Opioid antagonist compositions and dosage forms

• US 20030191147A1
• Filed: 04/09/2002
• Published: 10/09/2003
• Est. Priority Date: 04/09/2002
• Status: Abandoned Application

• Current Assignee: Barry Sherman, James W. Mcginity, Mary Remien, Remi Barbier
• Original Assignee: Barry Sherman, James W. Mcginity, Mary Remien, Remi Barbier
• Inventors: Barbier, Remi, McGinity, James W., Sherman, Barry, Remien, Mary
• Application Number:
  US10/119,615
• Publication Number:
  US 20030191147A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• 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 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

The present invention is directed to novel dosage forms, pharmaceutical compositions, kits, and methods of administration of an opioid antagonist in an amount of at least about 0.0001 mg to about or less than about 1.0 mg, including from about 0.0001 mg to less than about 0.5 mg. Solid oral dosage forms are disclosed consisting essentially of an opioid antagonist or alternatively comprising an opioid antagonist and another active ingredient, such as an opioid agonist. Immediate release oral dosage forms are disclosed that release all or a substantial percentage of opioid antagonist, and another active ingredient when present, in a desired time. Concurrent release dosage forms are disclosed that provide concurrent release of an opioid antagonist and another active ingredient.

Claims

1. A dosage form comprising an opioid antagonist in an amount from about 0.0001 mg to about 1 mg or less than 1 mg.

2. The dosage form of claim 1 wherein the amount of antagonist is about 1 mg.

3. The dosage form of claim 1 wherein the amount of antagonist is less than 1 mg.

4. The dosage form of claim 1 wherein the amount of antagonist is less than about 0.5 mg.

5. The dosage form according to claims 1 or 4 wherein the amount of antagonist is about 0.1 mg.

6. The dosage form according to claims 1 or 4 wherein the amount of antagonist is less than 0.1 mg.

7. The dosage form according to claims 1 or 4 wherein the amount of antagonist is more than 0.1 mg.

8. The dosage form according to claims 1 or 4 wherein the amount of antagonist is about 0.01 mg.

9. The dosage form according to claims 1 or 4 wherein the amount of antagonist is less than 0.01 mg.

10. The dosage form according to claims 1 or 4 wherein the amount of antagonist is more than 0.01 mg.

11. The dosage form according to claims 1 or 4 wherein the amount of antagonist is about 0.001 mg.

12. The dosage form according to claims 1 or 4 wherein the amount of antagonist is less than 0.001 mg.

13. The dosage form according to claims 1 or 4 wherein the amount of antagonist is more than 0.001 mg.

14. The dosage form according to claims 1 or 4 wherein the amount of antagonist is about 0.0001 mg.

15. The dosage form according to claims 1 or 4 wherein the amount of antagonist is more than 0.0001 mg.

16. The dosage form according to claims 1 or 4 wherein the antagonist is present as the pharmaceutically acceptable salt.

17. The dosage form according to claims 1 or 4 wherein the antagonist is naltrexone, nalmefene or naloxone.

18. The dosage form according to claims 1 or 4 further comprising an opioid agonist.

19. The dosage form of claim 18 wherein the agonist is in an analgesic or subanalgesic amount.

20. The dosage form of claim 18 wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol.

21. The dosage form of claim 18 wherein the agonist is morphine, hydrocodone, oxycodone, or tramadol.

22. The dosage form according to claims 1 or 4 wherein the antagonist is formulated as a capsule, tablet or pill.

44. A method of administering a therapeutic dose of an opioid antagonist to a human subject comprising administering the dosage form according to claims 1 or 4.

45. A method of administering a therapeutic dose of an opioid antagonist to a human subject comprising administering the dosage form of claims 18.

46. A pharmaceutical kit comprising a dosage form according to claims 1 or 4.

47. A pharmaceutical kit comprising a dosage form of claim 18 and a container.

98. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 22.

102. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 46.

105. A pharmaceutical kit comprising a dosage form according to claims 1, 4 or 46.

106. The kit of claim 105, further comprising a dosage form of an opioid agonist.

107. The kit of claim 106, wherein the agonist dosage form and the antagonist dosage form are separate dosage forms.

108. The solid oral dosage form according to claims 1 or 4, provided in an immediate release formulation.

109. The solid oral dosage form according to claim 22, provided in an immediate release formulation.

23. A pharmaceutical composition comprising an opioid antagonist in an amount from about 0.0001 mg to about 1 mg or less than 1 mg and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23 wherein the amount of antagonist is about 1 mg.

