OPIOID ANTAGONIST COMPOSITIONS AND DOSAGE FORMS

COMPOSITIONS D'ANTAGONISTE OPIOIDE ET FORMES DE DOSAGE

English 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.

French Abstract

La présente invention concerne de nouvelles formes de dosage, des compositions pharmaceutiques, des kits et des techniques d'administration d'un antagoniste opioïde en quantité comprise au moins entre environ 0,0001mg et environ 1,0 mg ou moins notamment entre environ 0,0001mg et moins de 0,5mg environ. Cette invention concerne aussi des formes de dosage oral solides constituées essentiellement d'un antagoniste opioïde ou encore qui comprennent un antagoniste opioïde et un autre principe actif, tel qu'un agoniste opioïde. Cette invention concerne encore des formes de dosage oral à libération immédiate qui libèrent entièrement l'antagoniste opioïde ou une proportion substantielle de ce dernier, et un autre principe actif lorsqu'il est présent, dans un temps défini. Cette invention concerne aussi des formes de dosage à libération différentes qui permettent une libération différente d'un antagoniste opioïde et d'un autre principe actif.

Claims

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WHAT IS CLAIMED IS
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.

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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.

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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.
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.

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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.

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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.
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 claim 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.

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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.

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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.
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.
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.

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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.

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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.

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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.

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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.
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.
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.
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.
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.
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.

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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.
110. The solid oral dosage form according to claim 43, provided in an
immediate release formulation.
111. The solid oral dosage form according to claim 48, provided in an
immediate release formulation.
112. The solid oral dosage form according to claim 64, provided in an
immediate release formulation.
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.

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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.

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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.

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133. A concurrent release combination solid oral dosage form comprising:
an opioid antagonist present in an about 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.
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.
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.

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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.

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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.

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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.

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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.

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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.

Description

CA 02408106 2002-11-05
WO 01/85257 PCT/USO1/14377
OPIOID ANTAGONIST COMPOSITIONS AND DOSAGE FORMS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of the following U.S. Patent Application
Nos. 60/202,227 filed May 5, 2000 (provisional); 60/202,268 filed May 5, 2000
(provisional); 09/756,331 filed January 8, 2001, which is a continuation of
09/566,071
filed May 5, 2000; 60/244,482 filed October 30, 2000 (provisional); 60/245,110
filed
November 1, 2000 (provisional); and 60/246,235 filed November 2, 2000
(provisional); and PCT/US00/12493 [WO 00/67739] filed May 5, 2000. The
applications cited above are hereby incorporated herein by reference in their
entirety
to provide continuity of disclosure.
FIELD OF THE INVENTION
The present invention relates to novel dosage forms and pharmaceutical
compositions containing a low dose of an opioid antagonist. The present
invention
also relates to dosage forms comprising an opioid antagonist and another
active
pharmaceutical ingredient, such as an opioid agonist.
BACKGROiJND OF THE INVENTION
The pharmacology of opioid antagonist compounds is described in Goodman
and Gilhnan, PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 22, "Opioid
Antagoyaists," incorporated by reference herein. Opioid antagonists include,
but are
not limited to, naloxone, cyclazocine, opioid antagonist compounds having the
same
pentacyclic nucleus as nalinefene, naltrexone, nalorphine, nalbuphine,
thebaine,
levallorphon, pentazocine, oxymorphine, butorphanol, bupremorphine,
levorphanol,
meptazinol, dezocine, or pentazocine or their pharmacologically effective
salts or
esters such as, but not limited to, their hydrochlorides, maleates, tartrates
and lactates.
The generally accepted use for opioid antagonists has been to treat overdoses
and to prevent abuse of opioid agonists such as heroin or morphine. For these
conventional uses, the antagonist such as naloxone or naltrexone is used in
relatively
high concentrations to effectively block the activi~.y or effects of the
opioid agonist.
The previously employed high concentration of an opioid antagonst is believed
to act
antagonistically to the opioid agonist on a biochemical level at opioid
receptors on
nociceptive neurons.

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Naloxone (4,5-epoxy-3,14-dihydroxy-17-(2-prophenyl)morphinan-6-one), the
first of the opioid antagonist compounds to be synthesized in 1960, was
shortly
thereafter discovered to have "pure" antagonist character, i.e., exhibiting
virtually no
agonist activity. Thus, naloxone became the preferred regime for the treatment
of
acute narcoticism (the habitual use of narcotics). However, since naloxone
exhibited
a relatively short duration in the body, it became clear that a longer acting
agent
having similarly "pure" antagonist character would be even more advantageous.
Naltrexone (17-(cyclopropylinethyl)-4,5-epoxy-3,14-dihydroxy-morphinan-6-one)
was thus developed in 1965 to fulfill this requirement and was found to have
greater
potency and longer action than its N-allyl congener, naloxone, as well as
activity
when given orally. For example, 50 mg dosage forms of naltrexone are marketed
as
ReVia~ in the United States or Trexan in other countries. Nalmefene (6-
methylene-6-
desoxy-N-cyclopropyl-methyl-14-hydroxydihydroxy-dihydxonormorphine) was also
developed and is a long acting, orally available, potent opioid antagonist,
also with
"pure" antagonist properties. These drugs are presently commercially available
in
certain dosage forms, and are so far as is knovv~i, the only pure opioid
antagonists
which have received governmental approval for administration to humans.
Crain and Shen (BRAIN RESEARCH 757: 176-190 (1997)) have shown that
opioid agonists not only activate inhibitory opioid receptors, leading to
analgesic
activity, but also simultaneously activate a smaller group of excitatory
opioid
receptors on sensory nerve cells. These effects on the excitatory opioid
receptors
were proposed to weaken opioid induced analgesia and under certain conditions
actually enhance pain. Surprisingly, Crain and Shen (e.g., U.S. Patent No.
5,512,578,
reissued as RE 36,457) showed that co-administration of remarlcably low doses
of an
opioid antagonist, such as naloxone or naltrexone on the order of
nanograms/kilogram
(ng/lcg), when administered to mice with morphine or similar opioid agonists,
selectively blocked their effects on excitatory, but not inhibitory, opioid
receptors,
thus markedly enhancing the analgesic potency of opioid agonists. These
discoveries
of Crain and Shen have been described in U.S. Patents No. 5,472,943; 5,512,578
reissued as RE 36,457; 5,580,876; and 5,767,125, which are directed to methods
for

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selectively enhancing the analgesic potency of a bimodally-acting opioid
agonist and
simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability,
physical
dependence and/or tolerance effects associated with the administration of the
bimodally-acting opioid agonist.
These methods comprise administering to a subject an analgesic or sub-
analgesic amount of a bimodally-acting opioid agonist and an amount of an
excitatory
opioid receptor antagonist effective to enhance the analgesic potency of the
bimodally-acting opioid agonist and attenuate the anti-analgesia,
hyperalgesia,
hyperexcitability, physical dependence and/or tolerance effects of the
bimodally-
acting opioid agonist. Also included in these patents are methods for treating
pain in
a subj ect by administering to the subj ect an analgesic or sub-analgesic
amount of a
bimodally-acting opioid agonist and an amount of an excitatory opioid receptor
antagonist effective to enhance the analgesic potency of the bimodally-acting
opioid
agonist and simultaneously attenuate anti-analgesia, hyperalgesia,
hyperexcitability,
physical dependence and/or tolerance effects of the bimodally-acting opioid
agonist.
Also included in these patents are methods for treating an opiate addict by
administering to the opiate addict an amount of an excitatory opioid receptor
antagonist either alone or in combination with a bimodally-acting opioid
agonist
effective to attenuate physical dependence caused by a bimodally-acting opioid
agonist and enhance the analgesic potency of a bimodally-acting opioid
agonist. Also
included axe compositions of an analgesic or sub-analgesic amount of a
bimodally-
acting opioid agonist and an amount of an excitatory opioid receptor
antagonist
effective to enhance the analgesic potency of the bimodally-acting opioid
agonist and
attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical
dependence
and/or tolerance effects of the bimodally-acting opioid agonist in a subject
administered the composition. In all of these studies, the antagonist
simultaneously
enhanced potency while attenuating such adverse effects.
Two clinical studies on postsurgical patients (Joshi, et. al., ANESTHESIOL.
90:
1007-1011 (1999); Gan et al., ANESTHESIOL. 87: 1075-1081 (1997)) demonstrated
that cotreatment of patients with PCA1IV morphine together with a low dose of
the

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opioid antagonist naloxone (IV) or nalmefene (IV) markedly enhanced potency of
morphine in varying cumulative daily doses of morphine. Adverse side effects
were
attenuated in these studies.
A variety of other uses for opioid antagonists have been described or proposed
for human treatment where the opioid antagonist is administered in relatively
high
concentrations, including in amounts similar to that used for treatment of
opioid
overdose or addiction.
U.S. Patent No. 6,194,382 B1 describes a method for treating irritable bowel
syndrome (IBS) by administration of an amount of an opioid receptor antagonist
effective to treat IBS. For example, a daily dose of naltrexone in the range
between
0.1 mg/day and about 5 mg/day and of nalinefene in the range between 0.01
mg/day
and about 1 mg/day is described.
U.S. Patent No. 6,187,782 B1 describes morphinan derivatives of a certain
formula as compounds having abilities to bind to opioid ~-receptor, which have
agonist or antagonist activities. Results of an iya vitro antagonist activity
assay for
eight compounds are shown.
U.S. Patent No. 6,153,621 describes compositions and methods for treating
excitable system disorders, pain and psychiatric disorders with a combination
of
antagonists of different excitatory systems, such as nicotinic, opioid,
serotonergic and
andrenergic antagonists, including specifically the combination of the opioid
antagonist naltrexone or naloxone and the nicotinic antagonist mecamylamine.
U.S. Patent No. 6,136,780 describes a method of treating and preventing
cancers which are characterized by the presence of zeta receptors,
particularly
gastrointestinal cancer, by administering an amount of naltrexone, naloxone or
[Mets]-enkephalin sufficient to block zeta receptors thereby inhibiting or
arresting the
growth of the cancer. Daily subcutaneous injection of 0.1 mg/kg to mice
inoculated
with tumor cells resulted in a decrease in tumor incidences and growth.
U.S. Patent No. 6,110,926 describes an eye drop composition for opioid
addiction testing with enhanced stability in the form of a solution of
naloxone

