method of claim 101 wherein the dose is administered without prior dose escalation.

105. The method of claim 100 wherein the subject has Parkinson'"'"'s disease.

107. The composition of claim 91 in which the rate of release of the rimantadine is less than 60% of the rate for an IR formulation comprising rimantadine over the first 1 hour.

106. A solid pharmaceutical composition in a unit dosage form for oral administration comprising rimantadine or pharmaceutically acceptable salt thereof in an extended release form, wherein the composition has a rimantadine in vitro dissolution profile in water in which less than 25% of the rimantadine is released in 30 minutes as measured using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37±

0.5°

C.

108. A method of treating a subject in need of rimantadine therapy comprising administering to the subject the composition of claim 106.