25. The pharmaceutical composition of claim 23 wherein the amount of antagonist is less than 1 mg.

26. The pharmaceutical composition of claim 23 wherein the amount of antagonist is about 0.1 mg.

27. The pharmaceutical composition of claim 23 wherein the amount of antagonist is less than 0.1 mg.

28. The pharmaceutical composition of claim 23 wherein the amount of antagonist is more than 0.1 mg.

29. The pharmaceutical composition of claim 23 wherein the amount of antagonist is about 0.01 mg.

30. The pharmaceutical composition of claim 23 wherein the amount of antagonist is less than 0.01 mg.

31. The pharmaceutical composition of claim 23 wherein the amount of antagonist is more than 0.01 mg.

32. The pharmaceutical composition of claim 23 wherein the amount of antagonist is about 0.001 mg.

33. The pharmaceutical composition of claim 23 wherein the amount of antagonist is less than 0.001 mg.

34. The pharmaceutical composition of claim 23 wherein the amount of antagonist is more than 0.001 mg.

35. The pharmaceutical composition of claim 23 wherein the amount of antagonist is about 0.0001 mg.

36. The pharmaceutical composition of claim 23 wherein the amount of antagonist is more than 0.0001 mg.

37. The pharmaceutical composition of claim 23 wherein the antagonist is present as the pharmaceutically acceptable salt.

38. The pharmaceutical composition of claim 23 wherein the antagonist is naltrexone, nalmefene or naloxone.

39. The pharmaceutical composition of claim 23 further comprising an opioid agonist.

40. The pharmaceutical composition of claim 39 wherein the agonist is in an analgesic or subanalgesic amount.

41. The dosage form of claim 39 wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol.

42. The pharmaceutical composition of claim 39 wherein the agonist is morphine, hydrocodone, oxycodone or tramadol.

43. The pharmaceutical composition according to claims 23 or 39 wherein the antagonist is formulated as a capsule, tablet or pill.

99. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 23.

100. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 42.

101. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 43.

110. The solid oral dosage form according to claim 43, provided in an immediate release formulation.

48. A solid oral dosage form consisting essentially of an opioid antagonist in an amount from about 0.0001 mg to less than 0.5 mg.

49. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than about 0.4 mg.

50. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than about 0.3 mg.

51. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than about 0.2 mg.

52. The solid oral dosage form of claim 48 wherein the amount of antagonist is about 0.1 mg.

53. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than 0.1 mg.

54. The solid oral dosage form of claim 48 wherein the amount of antagonist is more than 0.1 mg.

55. The solid oral dosage form of claim 48 wherein the amount of antagonist is about 0.01 mg.

56. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than 0.01 mg.

57. The solid oral dosage form of claim 48 wherein the amount of antagonist is more than 0.01 mg.

58. The solid oral dosage form of claim 48 wherein the amount of antagonist is about 0.001 mg.

59. The solid oral dosage form of claim 48 wherein the amount of antagonist is less than 0.001 mg.

60. The solid oral dosage form of claim 48 wherein the amount of antagonist is more than 0.001 mg.

61. The solid oral dosage form of claim 48 wherein the amount of antagonist is about 0.0001 mg.

62. The solid oral dosage form of claim 48 wherein the amount of antagonist is more than 0.0001 mg.

63. The solid oral dosage form of claim 48 wherein the antagonist is naltrexone or nalmefene.

103. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 62.

111. The solid oral dosage form according to claim 48, provided in an immediate release formulation.

64. A solid oral dosage form consisting essentially of naltrexone in an amount from about 0.0001 mg to less than about 0.5 mg.

65. The solid oral dosage form of claim 64 wherein the amount of naltrexone is less than an effective antagonistic amount.

112. The solid oral dosage form according to claim 64, provided in an immediate release formulation.

66. A solid oral dosage form consisting essentially of nalmefene in an amount from about 0.0001 mg to less than about 0.5 mg.

67. The solid oral dosage form of claim 66 wherein the amount of nalmefene is less than an effective antagonistic amount.

68. A solid oral dosage form comprising an opioid antagonist in an amount from about 0.0001 mg to less than about 0.5 mg and an opioid agonist in an amount from about 0.1 mg to about 300 mg.

69. The solid oral dosage form of claim 68 wherein the antagonist is present in less than an effective antagonistic amount.