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hydrochloride, (e.g., 0.1-1% w/v) in a mixture of water and at least one
pharmaceutically acceptable polyhydric alcohol.
U.S. Patent No. 6,103,734 describes a mufti-step method for suppressing
dependence of a patient upon opiates by, among other steps, administration of
an
opiate antagoiust. According to the method, naltrexone may be administered at
between 6 mg and 40 mg per hour and naloxone may be administered at between
0.4
mg to 1.5 mg per hour.
U.S. Patent No. 6,103,258 describes methods for optimizing dopamine,
homeostasis during administration of opioid analgesics by achninstration of an
opioid
agonist and an amount of a kappa-preferring opioid antagonist, specifically
nalmefene, sufficient to inhibit binding of the opioid agonist analgesic at
kappa-opioid
receptors with only miasmal antagonism of the agonist analgesic at mu-opioid
receptors. Parenteral administration of nalmefene at 0.00025-0.00015 mg/kg is
recommended.
U.S. Patent No. 6,087,369 describes indole derivative compounds of a certain
formula with delta-opioid antagonist activity, and methods with the compounds
in
immunosuppressive, anti-allergic, anti-inflammatory and brain cell-protecting
amounts.
U.S. Patent No. 6,071,918 describes methods and compositions for treating
alcoholism and alcohol dependence by administering a therapeutically effective
amount of a synergistic combination of at least one opioid antagonist and at
least one
selective serotonin reuptake inhibitor.
U.S. Patent No. 6,034,091 describes a method for treating depression, with
claims to the depression associated with alcoholism, by administering a
pharmacologically effective dose of opioid antagonist and a pharmacologically
effective dose of antidepressant compound.
U.S. Patent No. 6,026,817 describes a method of treating humans suffering
from one or more conditions included within the syndrome of coronary heart
disease
risk factors (CHDRF) by a stepwise dosing regimen including an opioid
antagonist or

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a drug which substantially equally reduces the specified amounts of
catecholamines in
higher primary doses and lower maintaining doses.
U.S. Patent No. 6,004,970 describes a method for treating a person with a
nicotine dependency by administering an effective amount of an opioid
antagonist and
an effective amount of nicotine.
U.S. Patent No. 6,004,962 describes a mufti-step method of rapid opioid
detoxification of a patient which includes a step of detoxifying the patient
by injecting
an opioid antagonist while the patient is sedated, followed by achninistering
antagonist
maintenance therapy to the patient.
U.S. Patent No. 5,972,954 describes a method for preventing or treating opioid
induced side effects and non-opioid induced changes in gastrointestinal
motility by
achninistering methylnaltrexone, with oral dosages of about 1.0 - 40.0 mg/kg
or as an
enterically coated tablet at dosages of about 1.0 - 80.0 mg/kg.
U.S. Patent No. 5,958,962 describes a method of treating alcoholism and
alcohol dependence with naltrexone and fluoxetine.
U.S. Patent Nos. 5,922,705 and 5,783,583 describe a method for rapid
detoxification of patients addicted to opioid narcotics by infusing
nalinefene.
U.S. Patent No. 5,919,760 describes a method for rapid narcotic
detoxification, wherein the acute withdrawal is induced by administering
nalmefene,
and wherein octreotide is administered in an amount sufficient to alleviate
acute and
severe diarrhea without precipitating clinically significant bradycardia.
U.S. Patent No. 5,866,164 describes an osmotic dosage form for lessening the
incidence of drug abuse containing in combination an opioid antagonist and an
opioid
agonist wherein the antagonist and the agonist are maintained as separate in
the
dosage form. This dosage form provides an osmotically controlled release of
the
agonist but not the antagonist, characterized by administration of a drug
opioid
composition free of an antagonist.
U.S. Patent No. 5,852,032 describes a method of treating a human subject
afflicted with nicotine dependence by administering nalinefene to decrease the
nicotine dependence.

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U.S. Patent No. 5,817,665 describes a method of and compositions for treating
depression with a pharmacologically effective dose of an opioid antagonist
having a
pentacyclic nucleus structurally analogous to naltrexone, naloxone, nalmefene,
nalorphine, . nalbuphine, oxymorphone, buprenorphine, thebaine, ~ their
pharmacologically effective salts and esters, and combinations thereof, and a
pharmacologically effective dose of a compound of one or more nontricyclic
antidepressants exhibiting serotonin reuptake activity inhibition in the
synapses of the
central nervous system, their pharmacologically effective salts and esters, or
combinations thereof.
U.S. Patent No. 5,780,479 describes a therapeutic method of treating an
impulse-control disorder, with the exception of trichotillomania, by
administering an
amount of at least one opioid receptor antagonist effective to reduce or
eliminate at
least one of the symptoms of the impulse-control disorder.
U.S. Patent No. 5,714,483 describes antitussive compounds of a certain
formula that are delta-opioid antagonists and claims a method for suppressing
cough
in a subj ect with an amount of such an antagonist effective to decrease the
frequency
of coughing. In the case of oral administration, the dose was suggested to be
10
micrograms to 1 gram per day, although test compounds were administered to
rats
intraperitoneally.
U.S. Patent No. 5,512,593 describes a method of treating depression with a
pharmacologically effective dose of an opioid antagonist selected from the
group
consisting of naltrexone, naloxone, their pharmacologically effective salts
and esters,
or combinations thereof, and a pharmacologically effective dose of a compound
selected from the group consisting of one or more nontricyclic antidepressants
exhibiting serotonin reuptake inhibition in the synapses of the central
nervous system,
their pharmacologically effective salts and esters, or combinations thereof.
U.S. Patent No. 5,426,112 describes a method for the treatment and alleviation
of pain and addictive behavior in a human with at least one opioid antagonist
to effect
temporary blockade of the opioid receptor site by administering at least one
opioid
antagonist in a cumulative amount of less than about 10 mg per day.

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_$_
U.S. Patent No. 5,356,900 describes a method of treating humans suffering
from chronic herpes virus infections with an essentially pure opiate receptor
antagonist having a selectively higher bloclcing action against Mu opiate
receptors
than against Delta receptors in an amount wluch is effective to exert a
substantial
opiate receptor blocking action against Mu receptors but insufficient to exert
such
action against Delta receptors.
U.S. Patent No. 5,352,680 describes delta-opioid receptor antagonists of a
certain formula and claims a method for treating the tolerance in a human
undergoing
administration of an opioid agonist by administering an amount of such an
antagonist
effective to block or reduce tolerance to an opioid mu reception agonist.
U.S. Patent No. 5,272,149 describes a method for the treatment of addiction
(e.g., to heroin) carried out by reducing the amount of the target addictive
agent in the
subject, wherein the method comprises multiple specific steps for the
successive
administration of a plurality of therapeutic agents, each in an amount
effective to
reduce the physiological level of the target agent in the subj ect, and
wherein the
therapeutic agents include naloxone, naltrexone, buprenorphine and
hydroxyzine.
U.S. Patent No. 5,266,574 describes a method of enhancing the wound healing
processes by accelerating the growth of wounded tissue and related cells by
administering naltrexone in an amount sufficient to continuously blockade the
receptor sites of the wounded tissue and related cells.
U.S. Patent No. 5,025,018 describes a method of inducing kappa-opiate-
receptor antagonist activity in a patient suffering from ischemic or traumatic
central
nervous system injury by administering an effective amount of a kappa-opiate-
receptor antagonist suitable to permit the induction of kappa-opiate receptor
antagonistic activity. In a preferred embodiment, the kappa opiate receptor
antagonist
is nalmefene.
U.S. Patent No. 5,013,739 describes a method of treating humans suffering
from chronic fatigue syndrome by the steps of administering by a
pharmacologically
effective mode to such patient a therapeutically effective dose of an
essentially pure

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_g_
opiate receptor antagonist, where the dose corresponding to the therapeutic
results
produced by Naltrexone in the range from about 1.0 mg to about 10.0 mg.
U.S. Patent No: 4,935,428 describes a method of treating opiate dependent
subjects in which addicts are treated by sublingual administration with a
daily dose of
2 to 8 mg buprenorphine for 1 to 4 weeks followed by, as maintenance
treatment, the
daily simultaneous administration sublingually of 2 to 8 mg buprenorphine and
an
amount of naltrexone wherein the weights of naltrexone and buprenorphine are
Within
the ratio of 1:4 to 1:1.
U.S. Patent No. 4,906,637 has the same disclosure as U.S. Patent No.
5,025,018 and describes a method of treating a patient suffering from ischemic
or
traumatic brain injury by parenterally administering an effective amount of
kappa-
opiate receptor antagonist suitable to permit the induction of kappa-opiate-
receptor
antagonistic activity.
U.S. Patent No. 4,877,791 describes a method of treating a patient suffering
from interstitial cystitis by the daily administration to the patient of from
about 1 to
about 50 mg of nalmefene or naltrexone.
U.S. Patent No. 4,863,928 describes a method of treating a patient suffering
from an arthritic disease or associated inflammatory disease with daily
administration
to the patient of from about 1 to about 100 mg of nalmefene or naltrexone.
U.S. Patent No. 4,857,533 describes a method of treating a patient suffering
from an autoimmmie disease comprising daily administration of from about 1 to
about
100 mg of the narcotic antagonist nahnefene or naltrexone. Oral dosage forms
may
include generally from about 0.5 to about 50.0 mg of nalmefene or naltrexone
per
dosage unit.
U.S. Patent Nos. 4,769,372 and 4,785,000 describe methods of treating
patients in chronic pain or suffering from chronic cough without provoking
intestinal
hypomotility by the oral administration of dosage units comprising in
combination
opioid analgesics or antitussives and selected opioid antagonists which are
substantially devoid of systemic antagonist activity when administered orally.

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U.S. Patent No. 4,774,230 describes a method and compositions for providing
glucuronic acid derivatives of opioid antagousts which has a local therapeutic
effect
in the intestinal tract (e.g. for the treatment of intestinal dysmotility)
with a minimmn
of systemic effects, particularly central nervous system effects. Such
derivatives of
opioid antagonists are used for intestinal specif c drug delivery and in
amounts
sufficient to provide opioid antagonist to the intestine of the subject, for
example,
from about 0.1 to 50 mg.
U.S. Patent No. 4,767,764 describes compounds of a certain formula that are
lcappa and mu receptor antagonists, but are more selective as kappa-opioid
receptor
antagonists. Also described are methods for alleviating the effect of an
opioid drug
and/or exerting an appetite controlling effect by administering such
compounds.
U.S. Patent No. 4,668,685 describes compounds that are substituted benzoate
ester prodrug derivatives of 3-hydroxymorphinans of a certain formula, useful
in
effective analgesic amounts or effective narcotic antagonist amounts.
U.S. Patent No. 4,600,718 describes a method of treating weight loss disorders
consisting essentially of administering to a mammal having a weight loss
disorder a
daily dosage of an effective amount which consists essentially of at least
about 10
milligrams per 37 l~ilogram body weight of at least one opiate antagonist.
U.S. Patent 4,582,835 describes a method of treating pain by administration of
a parenterally or sublingually effective dose of buprenorphine together with
am
amount of naloxone, for example 0.1 mg per tablet, sufficient to prevent
substitution
in an opiate dependent subject.
U.S. Patent No. 4,464,378 describes a method for eliciting an analgesic or
narcotic antagonist response in a warm-blooded animal, by nasally
administering (a)
an analgesically effective amount of morphine, hydromorphone, metopon,
oxymorphone, desomorphine, dihydromorphine, levorphanol, cyclazocine,
phenazocine, levallorphan, 3-hydroxy-N-methylmorplunan, levophenacylmorphan,
metazocine, norlevorphanol, phenomorphan, nalorphine, nalbuphine,
buprenorphine,
butorphanol or pentazocine, or a nontoxic pharmaceutically acceptable acid
addition
salt thereof to elicit an analgesic response; or (b) a narcotic antagonist
effective

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amount of naloxone, naltrexone, diprenorphine, nalmexone, cyprenorphine,
levallorphan, alazocine, oxilorphan, cyclorphan, nalorphine, nalbuphine,
buprenorphine, butorphanol, cyclazocine or pentazocine, or a nontoxic
pharmaceutically acceptable acid addition salt thereof to elicit a narcotic
antagonist
response.
U.S. Patent No. 4,181,726 describes a method of relieving severe itching by
administering an effective dosage of naloxone to a patient suffering from such
itching,
for example, in dosages of from 0.4 to 1000 mg.
U.S. Patent No. 3,966,940 describes methods for the treatment of a narcotic
addicted subject by administering an orally effective, but parenterally
inactive
analgetic composition. Such compositions can contain from about 0.1 mg to
about 10
mg of naloxone.
U.S. Pat. No. 3,773,955 describes methods of treating drug-addicted subjects
by administering orally effective, but parenterally inactive analgetic
compositions
comprising the combination of naloxone with opiates such as phenazocine and
methadone.
Since opioid antagonists have been manufactured for use conventionally in
relatively high concentration dosage forms to treat opioid agonist overdoses
and/or to
prevent abuse of such agonists (e.g., REVIA~ 50 mg naltrexone), compositions
and
dosage forms of opioid antagonists have not yet been manufactured for use in
significantly lower concentrations.
In particular, the commercial manufacture of immediate release dosage forms
that provide a dose of a first active agent (e.g., opioid antagonist) and
concurrently a
substantially lower dose of a second active agent (e.g., opioid agonist) is
difficult due
to batch-to-batch variability in the amounts of active agent present in
individual unit
doses. Although a variety of different methods have been developed to address
this
problem, no particular method is broadly applicable to all combinations of
drugs:
issues such as undesirable drug/excipient interactions, drug instability,
instability of

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the formulation and unexpected dosage form performance create a continuing
demand
for formulations aazd processes tailored to specific drug combinations.
SUMMARY OF THE INVENTION
The present invention is directed to novel pharmaceutical compositions,
dosage forms, and lcits with an opioid antagonist. This invention also relates
to novel
pharmaceutical compositions, dosage forms, and kits with an opioid antagonist
and
another active pharmaceutical ingredient, for example, an opioid antagonist.
The
invention further relates to methods for administering to human subjects such
pharmaceutical compositions, dosage forms, and kits including an opioid
antagonist
alone or in combination with another active pharmaceutical ingredient, such as
an
opioid agonist. Preferred opioid antagonists include naltrexone, nalmefene or
naloxone. Particularly preferred is naltrexone. For pharmaceutical
compositions,
dosage forms, kits and methods according to the invention, an opioid
antagonist is
provided in an amount from at least about 0.0001 mg to about or less than
about 1.0
mg, or at least about 0.001 mg to about or less than about 1.0 mg, or at least
about
0.01 mg to about or less than about 1.0 mg, or at least about 0.1 mg to about
or less
than about 1 mg. Preferred ranges of opioid antagonists also include: from
about
0.0001 mg to less than 1.0 mg; from about 0.001 mg to less than 1.0 mg; from
about
0.01 mg to less than 1.0 mg; or from about 0.1 mg to less than 1.0 mg.
Additional
preferred ranges of opioid antagonists include: from about 0.0001 mg to about
0.1
mg; from about 0.001 mg to about 0.1 mg; from about 0.01 mg. to about 0.1 mg;
from
about 0.001 mg to about 0.1 mg; from about 0.001 mg to about 0.01 mg ; or from
about 0.01 mg to about 0.1 mg. Further preferred ranges of opioid antagoW sts
include: from at least about 0.0001 to less than about 0.5 mg; from at least
about 0.01
to less than about 0.5 mg; or from at least about 0.1 to less than about 0.5
mg.
Each of these dosage forms can be a solid oral dosage form or another dosage
form. Each of these pharmaceutical compositions can consist essentially of
opioid
antagonist and a pharmaceutically acceptable carrier. Each of these kits can
consist
essentially of a solid oral dosage form of an antagonist and a container. Each
of these

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pharmaceutical compositions or kits can fiu-ther consist essentially of
another active
pharmaceutical ingredient, such as an opioid agonist, optionally in a solid
oral dosage
form. Alternatively, the other active pharmaceutical ingredient, such as an
agonist is
optionally provided in an injectable, transdermal, transmucosal, oral
solution, syrup,
elixir or other dosage form.
Each of the pharmaceutical compositions can comprise or consist essentially
of opioid antagonist together with another active pharmaceutical ingredient,
such as
an opioid agonist, formulated with one or more pharmaceutically acceptable
materials
into a dose form designed for the specific route of achninistration. Each kit
can
comprise or consist essentially of one or more containers of medication, each
having
one or more dosage forms containing either the opioid antagonist alone,
combinations) of the opioid antagonist with the other active pharmaceutical
ingredient, such as an opioid agonist, or both. Furthermore the dosage forms
and kits
may, by their design, constitute a dosing system that provides for the
administration
of one or both medications in one or more dose forms in a specific regimen
necessary
to achieve the therapeutic benefits.
The maximmn amount of antagonist in the dosage form is 1 mg, alternatively
less than 1 mg, alternatively 0.99 mg, alternatively 0.98 mg, alternatively
0.97 mg,
alternatively 0.96 mg, alternatively 0.95 mg, alternatively 0.94 mg,
alternatively 0.93
mg, alternatively 0.92 mg, alternatively 0.91 mg, alternatively 0.90 mg,
alternatively
0.89 mg, alternatively 0.88 mg, alternatively 0.87 mg, alternatively 0.86 mg,
alternatively 0.85 mg, alternatively 0.84 mg, alternatively 0.83 mg,
alternatively 0.82
mg, alternatively 0.81 mg, alternatively 0.80 mg, alternatively 0.79 mg,
alternatively
0.78 mg, alternatively 0.77 mg, alternatively 0.76 mg, alternatively 0.75 mg,
alternatively 0.74 mg, alternatively 0.73 mg, alternatively 0.72 mg,
alternatively 0.71
mg, alternatively 0.70 mg, alternatively 0.69 mg, alternatively 0.68 mg,
alternatively
0.67 mg, alternatively 0.66 mg, alternatively 0.65 mg, alternatively 0.64 mg,
alternatively 0.63 mg, alternatively 0.62 mg, alternatively 0.61 mg,
alternatively 0.60
mg, alternatively 0.59 mg, alternatively 0.58 mg, alternatively 0.57 mg,
alternatively

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0.56 mg, alternatively 0.55 mg, alternatively 0.54 mg, alternatively 0.53 mg,
alternatively 0.52 mg, alternatively 0.51 mg, alternatively 0.50 mg.
Additionally, the maximum amount of antagonist in the dosage form is less
than 0.5 mg, alternatively 0.49 mg, alternatively 0.48 mg, alternatively 0.47
mg,
alternatively 0.46 mg, alternatively 0.45 mg, alternatively 0.44 mg,
alternatively 0.43
mg, alternatively 0.42 mg, alternatively 0.41 mg, alternatively 0.40 mg,
alternatively
0.39 mg, alternatively 0.38 mg, alternatively 0.37 mg, alternatively 0.36 mg,
alternatively 0.35 mg, alternatively 0.34 mg, alternatively 0.33 mg,
alternatively 0.32
mg, alternatively 0.31 mg, alternatively 0.30 mg, alternatively 0.29 mg,
alternatively
0.28 mg, alternatively 0.27 mg, alternatively 0.26 mg, alternatively 0.25 mg,
alternatively 0.24 mg, alternatively 0.23 mg, alternatively 0.22 mg,
alternatively 0.21
mg, alternatively 0.20 mg, alternatively 0.19 mg, alternatively 0.18 mg,
alternatively
0.17 mg, alternatively 0.16 mg, alternatively 0.15 mg, alternatively 0.14 mg,
alternatively 0.13 mg, alternatively 0.12 mg, alternatively 0.11 mg,
alternatively 0.10
mg, alternatively 0.09 mg, alternatively 0.08 mg, alternatively 0.07 mg,
alternatively
0.06 mg, alternatively 0.05 mg, alternatively 0.04 mg, alternatively 0.03 mg,
alternatively 0.02 mg, alternatively 0.01 mg, alternatively 0.009 mg,
alternatively
0.008 mg, alternatively 0.007 mg, alternatively 0.006 mg, alternatively 0.005
mg,
alternatively 0.004 mg, alternatively 0.003 mg, alternatively 0.002 mg,
alternatively
0.001 mg, alternatively 0.0009 mg, alternatively 0.0008 mg, alternatively
0.0007 mg,
alternatively 0.0006 mg, alternatively 0.0005 mg, alternatively 0.0004 mg,
alternatively 0.0003 mg, alternatively 0.0002 mg.
The minimum amount of antagonist in the dosage form is 0.0001 mg,
alternatively 0.0002 mg, alternatively 0.0003 mg, alternatively 0.0004 mg,
alternatively 0.0005 mg, 0.0006 mg, alternatively 0.0007 mg, alternatively
0.0008 mg,
alternatively 0.0009 mg, alternatively 0.001 mg, alternatively 0.002 mg,
alternatively
0.003 mg, alternatively 0.004 mg, alternatively 0.005 mg, alternatively 0.006
mg,
alternatively 0.007 mg, alternatively 0.008 mg, alternatively 0.009 mg,
alternatively
0.01 mg, alternatively 0.011 mg, alternatively 0.012 mg, alternatively 0.013
mg,
alternatively 0.014 mg, alternatively 0.015 mg, alternatively 0.016 mg,
alternatively