70. The solid oral dosage form of claim 68 wherein the amount of antagonist is about 0.1 mg.

71. The solid oral dosage form of claim 68 wherein the amount of antagonist is less than 0.1 mg.

72. The solid oral dosage form of claim 68 wherein the amount of antagonist is more than 0.1 mg.

73. The solid oral dosage form of claim 68 wherein the amount of antagonist is about 0.01 mg.

74. The solid oral dosage form of claim 68 wherein the amount of antagonist is less than 0.01 mg.

75. The solid oral dosage form of claim 68 wherein the amount of antagonist is more than 0.01 mg.

76. The solid oral dosage form of claim 68 wherein the amount of antagonist is about 0.001 mg.

77. The solid oral dosage form of claim 68 wherein the amount of antagonist is less than 0.001 mg.

78. The solid oral dosage form of claim 68 wherein the amount of antagonist is more than 0.001 mg.

79. The solid oral dosage form of claim 68 wherein the amount of antagonist is about 0.0001 mg.

80. The solid oral dosage form of claim 68 wherein the amount of antagonist is more than 0.0001 mg.

81. The solid oral dosage form of claim 68 wherein the antagonist is present as a pharmaceutically acceptable salt.

82. The solid oral dosage form of claim 68 wherein the antagonist is naltrexone or nalmefene.

83. The solid oral dosage form of claim 68 comprising naltrexone as the antagonist.

84. The solid oral dosage form of claim 68 comprising nalmefene as the antagonist.

85. The solid oral dosage form of claim 68 wherein the agonist is present in a subanalgesic amount.

86. The dosage form of claim 68 wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol.

87. The solid oral dosage form of claim 68 wherein the agonist is morphine, hydrocodone, oxycodone or tramadol.

88. The solid oral dosage form of claim 68, wherein the antagonist is naltrexone and the agonist is morphine.

89. The solid oral dosage form of claim 68, wherein the antagonist is naltrexone and the agonist is oxycodone.

90. The solid oral dosage form of claim 68 wherein the antagonist is naltrexone and the agonist is hydrocodone.

91. The solid oral dosage form of claim 68, wherein the antagonist is naltrexone and the agonist is tramadol.

92. The solid oral dosage form of claim 68, wherein the antagonist is nalmefene and the agonist is morphine.

93. The solid oral dosage form of claim 68, wherein the antagonist is nalmefene and the agonist is oxycodone.

94. The solid oral dosage form of claim 68, wherein the antagonist is nalmefene and the agonist is tramadol.

95. The solid oral dosage from of claim 68 wherein the antagonist is nalmefene and the agonist is hydrocone.

96. The solid oral dosage form of claim 68, wherein the antagonist is formulated as a capsule, tablet or pill.

97. The solid oral dosage form of claim 68 additionally comprising another active pharmaceutical ingredient selected from the group of acetaminophen, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, COX-1 inhibitors and COX-2 inhibitors.

104. A method of administering a therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering the solid oral dosage form according to claim 68.

113. The solid oral dosage form according to claim 68, provided in an immediate release formulation.

114. An immediate release solid oral dosage form comprising an opioid antagonist present in an amount from about 0.0001 to less than about 0.5 mg;

at least one pharmaceutical excipient;

wherein greater than 90% of the opioid antagonist is released in less than about 45 minutes after exposure to an aqueous environment.

115. The immediate release solid oral dosage form of claim 114, wherein greater than 90% of the opioid antagonist is released in less than about 30 minutes after exposure to an aqueous environment.

116. The immediate release solid oral dosage form of claim 114, wherein greater than 90% of the opioid antagonist is released in less than about 20 minutes after exposure to an aqueous environment.

117. The solid oral dosage form of claim 114 wherein the dosage form comprises a pharmaceutical composition comprising a coated solid substrate, the solid substrate comprising:

an inert substrate;

a coat at least partially surrounding the inert substrate; and

the coat comprises the opioid antagonist and at least one pharmaceutical excipient, and optionally a binder and a plasticizer.

118. The solid oral dosage form of claim 117, wherein the coat comprises about 1-70% wt. of the coated solid substrate.

119. The dosage form of claim 118, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the coated solid substrate.

120. The solid oral dosage form of claim 118, wherein the dosage form is a capsule or tablet.

121. The solid oral dosage form of claim 114 wherein the solid dosage form comprises a pharmaceutical composition comprising a coated granulation, the coated granulation comprising:

granules comprising a mixture of two or more pharmaceutical excipients; and

a coat at least partially surrounding each of the granules; and

the coat comprises the pharmaceutical excipient and the opioid antagonist.