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0.017 mg, alternatively 0.018 mg, alternatively 0.019 mg, alternatively 0.02
mg,
alternatively 0.021 mg, alternatively 0.022 mg, alternatively 0.023 mg,
alternatively
0.024 mg, alternatively 0.025 mg, alternatively 0.026 mg, alternatively 0.027
mg,
alternatively 0.028 mg, alternatively 0.029 mg, alternatively 0.03 mg,
alternatively
0.031 mg, alternatively 0.032 mg, alternatively 0.033 mg, alternatively 0.034
mg,
alternatively 0.035 mg, alternatively 0.036 mg, alternatively 0.037 mg,
alternatively
0.038 mg, alternatively 0.039 mg, alternatively 0.04 mg, alternatively 0.041
mg,
alternatively 0.042 mg, alternatively 0.043 mg, alternatively 0.044 mg,
alternatively
0.045 mg, alternatively 0.046 mg, alternatively 0.047 mg, alternatively 0.048
mg,
alternatively 0.049 mg, alternatively 0.05 mg, alternatively 0.051 mg,
alternatively
0.052 mg, alternatively 0.053 mg, alternatively 0.054 mg, alternatively 0.055
mg,
alternatively 0.056 mg, alternatively 0.057 mg, alternatively 0.058 mg,
alternatively
0.059 mg, alternatively 0.06 mg, alternatively 0.061 mg, alternatively 0.062
mg,
alternatively 0.063 mg, alternatively 0.064 mg, alternatively 0.065 mg,
alternatively
0.066 mg, alternatively 0.067 mg, alternatively 0.068 mg, alternatively 0.069
mg,
alternatively 0.07 mg, alternatively 0.071 mg, alternatively 0.072 mg,
alternatively
0.073 mg, alternatively 0.074 mg, alternatively 0.075 mg, alternatively 0.076
mg,
alternatively 0.077 mg, alternatively 0.078 mg, alternatively 0.079 mg,
alternatively
0.08 mg, alternatively 0.081 mg, alternatively 0.082 mg, alternatively 0.083
mg,
alternatively 0.084 mg, alternatively 0.085 mg, alternatively 0.086 mg,
alternatively
0.087 mg, alternatively 0.088 mg, alternatively 0.089 mg, alternatively 0.09
mg,
alternatively 0.091 mg, alternatively 0.092 mg, alternatively 0.093 mg,
alternatively
0.094 mg, alternatively 0.095 mg, alternatively 0.096 mg, alternatively 0.097
mg,
alternatively 0.098 mg, alternatively 0.099 mg, alternatively 0.1 mg,
alternatively 0.11
mg, alternatively 0.12 mg, alternatively 0.13 mg, alternatively 0.14 mg, 0.15
mg,
alternatively 0.16 mg, alternatively 0.17 mg, alternatively 0.18 mg,
alternatively 0.19
mg, alternatively 0.2 mg, alternatively 0.21 mg, alternatively 0.22 mg,
alternatively
0.23 mg, alternatively 0.24 mg, alternatively 0.25 mg, alternatively 0.26 mg,
alternatively 0.27 mg, alternatively 0.28 mg, alternatively 0.29 mg,
alternatively 0.3
mg, alternatively 0.31 mg, alternatively 0.32 mg, alternatively 0.33 mg,
alternatively

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0.34 mg, alternatively 0.35 mg, alternatively 0.36 mg, alternatively 0.37 mg,
alternatively 0.38 mg, alternatively 0.39 mg alternatively 0.40 mg,
alternatively 0.41
mg, alternatively 0.42 mg, alternatively 0.43 mg, alternatively 0.44 mg,
alternatively
0.45 mg, alternatively 0.46 mg, alternatively 0.47 mg, alternatively 0.48 mg,
alternatively 0.49 mg, alternatively 0.5 mg, alternatively 0.51 mg,
alternatively 0.52
mg, alternatively 0.53 mg, alternatively 0.54 mg, alternatively 0.55 mg,
alternatively
0.56 mg, alternatively 0.57 mg, alternatively 0.58 mg, alternatively 0.59 mg,
alternatively 0.6 mg, alternatively 0.61 mg, alternatively 0.62 mg,
alternatively 0.63
mg, alternatively 0.64 mg, alternatively 0.65 mg, alternatively 0.66 mg,
alternatively
0.67 mg, alternatively 0.68 mg, alternatively 0.69 mg, alternatively 0.7 mg,
alternatively 0.71 mg, alternatively 0.72 mg, alternatively 0.73 mg,
alternatively 0.74
mg, alternatively 0.75 mg, alternatively 0.76 mg, alternatively 0.77 mg,
alternatively
0.78 mg, alternatively 0.79 mg, alternatively 0.8 mg, alternatively 0.81 mg,
alternatively 0.82 mg, alternatively 0.83 mg, alternatively 0.84 mg,
alternatively 0.85
mg, alternatively 0.86 mg, alternatively 0.87 mg, alternatively 0.88 mg,
alternatively
0.89 mg, alternatively 0.9 mg, alternatively 0.91 mg, alternatively 0.92 mg,
alternatively 0.93 mg, alternatively 0.94 mg, alternatively 0.95 mg,
alternatively 0.96
mg, alternatively 0.97 mg, alternatively 0.98 mg, alternatively 0.99 mg.
Any minimum amount and any maximum amount of antagonist in the dosage
form, as specified above, may be combined to define a range of amounts,
providing
that the minimum selected is equal to or less than the maximum selected. In
one
alternative embodiment of the invention the amount of antagonist in the dosage
form
is less than an effective amount to antagonize an exogenous or endogenous
opioid
agonist, but such an amount may include an amount that enhances the potency
and/or
attenuates an adverse effect of the agonist and/or an amount that attenuates
tolerance,
withdrawal, dependence and/or addiction.
In one alternative embodiment of the invention, the antagonist is present in
the
form of a pharmaceutically acceptable salt. For example, a dosage form may
contain
naltrexone hydrochloride as the antagonist. The antagonist can be provided in
a form

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suitable for oral administration. The antagonist can be formulated as a
capsule, tablet,
pill, or solid sprinkle form.
Yet another aspect of the invention is a method of administering a dose of an
opioid antagonist to a human subject by administering a solid dosage form or
kit as
described above, including, for example, wherein the dose of antagonist is
less than an
amount effective to antagonize an exogenous or endogenous opioid agonist,
(e.g., less
than an effective antagonistic amount) but such an amount may include an
amount
that enhances the potency and/or attenuates an adverse effect of the agonist
and/or an
amount that attenuates tolerance, withdrawal, dependence, and/or addiction. In
one
aspect of the invention the method further comprises administering another
active
pharmaceutical ingredient, such as an opioid agonist, either in a combined
dosage
form with the antagonist or in a separate dosage form. Such separate agonist
dosage
form may include solid oral, oral solution, syrup, elixir, inj ectable,
transdermal,
transmucosal, or other dosage form.
Even another aspect of the invention is a pharmaceutical kit comprising a
dosage form of the opioid antagoust and a container. The kit optionally can
also
contain a dosage form of an opioid agonist or another active pharmaceutical
ingredient. The opioid antagonist and another active pharmaceutical ingredient
can be
combined in one dosage form or supplied in separate dosage forms that are
usable
together or sequentially. The opioid antagonist and another active
pharmaceutical
ingredient can be administered, concurrently, before or after the other.
In another alternative embodiment of the invention, an agonist is present as
the
other active pharmaceutical ingredient along with the antagonist. The agonist
may be
present in its original form or in the form of a pharmaceutically acceptable
salt. The
agonist may be present in an amount that is analgesic or subanalgesic (e.g.,
non-
analgesic) in the human subject. The agonist may also be present in an amount
that is
anti-analgesic in the human subject. Agousts include alfentanil,
buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone,
hydromorphone, leuallorphan, leuorphanol, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxmorphone, pentazocine, propoxyphene, and tramadol.
The

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agonist is preferably morphine, hydrocodone, tramadol, or oxycodone, or may
include
combinations thereof.
In another alternative embodiment of the invention, the opioid antagonist is
present with one or more other active pharmaceutical ingredients. For example,
other
active pharmaceutical ingredients include acetaminophen, steroidal or non-
steroidal
anti-inflammatory drugs (NSI~IDs) such as ibuprofen, COX-1 and/or COX-2
inhibitors such as aspirin, rofecoxib (marketed as VIOXX~), and celecoxib
(marketed
as CELEBREXTM).
Still another aspect of the invention provides an immediate release solid oral
dosage form consisting essentially of one or more pharmaceutical excipients, a
dose
of an opioid agonist and a low dose of an opioid antagonist, wherein the
opioid
agonist and opioid antagonist are released concurrently when placed in an
aqueous
enviroimnent. Yet another aspect of the invention provides a solid oral dosage
form
that comprises an opioid agonist and an opioid antagonist and that is
essentially free
of other active pharmaceutical ingredients.
Yet another aspect of the invention is an immediate release combination solid
oral dosage form consisting essentially of an opioid antagonist, another
active
pharmaceutical ingredient such as an opioid agonist, and one or more
pharmaceutical
excipients. The opioid antagonist is present in an amount of about 0.0001 to
about 1.0
mg, alternatively less than about 1.0 mg, alternatively less than about 0.5
mg. The
opioid agonist is present in an amount of about 0.1 to about 300 mg. The
opioid
antagonist and opioid agonist axe released concurrently over a period of less
than
about 1.5 hours.
Specific embodiments of the invention include those wherein: 1) the dosage
form comprises no pharmaceutical excipients that significantly bind, adsorb or
complex the opioid antagonist in an aqueous environment; 2) the opioid
antagonist is
present in an amount ranging from at least about 0.0001 to about 1.0 mg or
less than
about 1.0 mg or from at least about 0.0001 to less than about 0.5 mg, and an
opioid
agonist is optimally present in an amount ranging from about 0.1 to about 300
mg; 3)
the dosage form comprises at least two pharmaceutical excipients; 4) the
dosage form

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comprises a first pellet of the opioid antagonist coated onto a first
nonpareil pellet and
optionally a second pellet of the opioid agonist (or another active
pharmaceutical
ingredient) coated onto a second nonpareil pellet; 5) the dosage form
comprises a
nonpareil pellet coated with a composition of the opioid antagonist,
optionally another
active pharmaceutical ingredient such as an opioid agonist, at least one
polymer, and
at least one plasticizer; 6) the dosage form comprises a first granulation of
another the
opioid antagonist and a first blend of pharmaceutical excipients and
optionally a
second granulation of another active pharmaceutical ingredient such as an
opioid
agonist and a second blend of pharmaceutical excipients; 7) the dosage form
comprises a second granulate containing a mixture of a first granulation, the
opioid
antagonist and at least one pharmaceutical excipient, wherein the first
granulation
comprises another active pharmaceutical ingredient such as an opioid agonist
and at
least one pharmaceutical excipient; 8) the dosage form comprises a coated
granulation
of a mixture of pharmaceutical excipients coated with a binder composition of
a
binder, the opioid antagonist and optionally another active pharmaceutical
ingredient
such as an opioid agonist; 9) the dosage form comprises a coated first
granulate,
wherein the granulate comprises another active pharmaceutical ingredient such
as an
opioid agonist and a mixture of pharmaceutical excipients and the coating
comprises
an opioid antagonist; 10) the dosage form comprises spray-dried granules of
the
opioid antagoW st, optionally another active pharmaceutical ingredient such as
an
opioid agonist and at least one pharmaceutical excipient; 11) the dosage form
comprises a soft gelatin capsule filled with a suspension of the opioid
antagonist,
optionally another active pharmaceutical ingredient such as an opioid agonist
and at
least one nonaqueous vehicle.
Another aspect of the invention provides methods of making an immediate
release solid oral dosage form with a dose of an opioid antagonist and
optionally a
dose of another active pharmaceutical ingredient such as an opioid agonist,
wherein
the opioid antagonist or the opioid antagonist and another active
pharmaceutical
ingredient axe greater than 90% released in less than about 45 minutes after
exposure
to an aqueous environment. Immediate release solid oral dosage forms with

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antagonist and agonist include those wherein the opioid agonist and opioid
antagonist
are released concurrently when placed in an aqueous environment.
Other specific embodiments of the invention.include those wherein the dosage
form is made by: 1) forming a mixture of at least two different coated
pellets, wherein
the first pellet is made by coating the opioid antagonist onto a first
nonpareil pellet
and the second pellet is made by coating another active pharmaceutical
ingredient
onto a second nonpareil pellet; 2) preparing a composition of the opioid
antagonist,
another active pharmaceutical ingredient, at least one polymer, and at least
one
plasticizes and applying the composition to a nonpareil pellet; 3) forming a
first
granulation of an opioid antagonist and a first blend of pharmaceutical
excipients,
forming a second granulation of another active pharmaceutical ingredient and a
second blend of pharmaceutical excipients, and mixing the first and second
granulations; 4) forming a first granulation of an active pharmaceutical
ingredient and
at least one pharmaceutical excipient, and mixing the first granulation, the
opioid
antagonist and at least one pharmaceutical excipient to form a second
granulation; 5)
preparing a binder composition of a binder, an opioid antagonist, another
active
pharmaceutical ingredient and coating a mixture of pharmaceutical excipients
with the
binder composition to form a coated granulation; 6) coating a composition of
an
active pharmaceutical ingredient and a mixture of pharmaceutical excipients
and with
a coating composition of an opioid antagonist; 7) spray-drying a solution of
an opioid
antagonist, another active pharmaceutical ingredient and at least one
pharmaceutical
excipient to form spray-dried granules; or 8) filling a soft gelatin capsule
with a
dispersion of an opioid antagonist, another active pharmaceutical ingredient
and at
least one non-aqueous vehicle.
BRIEF DESCRIPTION OF THE DRAWINGS
The following figures form part of the present description and describe
exemplary embodiments of the claimed invention. The skilled artisan will, in
light of
these figures and the description herein, be able to practice the invention
without
undue experimentation.

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FIG. lA-1B is a flow diagram illustrating a method of manufacturing
naltrexone capsule dosage forms according to a disclosed embodiment.
FIG. 2 depicts an embodiment of an immediate release dosage form with two
different types of coated nonpareil pellets.
FIG. 3 depicts an embodiment of an immediate release dosage form with a
single type of coated nonpareil pellets.
FIG. 4 depicts an embodiment of the invention of a mixture containing two
different types of granules.
FIG. 5 depicts an embodiment of the invention of a coated granule.
FIG. 6 depicts an embodiment of the invention of a granule dispersed within
an optional pharmaceutical excipient composition.
FIG. 7 depicts a graph demonstrating the relationship between opioid agonist
to opioid antagonist ratio and the amount of a formulation with respect to the
total
weight of a pharmaceutical composition according to the invention. This
relationship
holds true for the embodiments of FIGS. 2 and 4.
FIG. 8 depicts a graph demonstrating the relationship between opioid agonist
to opioid antagonist ratio and the amount of a first formulation with respect
to the
total weight of a pharmaceutical composition according to the invention. This
relationship holds true for the embodiments of FIGS. 3, 5 and 6.
FIG. 9 depicts an i~z vity°~ dissolution profile for the exemplary
coated tablets
of Example 12.
DETAILED DESCRIPTION
The present disclosure is directed to novel pharmaceutical compositions of
very low doses of opioid antagonists. Novel dosage forms of such mtagonists
have
been manufactured for the first time and administered to human subjects with
unexpected benefits. Such novel dosage forms when administered to human
subjects
enhance the analgesic potency of opioid agonists and/or attenuate (e.g.,
reduce, block,
inhibit or prevent) their adverse side effects and/or attenuate tolerance,
withdrawal,
dependence and/or addiction. For example, such novel dosage forms
simultaneously

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enhance the analgesic potency of an opioid agonist while attenuating side
effects of
the agonist, or enhance the analgesic potency of an opioid agonist without
attenuating
side effects of the agonist, or maintain the analgesic potency of an agonist
while
attenuating side effects of the agonist, while at the same time or
alternatively,
attenuate tolerance, withdrawal, dependence and/or addiction. For compositions
and
methods of the invention that attenuate (e.g., reduce, block or prevent) an
adverse
effect of the opioid agonist, it is advantageous that the analgesic potency is
maintained without increasing or decreasing the cumulative daily dose of
agonist.
The present invention includes the manufacture and use of new dosage forms
of very small amounts of an opioid antagoiust. Clinical trials have yielded
surprising
effects and benefits in humans. For example, using novel pharmaceutical
compositions or dosage forms according to the invention, it was unexpectedly
demonstrated that the analgesic potency effects of opioid agonists can be
dissociated
from their adverse effects in humans. Thus, for the first time, the present
invention
provides novel pharmaceutical compositions, dosage forms, kits, and methods to
dose
or treat humans with opioid antagonists. An opioid antagonist is provided in
an
amount from at least about 0.0001 mg to about or less than about 1.0 mg, or at
least
about 0.001 mg to about or less than about 1.0 mg, or at least about 0.01 mg
to about
or less than about 1.0 mg ar at least about 0.1 mg to about or less than about
1 mg.
Preferred ranges of opioid antagonists also include: from about 0.0001 mg to
less
than 1.0 mg; from about 0.001 mg to less than 1.0 mg; from about 0.01 mg to
less
than 1.0 mg; or from about 0.1 mg to less than 1.0 mg. Additional preferred
ranges of
opioid antagonists include from about 0.0001 mg to about 0.1 mg; from about
0.001
mg to about 0.1 mg; from about 0.01 mg. to about 0.1 mg; from about 0.001 mg
to
about 0.1 mg; from about 0.001 mg to about 0.01 mg; or from about 0.01 mg to
about
0.1 mg. Further preferred ranges of opioid antagonists include: from at least
about
0.0001 to less than about 0.5 mg; from at least about 0.01 to less than about
0.5 mg; or
from at least about 0.1 to less than about 0.5 mg.
The term "opioid'° refers to compounds or compositions including
metabolites
of such compounds or compositions which bind to specific opioid receptors and
have

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agonist (activation) or antagonist (inactivation) effects at these receptors,
such as
opioid alkaloids, including the agonist morphine and its metabolite morphine-6-
glucuronide and the antagonist naltrexone and its metabolite and opioid
peptides,
including enkephalins, dynorphins and endorphins. The opioid can be present in
the
present compositions as an opioid base, an opioid pharmaceutically acceptable
salt, or
a combination thereof. The pharmaceutically acceptable salt embraces an
inorganic
or an organic salt. Representative salts include hydrobromide, hydrochloride,
mucate,
succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate
monobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate,
bi(methylcarbamate),
bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate),
bi(trifluoroacetate),
bitartrate, chlorhydrate, fumarate and sulfate pentahydrate. The term "opiate"
refers
to drugs derived from opium or related natural or synthetic analogs.
An "opioid receptor agonist" or "opioid agonist" is an opioid compound or
composition including any active metabolite of such compound or composition
that
binds to and activates opioid receptors on nociceptive neurons which mediate
pain.
Such opioid agonists have analgesic activity (with measurable onset, peak,
duration
and/or total effect and can produce analgesia. Opioid agonists according to
the
present invention include: alfentanil, allylprodine, alphaprodine,
anileridine,
apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine,
butorphanol,
clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate,
dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorplune,
etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan,
levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,
metazocine,
methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine,
nicomorphine, norlevorphanol, nonnethadone, nalorphine, normorphine,
norpipanone,
ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, pholcodine, piminodine,

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piritramide, propheptazine, promedol, profadol, properidine, propiram,
propoxyphene,
remifentanyl, sufentanyl, tramadol, tilidine, salts thereof, mixtures of any
of the
foregoing, mixed mu-agonists/antagonists, mu-antagonist combinations, or
others
known to those skilled in the art. Preferred opioid agonists for human use are
morphine, hydrocodone, oxycodone, codeine, fentanyl (and its relatives),
hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol,
or mixtures thereof. Particularly preferred contemplated agonists include
morphine,
hydrocodone, oxycodone or tramadol. Opioid agonists include exogenous or
endogenous opioids.
"Bimodally-acting opioid agonists" are opioid agonists that bind to and
activate both inhibitory and excitatory opioid receptors on nociceptive
neurons which
mediate pain. Activation of inhibitory receptors by said agonists causes
analgesia.
Activation of excitatory receptors by said agonists results in anti-analgesia,
hyperexcitability, hyperalgesia, as well as development of physical
dependence,
tolerance and other undesirable side effects. Bimodally-acting opioid agonists
may be
identified by measuring the opioid's effect on the action potential duration
(APD) of
dorsal root ganglion (DRG) neurons in tissue cultures. In this regard,
bimodally-
acting opioid agonists are compounds which elicit prolongation of the APD of
DRG
neurons at pM-nM concentrations (i.e. excitatory effects), and shortening of
the APD
of DRG neurons at ~M concentrations (z. e., inhibitory effects).
An "opioid antagonist" is an opioid compound or composition including any
active metabolite of such compound or composition that in a sufficient amount
attenuates (e.g., blocks, inhibits, prevents or competes with) the action of
an opioid
agonist. An "effective antagonistic" amount is one which effectively
attenuates the
analgesic activity of an opioid agonist. For example, 50 mg naltrexone is
recognized
to be an effective antagonistic amount. Such attenuation is demonstrated when
the
compouxld or composition is used in an effective antagonistic dose. An opioid
antagonist binds to and blocks (e.g., inhibits) opioid receptors on
nociceptive neurons
which mediate pain. Opioid antagonists include: naltrexone (marketed in 50 mg
dosage forms as ReVia° or Trexari ), naloxone (marketed as Narcan~),
nahnefene,