122. The solid oral dosage form of claim 121 wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the coated granulation.

123. The solid oral dosage form of claim 122 wherein the coated granulation comprises about 10-85% wt. of the solid pharmaceutical composition.

124. The solid oral dosage form of claim 123 wherein the dosage form is a capsule or tablet.

125. The solid oral dosage form of claim 114 wherein the solid dosage form comprises a spray-dried pharmaceutical composition comprising a mixture of the at least one pharmaceutical excipient and the opioid antagonist.

126. The dosage form of claim 125 wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the spray-dried pharmaceutical composition.

127. The solid oral dosage form of claim 126 wherein the spray-dried pharmaceutical composition comprises about 5-99% wt. of the dosage form.

128. The solid oral dosage form of claim 127, wherein the dosage form is a capsule or tablet.

129. The solid oral dosage form of claim 128 wherein the solid dosage form comprises a suspension-filled soft gelatin capsule comprising:

a soft gelatin capsule; and

a suspension within the capsule comprising a non-aqueous vehicle in liquid form and an opioid antagonist in solid form.

130. The dosage form of claim 128 wherein the suspension further comprises at least one pharmaceutical excipient.

131. An immediate release solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than 0.5 mg;

another active pharmaceutical ingredient;

at least one pharmaceutical excipient;

wherein the opioid antagonist and the other active ingredient are released in less than about 1.5 hours after exposure to an aqueous environment.

132. The solid oral dosage form of claim 131 wherein the other active pharmaceutical ingredient is an opioid agonist present in an amount from about 0.1 mg to about 300 mg.

136. The solid oral dosage form according to claims 131 or 133 wherein the dosage form is a capsule or tablet.

137. The solid oral dosage form according to claims 131 or 133 wherein greater than 90% of the opioid antagonist is released in less than about 45 minutes after exposure to an aqueous environment.

138. The solid oral dosage form according to claims 131 or 133 wherein greater than 90% of the other active pharmaceutical ingredient is released in less than about 45 minutes after exposure to an aqueous environment.

133. A concurrent release combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

another active pharmaceutical ingredient;

at least one pharmaceutical excipient;

wherein the opioid antagonist and the other active pharmaceutical ingredient are released concurrently.

134. The solid oral dosage form of claim 133, wherein greater than 90% of each of the opioid antagonist and the other active pharmaceutical ingredient are released in less than about 45 minutes after exposure to an aqueous environment.

135. The solid oral dosage form of claim 133 wherein the other active ingredient is an opioid agonist present in an amount from about 0.1 mg to about 300 mg.

139. The solid oral dosage form of claim 133 wherein a majority of the release of the opioid antagonist overlaps a majority of the release of the other active pharmaceutical ingredient.

140. The solid oral dosage form of claim 133 wherein about 90% of the opioid antagonist is released within a time period in which about 90% of the other active pharmaceutical ingredient is released.

141. The solid oral dosage form of claim 133, wherein the dosage form provides an antagonist dissolution profile and an other active pharmaceutical ingredient dissolution profile, and the dissolution profiles are substantially the same.

142. A combination solid oral dosage form comprising:

an opioid agonist;

an opioid antagonist;

at least one pharmaceutical excipient;

wherein the dosage form provides an agonist dissolution percentage and an antagonist dissolution percentage, as measured by the USP Paddle Method at 75 rpm in 500 ml of 0.1 HCl media at about 37°

C., and the agonist dissolution percentage and the antagonist dissolution percentage are substantially the same at any time from 5 minutes to 30 minutes.

143. The solid oral dosage form of claim 142 wherein the agonist dissolution percentage and the antagonist dissolution percentage are substantially the same at each of 5 minutes, 10 minutes, 15 minutes, 20 minutes and 30 minutes.

144. The solid oral dosage form of claim 142 wherein the agonist dissolution percentage and the antagonist dissolution percentage are the means of at least six measurements.

145. The solid oral dosage form of claim 144 wherein the difference between the agonist dissolution percentage and the antagonist dissolution percentage is about 10% or less.

146. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the dosage form comprises a pharmaceutical composition comprising a coated solid substrate, the coated solid substrate comprising;

a solid substrate comprising the opioid agonist and at least one pharmaceutical excipient; and

a coat at least partially surrounding the solid substrate, and the coat comprises the opioid antagonist and at least one pharmaceutical excipient.

147. The solid oral dosage form according to claim 146, wherein the solid substrate is a pellet, bead or granule.

148. A combination solid oral dosage form comprising:

a opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the dosage form comprises a pharmaceutical composition comprising a coated solid substrate, the coated solid substrate comprising;

an inert nonpareil bead or pellet;

a coat at least partially surrounding the bead or pellet, and the coat comprises the opioid antagonist, the opioid agonist, a binder, a plasticizer and at least one pharmaceutical excipient.

149. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a pharmaceutical composition comprising first and second coated solid substrates, and;

the first coated solid substrate comprises a nonpareil pellet or bead and a first coat at least partially surrounding the pellet or bead and the first coat comprises a binder and an opioid antagonist; and

the second coated solid substrate comprises a nonpareil pellet or bead and a second coat at least partially surrounding the pellet or bead, and the second coat comprises a binder and an opioid agonist.

150. The solid oral dosage form of claim 149, wherein the first coated solid substrate comprises about 0.5-80% wt. of the solid pharmaceutical composition;

and the second coated solid substrate comprises about 20-95% wt. of the solid pharmaceutical composition.

151. The solid oral dosage form of claim 150, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the first and second coated solid substrates.

152. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a pharmaceutical composition comprising first and second granulations; and

the first granulation comprises a binder and the opioid antagonist; and

the second granulation comprises a binder and the opioid agonist.

153. The solid oral dosage form of claim 152, wherein the first granulation comprises about 0.5-50% wt. of the solid pharmaceutical composition;

and the second granulation comprises about 20-95% wt. of the solid pharmaceutical composition.

154. The solid oral dosage form of claim 153, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the first and second granulations.

155. The solid oral dosage form of claim 154, wherein the dosage form is a capsule or tablet.

156. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a pharmaceutical composition comprising a coated granulation comprising a mixture of two or more pharmaceutical excipients; and

a coat at least partially surrounding the mixture, and the coat comprises a binder, an opioid agonist and an opioid antagonist.

157. The solid oral dosage form of claim 156, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the coated granulation.

158. The solid oral dosage form of claim 157, wherein the coated granulation comprises about 10-85% wt. of the solid pharmaceutical composition.

159. The solid oral dosage form of claim 158, wherein the dosage form is a capsule or tablet.

160. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a pharmaceutical composition comprising a coated granulation comprising a mixture of two or more pharmaceutical excipients and the opioid agonist; and

a coat at least partially surrounding the mixture, and the coat comprises a binder and the opioid antagonist.

161. The solid oral dosage form of claim 160, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the coated granulation.

162. The solid oral dosage form of claim 161, wherein the coated granulation comprises about 10-75% wt. of the solid pharmaceutical composition.

163. The solid oral dosage form of claim 162, wherein the dosage form is a capsule or tablet.

164. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about;

an opioid agonist present in an amount from about 0.1 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a spray-dried pharmaceutical composition comprising a mixture of the at least one pharmaceutical excipient, the opioid agonist and the opioid antagonist.

165. The solid oral dosage form of claim 164, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the spray-dried pharmaceutical composition.

166. The solid oral dosage form of claim 165, wherein the spray-dried pharmaceutical composition comprises about 5-99% wt. of the dosage form.

167. The solid oral dosage form of claim 166, wherein the dosage form is a capsule or tablet.

168. A combination solid oral dosage form comprising:

an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg;

an opioid agonist present in an amount from about 1.0 mg to about 300 mg; and

at least one pharmaceutical excipient;

wherein the solid dosage form comprises a suspension-filled soft gelatin capsule comprising;

a soft gelatin capsule; and

a suspension within the capsule comprising a non-aqueous vehicle in liquid form, the opioid agonist in solid form, and the opioid antagonist in solid form.

169. The solid oral dosage form of claim 168, wherein the suspension further comprises at least one pharmaceutical excipient.

170. A method for administering at therapeutic dose of an opioid antagonist to a human subject consisting essentially of administering a solid oral dosage form comprising an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg, and an opioid agonist present in an amount from about 0.1 mg to about 300 mg.

171. A pharmaceutical kit comprising a dosage form comprising an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg, and an opioid agonist present in an amount from about 0.1 mg to about 300 mg.