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methylnaltrexone, naloxone methiodide, nalorphine, naloxonazine, nalide,
nalmexone,
nalbuphine, nalorphine dinicotinate, naltrindole (NTI), naltrindole
isothiocyanate,
(NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI), b-funaltrexamine (b-
FNA),
BNTX, cyprodime, ICI-174,864, LY117413, MR2266, or an opioid antagonist having
the same pentacyclic nucleus as nalmefene, naltrexone, nalorphine, nalbuphine,
thebaine, levallorphan, oxymorphone, butorphanol, buprenorphine, levorphanol,
meptazinol, pentazocine, dezocine, or their pharmacologically effective esters
or salts.
In some embodiments, the opioid antagonist is naltrexone, nalmefene, naloxone,
or
mixtures thereof. A specifically contemplated antagonist is naltrexone.
"Excitatory opioid receptor antagonists" are opioids which bind to and act as
antagonists to excitatory but not inhibitory opioid receptors on nociceptive
neurons
which mediate pain. That is, excitatory opioid receptor antagonists are
compounds
which bind to excitatory opioid receptors and selectively block excitatory
opioid
receptor functions of nociceptive types of DRG neurons at 1,000 to 10,000-fold
lower
concentrations than are required to block inhibitory opioid receptor functions
in these
neurons. Excitatory opioid receptor antagonists may also be identified by
measuring
their effect on the action potential duration (APD) of dorsal root ganglion
(DRG)
neurons in tissue cultures. In this regard, excitatory opioid receptor
antagonists are
compounds that selectively block prolongation of the APD of DRG neurons (i.e.,
excitatory effects) but not the shortening of the APD of DRG neurons (i. e.,
inhibitory
effects) elicited by a bimodally-acting opioid receptor agonist. Suitable
excitatory
opioid receptor antagonists include nalinefene, naltrexone, naloxone,
etorphine and
dihydroetorphine, as well as similarly acting opioid alkaloids and opioid
peptides.
Preferred excitatory opioid receptor antagonists are naltrexone and nalinefene
because
of their longer duration of action as compared to naloxone and their greater
bioavailability after oral administration.
The opioid antagonists or (if used) opioid agonists or another active
pharmaceutical ingredients may be provided in the form of free bases or
pharmaceutically acceptable acid addition salts. As used herein,
"pharmaceutically
acceptable salts" refer to derivatives of the disclosed compounds wherein the

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therapeutic compound is modified by making acid or base salts thereof. The
pharmaceutically acceptable salt embraces an inorganic or an organic salt.
Exaanples of pharmaceutically acceptable salts include, but are not limited
to,
mineral or organic acid salts of the opioid antagonist or opioid agonist. The
pharmaceutically acceptable salts include the conventional non-toxic salts
made, for
example, from non-toxic inorganic or organic acids. For example, such
conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric,
hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known
to
those skilled in the art; and the salts prepared from organic acids such as
amino acids,
acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic,
tartaric, citric,
ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane
disulfonic, oxalic, isethionic, glucuronic, and other acids. Other
pharmaceutically
acceptable salts and variants include mutates, phosphate (dibasic), phosphate
(monobasic), acetate trihydrate, bi(heptafluorobutyrate), bi(methylcarbamate),
bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate),
bi(trifluoroacetate),
bitartrate, chlorhydrate, and sulfate pentahydrate. An oxide, though not
usually
referred to by chemists as a salt, is also a "pharmaceutically acceptable
salt" for the
present purpose. For acidic compounds, the salt may include an amine-based
(primary, secondary, tertiary or quaternary amine) counter ion, an allcali
metal canon,
or a metal ration. Lists of suitable salts are found in texts such as
Remington °s
Phaz~fnaceutical Sciences, 1 gti' Ed. (Alfonso R. Gennaro, ed.; Mack
Publislung
Company, Easton, PA, 1990); Reznirzgton: the Science and Practice of Phaf-macy
19~j'
Ed.( Lippincott, Williams 8L Wilkins, 1995); Handbook of Pharmaceutical
Excipients, 3rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999);
the
Plzannzaceutical Codex: Principles arzd P>"actice of Phaf°maceutics
12t~' Ed. (Walter
Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia:
The National Formulary (United States Pharmacopeial Convention); and Goodman
and Gilznafz °s: the Pharmacological Basis of Therapeutics (Louis S.
Goodman and

CA 02408106 2002-11-05
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Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby
incorporated by reference.
The phrase "pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the
scope
of sound medical judgment, suitable for use in contact with the tissues of
human
beings and animals Without excessive toxicity, irritation, allergic response,
or other
problem or complication, commensurate with a reasonable benefit/risk ratio.
The maximum amount of antagonist in the dosage form is 1 mg, alternatively
less than 1 mg, alternatively 0.99 mg, alternatively 0.98 mg, alternatively
0.97 mg,
alternatively 0.96 mg, alternatively 0.95 mg, alternatively 0.94 mg,
alternatively 0.93
mg, alternatively 0.92 mg, alternatively 0.91 mg, alternatively 0.90 mg,
alternatively
0.89 mg, alternatively 0.88 mg, alternatively 0.87 mg, alternatively 0.86 mg,
alternatively 0.85 mg, alternatively 0.84 mg, alternatively 0.83 mg,
alternatively 0.82
mg, alternatively 0.81 mg, alternatively 0.80 mg, alternatively 0.79 mg,
alternatively
0.78 mg, alternatively 0.77 mg, alternatively 0.76 mg, alternatively 0.75 mg,
alternatively 0.74 mg, alternatively 0.73 mg, alternatively 0.72 mg,
alternatively 0.71
mg, alternatively 0.70 mg, alternatively 0.69 mg, alternatively 0.68 mg,
alternatively
0.67 mg, alternatively 0.66 mg, alternatively 0.65 mg, alternatively 0.64 mg,
alternatively 0.63 mg, alternatively 0.62 mg, alternatively 0.61 mg,
alternatively 0.60
mg, alternatively 0.59 rng, alternatively 0.58 mg, alternatively 0.57 mg,
alternatively
0.56 mg, alternatively 0.55 mg, alternatively 0.54 mg, alternatively 0.53 mg,
alternatively 0.52 mg, alternatively 0.51 mg, alternatively 0.50 mg.
Additionally, the maximum amount of antagonist in the dosage form is less
than 0.5 mg, alternatively 0.49 mg, alternatively 0.48 mg, alternatively 0.47
mg,
alternatively 0.46 mg, alternatively 0.45 mg, alternatively 0.44 mg,
alternatively 0.43
mg, alternatively 0.42 mg, alternatively 0.41 mg, alternatively 0.40 mg,
alternatively
0.39 mg, alternatively 0.38 mg, alternatively 0.37 mg, alternatively 0.36 mg,
alternatively 0.35 mg, alternatively 0.34 mg, alternatively 0.33 mg,
alternatively 0.32
mg, alternatively 0.31 mg, alternatively 0.30 mg, alternatively 0.29 mg,
alternatively
0.28 mg, alternatively 0.27 mg, alternatively 0.26 mg, alternatively 0.25 mg,

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_ 28 _
alternatively 0.24 mg, alternatively 0.23 mg, alternatively 0.22 mg,
alternatively 0.21
mg, alternatively 0.20 mg, alternatively 0.19 mg, alternatively 0.18 mg,
alternatively
0.17 mg, alternatively 0.16 mg, alternatively 0.15 mg, alternatively 0.14 mg,
alternatively 0.13 mg, alternatively 0.12 mg, alternatively 0.11 mg,
alternatively 0.10
mg, alternatively 0.09 mg, alternatively 0.08 mg, alternatively 0.07 mg,
alternatively
0.06 mg, alternatively 0.05 mg, alternatively 0.04 mg, alternatively 0.03 rng,
alternatively 0.02 mg, alternatively 0.01 mg, alternatively 0.009 mg,
alternatively
0.008 mg, alternatively 0.007 mg, alternatively 0.006 mg, alternatively 0.005
mg,
alternatively 0.004 mg, alternatively 0.003 mg, alternatively 0.002 mg,
alternatively
0.001 mg, alternatively 0.0009 mg, alternatively 0.0008 mg, alternatively
0.0007 mg,
alternatively 0.0006 mg, alternatively 0.0005 mg, alternatively 0.0004 mg,
alternatively 0.0003 mg, alternatively 0.0002 mg.
The minimum amount of antagonist in the dosage form is 0.0001 mg,
alternatively 0.0002 mg, alternatively 0.0003 mg, alternatively 0.0004 mg,
alternatively 0.0005 mg, 0.0006 mg, alternatively 0.0007 mg, alternatively
0.0008 mg,
alternatively 0.0009 mg, alternatively 0.001 mg, alternatively 0.002 mg,
alternatively
0.003 mg, alternatively 0.004 mg, alternatively 0.005 mg, alternatively 0.006
mg,
alternatively 0.007 mg, alternatively 0.008 mg, alternatively 0.009 mg,
alternatively
0.01 mg, alternatively 0.011 mg, alternatively 0.012 mg, alternatively 0.013
mg,
alternatively 0.014 mg, alternatively 0.015 mg, alternatively 0.016 mg,
alternatively
0.017 mg, alternatively 0.018 mg, alternatively 0.019 mg, alternatively 0.02
mg,
alternatively 0.021 mg, alternatively 0.022 mg, alternatively 0.023 mg,
alternatively
0.024 mg, alternatively 0.025 mg, alternatively 0.026 mg, alternatively 0.027
mg,
alternatively 0.028 mg, alternatively 0.029 mg, alternatively 0.03 mg,
alternatively
0.031 mg, alternatively 0.032 mg, alternatively 0.033 mg, alternatively 0.034
mg,
alternatively 0.035 mg, alternatively 0.036 mg, alternatively 0.037 mg,
alternatively
0.038 mg, alternatively 0.039 mg, alternatively 0.04 mg, alternatively 0.041
mg,
alternatively 0.042 mg, alternatively 0.043 mg, alternatively 0.044 mg,
alternatively
0.045 mg, alternatively 0.046 mg, alternatively 0.047 mg, alternatively 0.048
mg,
alternatively 0.049 mg, alternatively 0.05 mg, alternatively 0.051 mg,
alternatively

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0.052 mg, alternatively 0.053 mg, alternatively 0.054 mg, alternatively 0.055
mg,
alternatively 0.056 mg, alternatively 0.057 mg, alternatively 0.058 mg,
alternatively
0.059 mg, alternatively 0.06 mg, alternatively 0.061 mg, alternatively 0.062
mg,
alternatively 0.063 mg, alternatively 0.064 mg, alternatively 0.065 mg,
alternatively
0.066 mg, alternatively 0.067 mg, alternatively 0.068 mg, alternatively 0.069
mg,
alternatively 0.07 mg, alternatively 0.071 mg, alternatively 0.072 mg,
alternatively
0.073 mg, alternatively 0.074 mg, alternatively 0.075 mg, alternatively 0.076
mg,
alternatively 0.077 mg, alternatively 0.078 mg, alternatively 0.079 mg,
alternatively
0.08 mg, alternatively 0.081 mg, alternatively 0.082 mg, alternatively 0.083
mg,
alternatively 0.084 mg, alternatively 0.085 mg, alternatively 0.086 mg,
alternatively
0.087 mg, alternatively 0.088 mg, alternatively 0.089 mg, alternatively 0.09
mg,
alternatively 0.091 mg, alternatively 0.092 mg, alternatively 0.093 mg,
alternatively
0.094 mg, alternatively 0.095 mg, alternatively 0.096 mg, alternatively 0.097
mg,
alternatively 0.098 mg, alternatively 0.099 mg, alternatively 0.1 mg,
alternatively 0.11
mg, alternatively 0.12 mg, alternatively 0.13 mg, alternatively 0.14 mg, 0.15
mg,
alternatively 0.16 mg, alternatively 0.17 mg, alternatively 0.18 mg,
alternatively 0.19
mg, alternatively 0.2 mg, alternatively 0.21 mg, alternatively 0.22 mg,
alternatively
0.23 mg, alternatively 0.24 mg, alternatively 0.25 mg, alternatively 0.26 mg,
alternatively 0.27 mg, alternatively 0.28 mg, alternatively 0.29 mg,
alternatively 0.3
mg, alternatively 0.31 mg, alternatively 0.32 rng, alternatively 0.33 mg,
alternatively
0.34 mg, alternatively 0.35 mg, alternatively 0.36 mg, alternatively 0.37 mg,
alternatively 0.38 mg, alternatively 0.39 mg alternatively 0.40 mg,
alternatively 0.41
mg, alternatively 0.42 mg, alternatively 0.43 mg, alternatively 0.44 mg,
alternatively
0.45 mg, alternatively 0.46 mg, alternatively 0.47 mg, alternatively 0.48 mg,
alternatively 0.49 mg, alternatively 0.5 mg, alternatively 0.51 mg,
alternatively 0.52
mg, alternatively 0.53 mg, alternatively 0.54 mg, alternatively 0.55 mg,
alternatively
0.56 mg, alternatively 0.57 mg, alternatively 0.58 mg, alternatively 0.59 mg,
alternatively 0.6 mg, alternatively 0.61 mg, alternatively 0.62 mg,
alternatively 0.63
mg, alternatively 0.64 mg, alternatively 0.65 mg, alternatively 0.66 mg,
alternatively
0.67 mg, alternatively 0.68 mg, alternatively 0.69 mg, alternatively 0.7 mg,

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alternatively 0.71 mg, alternatively 0.72 mg, alternatively 0.73 mg,
alternatively 0.74
mg, alternatively 0.75 mg., alternatively 0.76 mg, alternatively 0.77 mg,
alternatively
0.78 mg, alternatively 0.79 mg, alternatively 0.8 mg, alternatively 0.81 mg,
alternatively 0.82 mg, alternatively 0.83 mg, alternatively 0.84 mg,
alternatively 0.85
mg, alternatively 0.86 mg, alternatively 0.87 mg, alternatively 0.88 mg,
alternatively
0.89 mg, alternatively 0.9 mg, alternatively 0.91 mg, alternatively 0.92 mg,
alternatively 0.93 mg, alternatively 0.94 mg, alternatively 0.95 mg,
alternatively 0.96
mg, alternatively 0.97 mg, alternatively 0.98 mg, alternatively 0.99 mg.
Any minimum and any maximum amount of antagonist in the dosage form, as
specified above, may be combined to define a range of amounts, providing that
the
minimum selected is equal to or less than the maximum selected. In one
alternative
embodiment of the invention with an opioid antagonist and an opioid agonist,
the
amount of antagonist in the dosage form is less than an effective amount to
antagonize
an exogenous or endogenous opioid agonist, but such an amount may include an
amount that enhances the potency and/or attenuates an adverse effect of the
agonist,
and/or attenuates tolerance, withdrawal, dependence and/or addiction.
If used in combination with the opioid antagonist, the opioid agonist is
administered in dosage forms containing from about 0.1 to about 300 mg of
opioid
agonist. The opioid antagonist, alone or in conjunction with opioid agonist,
is
included in the dosage form in an amount sufficient to produce the desired
effect upon
the process or condition, including a variety of conditions and diseases in
mammals.
When the opioid antagonist is used in combination with the opioid agonist, the
amount of the opioid agonist administered may be an analgesic or sub-analgesic
amomit. As used herein, an "analgesic" amount is amount of the opioid agonist
which
causes analgesia in a subject administered the opioid agonist alone, and
includes
standard doses of the agonist which are typically administered to cause
analgesia
(e.g., mg doses). A "sub-analgesic" amount is an amount which does not cause
analgesia in a subject administered the opioid agonist alone, but when used
iii
combination with the opioid antagoiust, results in analgesia. A "non-
analgesic"
amount is an amount which does not cause analgesia when administered to a
subject

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while an "anti-analgesic" amount is an amount which causes algesia (i.e.,
pain) when
administered to a subject. The amount of the opioid antagonist may be an
amount
effective to enhance the analgesic potency of and/or attenuate the adverse
side effects
of the opioid agonist, while at the same time or alternatively, attenuate
tolerance,
withdrawal, dependence and/or addiction. The amount of the opioid antagonist
may
be less than an effective antagonistic amount or an ineffective antagonistic
amount,
yet still provide some or all of the foregoing benefits. The optimum amounts
of the
opioid antagonist administered alone or in combination with an opioid agonist
or
other therapeutic agent will of course depend upon the particular agonist and
antagonist used, the excipient chosen, the route of administration, and/or the
pharmacol~inetic properties of the patient being treated.
The dosage forms may be made and used in the form of a pharmaceutical
preparation, for example, in solid, semisolid, or liquid form, which contains
one or
more opioid antagonists as an active ingredient, alone or in combination with
one or
more additional active pharmaceutical ingredients, such as opioid agonists.
Dosage forms according to the invention may comprise a specified active
pharmaceutical ingredient, also referred to as an active ingredient or
therapeutic agent
either alone or in combination with pharmaceutical excipients and other active
pharmaceutical ingredient. An "active pharmaceutical ingredient" is defined as
any
substance or mixture of substances intended to be used in the manufacture of a
drug
(medicinal) product and that, when used in the production of a drug, becomes
an
active ingredient of the drug product. Such substances are intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation,
treatment, or prevention of disease or to affect the structure and function of
the body.
See Draft Consensus Guideline for Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredient, International Conference on Harmonisation of TechW
cal
Requirements for Registration of Pharmaceuticals for Human Use, release for
consultation on July 19, 2000. Other dosage forms may consist essentially of
one or
more active pharmaceutical ingredients. A dosage form "consisting essentially
of
one or more active pharmaceutical ingredients is one that contains only those
active

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pharmaceutical ingredients and one or more pharmaceutical excipients, but does
not
contain any other active pharmaceutical ingredients. As an example, a dosage
form
consisting essentially of an opioid antagonist may also contain a binder and a
lubricant, but does not contain an active pharmaceutical ingredient other than
the
opioid a~ztagonist. As another example, a dosage form consisting essentially
of an
opioid agonist and an opioid antagonist may also contain a binder and a
lubricant, but
does not contain an active pharmaceutical ingredient other than the opioid
agonist and
the opioid antagonist.
Any opioid antagonist or opioid agonist may be in admixture with an organic
or inorganic carrier or excipient suitable for administration in enteral or
parenteral
applications, such as orally, topically, transdermally, by inhalation spray,
rectally, by
subcutaneous, intravenous, intramuscular, subcutaneous, or intrasternal
injection or
infusion techniques.
The opioid antagonist, alone or in combination with mother active
pharmaceutical ingredient, such as an opioid agonist, may be compounded, for
example, with the usual non-toxic, pharmaceutically acceptable excipients,
carriers,
diluents or other adjuvants. The choice of adjuvants will depend upon the
active
ingredients employed, the physical form of the composition, the route of
administration, and other factors.
The excipients, binders, carriers, and diluents which can be used include
water, glucose, lactose, natural sugars such as sucrose, glucose, or corn
sweeteners,
sorbitol, natural and synthetic gums such as gum acacia, tragacanth, sodium
alginate,
and gum arabic, gelatin, mannitol, starches such as starch paste, corn starch,
or potato
starch, magnesium trisilicate, talc, keratin, colloidal silica, urea, stearic
acid,
magnesium stearate, dibasic calcium phosphate, crystalline cellulose, methyl
cellulose, carboxymethyl cellulose, polyethylene glycol, waxes, glycerin, and
saline
solution, among others.
Suitable dispersing or suspending agents for aqueous suspensions include
synthetic and natural gums such as tragacanth, acacia, alginate, dextran,
sodium
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

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The dosage forms can also comprise one or more acidifying agents,
adsorbents, alkalizing agents, antiadherents, antioxidants, binders, buffering
agents,
colorants, complexing agents, diluents or fillers, direct compression
excipients,
disintegrants, flavorants, fragrances, glidants, lubricants, opaquants,
plasticizers,
polishing agents, preservatives, sweetening agents, or other ingredients known
for use
in pharmaceutical preparations.
As used herein, the term °'acidifying agent" is intended to mean a
compound
used to provide an acidic medium for product stability. Such compounds
include, by
way of example and without limitation, acetic acid, amino acid, citric acid,
fumaric
acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, nitric
acid,
phosphoric acid, and others known to those skilled in the art.
As used herein, the term "adsorbent" is intended to mean an agent capable of
holding other molecules onto its surface by physical or chemical
(chemisorption)
means. Such compounds include, by way of example and without limitation,
powdered and activated charcoal, zeolites, and other materials known to one of
ordinary skill in the art.
As used herein, the term "alkalizing agent" is intended to mean a compound
used to provide an alkaline medium for product stability. Such compounds
include,
by way of example and without limitation, ammonia solution, ammonium
carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium
carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and
trolamine and
others known to those skilled in the art.
As used herein, the term "antiadherent" is intended to mean an agent that
prevents the sticl~ing of solid dosage formulation ingredients to punches and
dies in a
tableting machine during production. Such compounds include, by way of example
and without limitation, magnesium stearate, talc, calcium stearate, glyceryl
behenate,
PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials
known
to one of ordinary shill in the art.
As used herein, the term "antioxidant" is intended to mean an agent which
inhibits oxidation and thus is used to prevent the deterioration of
preparations by the

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oxidative process. Such compounds include, by way of example and without
limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
butylated
hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium
ascorbate, sodium bisulfate, sodium formaldehyde sulfoxylate and sodium
metabisulfite and other materials known to one of ordinary skill in the art.
As used herein, the term "binder" is intended to mean a substance used to
cause adhesion of powder particles in solid dosage formulations. Such
compounds
include, by way of example and without limitation, acacia, alginic acid,
carboxymethylcellulose sodium, poly(vinylpyrrolidone), compressible sugar
(e.g.,
NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and
pregelatinized starch and other materials known to one of ordinary skill in
the art.
When needed, binders may also be included in the dosage forms. Exemplary
binders include acacia, tragacanth, gelatin, starch, cellulose materials such
as methyl
cellulose, HPMC, HPC, HEC and sodium carboxy methyl cellulose, alginic acids
and
salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites,
sugars, invert
sugars, poloxamers (PLURONICTM F68, PLURONICTM F127), collagen, albumin,
gelatin, cellulosics in nonaqueous solvents, combinations thereof and others
known to
those skilled in the art. Other binders include, for example, polypropylene
glycol,
polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene
sorbitan ester, polyethylene oxide, combinations thereof and other materials
known to
one of ordinary skill in the art.
As used herein, the term "buffering agent" is intended to mean a compound
used to resist changes in pH upon dilution or addition of acid or alkali. Such
compounds include, by way of example and without limitation, potassium
metaphosphate, potassium phosphate, monobasic sodium acetate and sodium
citrate
anhydrous and dihydrate and other materials known to one of ordinary skill in
the art.
As used herein, the term "sweetening agent" is intended to mean a compound
used to impart sweetness to a preparation. Such compounds include, by way of
example and without limitation, aspartame, dextrose, glycerin, mannitol,
saccharin
sodium, sorbitol, sucrose, and other materials known to one of ordinary skill
in the art.

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As used herein, the term "diluent" or "filler" is intended to mean an inert
substance used to create the desired bulk, flow properties, and compression
characteristics in the preparation of solid dosage forms. Such compounds
include, by
way of example and without limitation, dibasic calcium phosphate, kaolin,
lactose,
dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose,
powdered cellulose, precipitated calcium carbonate, calcium sulfate, sorbitol,
and
starch acid other materials known to one of ordinary skill in the art.
As used herein, the term "direct compression excipient" is intended to mean a
compound used in compressed solid dosage forms. Such compounds include, by way
of example and without limitation, dibasic calcium phosphate (e.g., Ditab) and
other
materials known to one of ordinary skill in the art.
As used herein, the term "disintegrant" is intended to mean a compound used
in solid dosage forms to promote the disruption of the solid mass into smaller
particles
which are more readily dispersed or dissolved. Exemplary disintegrants
include, by
way of example and without limitation, starches such as corn starch, potato
starch,
pre-gelatinized and modified starches thereof, sweeteners, clays such as
bentonite,
microcrystalline cellulose (e.g., Avicel), methyl cellulose,
carboxymethylcellulose
calcium, sodium carboxymethylcellulose, alginic acid, sodium alginate,
cellulose
polyacrilin potassium (e.g., Amberlite), alginates, sodium starch glycolate,
gums,
agar, guar, locust bean, karaya, xanthan, pectin, tragacanth, agar, bentonite,
and other
materials blown to one of ordinary skill in the art.
As used herein, the teen "glidant" is intended to mean an agent used in solid
dosage formulations to promote flowability of the solid mass. Such compounds
include, by way of example and without limitation, colloidal silica,
cornstarch, talc,
calcium silicate, magnesium silicate, colloidal silicon, tribasic calcium
phosphate,
silicon hydrogel and other materials known to one of ordinary skill in the
art.
As used herein, the term °'lubricant" is intended to mean a substance
used in
solid dosage formulations to reduce friction during compression. Such
compounds
include, by way of example and without limitation, sodium oleate, sodium
stearate,
calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol,
talc, mineral

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oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, and other
materials known to one of ordinary skill in the art.
As used herein, the term "opaquant" is intended to mean a compound used to
render a coating opaque. An opaquant may be used alone or in combination with
a
colorant. Such compounds include, by way of example and without limitation,
titanium dioxide, talc and other materials known to one of ordinary skill in
the art.
As used herein, the term '°polishing agent" is intended to mean a
compound
used to impart an attractive sheen to solid dosage forms. Such compounds
include, by
way of example and without limitation, carnauba wax, white wax and other
materials
known to one of ordinary skill in the art.
As used herein, the term "colorant" is intended to mean a compound used to
impart color to solid (e.g., tablets) pharmaceutical preparations. Such
compounds
include, by way of example and without limitation, FD&C Red No. 3, FD&C Red
No.
20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5,
D&C Red No. S, caramel, ferric oxide, other FD&C dyes and natural coloring
agents
such as grape skin extract, beet red powder, beta-carotene, annato, carmine,
turmeric,
paprika, and other materials known to one of ordinary skill in the art. The
amount of
coloring agent used will vary as desired.
As used herein, the term "flavorant" is intended to mean a compound used to
impart a pleasant flavor and often odor to a pharmaceutical preparation.
Exemplary
flavoring agents or flavorants include synthetic flavor oils and flavoring
aromatics
and/or natural oils, extracts from plants, leaves, flowers, fruits and so
forth and
combinations thereof. These may also include cinnamon oil, oil of wintergreen,
peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar
leave oil, oil
of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful
flavors
include vanilla, citrus oil, including lemon, orange, grape, lime and
grapefruit, and
fruit essences, including apple, pear, peach, strawberry, raspberry, cherry,
plum,
pineapple, apricot and so forth. Flavors which have been found to be
particularly
useful include commercially available orange, grape, cherry and bubble gum
flavors
and mixtures thereof. The amount of flavoring may depend on a number of
factors,

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including the organoleptic effect desired. Flavors will be present in any
amount as
desired by those skilled in the art. Particularly contemplated flavors are the
grape and
cherry flavors and citrus flavors such as orange.
Complexing agents include for example EDTA disodium or its other salts and
other agents known to one of ordinary skill in the art.
Exemplary fragrances include those generally accepted as FD&C grade.
Exemplary preservatives include materials that inhibit bacterial growth, such
as Nipagin, Nipasol, alcohol, antimicrobial agents, benzoic acid, sodium
benzoate,
benzyl alcohol, sorbic acid, parabens, isopropyl alcohol and others known to
one of
ordinary skill in the art.
The solid dosage forms of the invention can also employ one or more surface
active agents or cosolvents that improve wetting or disintegration of the core
and/or
layer of the solid dosage form.
Plasticizers can also be included in the tablets to modify the properties and
characteristics of the polymers used in the coats or core of the tablets. As
used herein,
the term "plasticizer" includes all compounds capable of plasticizing or
softening a
polymer or binder used in invention. The plasticizer should be able to lower
the
melting temperature or glass transition temperature (softening point
temperature) of
the polymer or binder. Plasticizers, such as low molecular weight PEG,
generally
broaden the average molecular weight of a polymer in which they are included
thereby lowering its glass transition temperature or softening point.
Plasticizers also
generally reduce the viscosity of a polymer. It is possible the plasticizer
will impart
some particularly advantageous physical properties to the dosage form of the
invention.
Plasticizers useful in the invention can include, by way of example and
without limitation, low molecular weight polymers, oligomers, copolymers,
oils,
small organic molecules, low molecular weight polyols having aliphatic
hydroxyls,
ester-type plasticizers, glycol ethers, polypropylene glycol), multi-block
polymers,
single block polymers, low molecular weight polyethylene glycol), citrate
ester-type
plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can
also

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include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene
glycol,
diethylene glycol, triethylene glycol, tetraethylene glycol and other
polyethylene
glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol
monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl
ether,
sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,
dibutylsebacate,
acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, ti-ibutyl
citrate and allyl
glycolate. All such plasticizers are commercially available from sources such
as
Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of
the
invention, that a combination of plasticizers may be used in the present
formulation.
The PEG based plasticizers are available commercially or can be made by a
variety of
methods, such as disclosed in Poly(etlZylene glycol) Claefnistry: Biotechnical
and
Biomedical Applicatioyas (J.M. Harris, Ed.; Plenum Press, NY) the disclosure
of which
is hereby incorporated by reference.
The solid dosage forms of the invention can also include oils, for example,
fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive
oil; fatty
acids, such as oleic acid, stearic acid and isostearic acid; and fatty acid
esters, such as
ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty
acid
glycerides. It can also be mixed with alcohols, such as ethanol, isopropanol,
hexadecyl alcohol, glycerol and propylene glycol; with glycerol lcetals, such
as 2,2-
dimethyl-1,3-dioxolane-4-methanol; with ethers, such as poly(ethyleneglycol)
450,
with petroleum hydrocarbons, such as mineral oil and petrolatum; with water,
or with
mixtures thereof; with or without the addition of a pharmaceutically suitable
surfactant, suspending agent or emulsifying agent.
Soaps and synthetic detergents may be employed as surfactants and as
vehicles for the solid pharmaceutical compositions. Suitable soaps include
fatty acid
allcali metal, annnonium, and triethanolamine salts. Suitable detergents
include
cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl
pyridinium halides, and alkylamine acetates; anionic detergents, for example,
alkyl,
aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates,
and
sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty
acid

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alkanolamides, and poly(oxyethylene)-blocl~-poly(oxypropylene) copolymers; and
amphoteric detergents, for example, alkyl (3-aminopropionates and 2-
alkylimidazoline
quaternary ammonium salts; and others known to one of ordinary skill in the
art; and
mixtures thereof.
A water soluble coat or layer can be formed to surround a solid dosage form or
a portion thereof. The water soluble coat or layer can either be inert or drug-
containing. Such a coat or layer will generally comprise an inert and non-
toxic
material which is at least partially, and optionally substantially completely,
soluble or
erodible in an environment of use. Selection of suitable materials will depend
upon
the desired behavior of the dosage form. A rapidly dissolving coat or layer
will be
soluble in the buccal cavity and/or upper GI tract, such as the stomach,
duodenum,
jejunum or upper small hztestines. Exemplary materials are disclosed in U.S.
Patents
No. 4,576,604 to Guittard et al. and No. 4,673,405 to Guittard et al., and No.
6,004,582 to Faour et al. and the text Pharmaceutical Dosage Fo~f~2s: Tablets
Volume
I, 2"'~ EditioTZ. (A. i,ieberma~.z. ed. 1989, Marcel Dekker, Inc.), the
disclosures of which
are hereby incorporated by reference. In some embodiments, the rapidly
dissolving
coat or layer will be soluble in saliva, gastric juices, or acidic fluids.
Materials which are suitable for making the water soluble coat or layer
include, by way of example and without limitation, water soluble
polysaccharide
gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan,
pectin,
and xanthan; water-soluble salts of polysaccharide gums such as sodium
alginate,
sodium tragacanthin, and sodium gum ghattate; water-soluble
hydroxyalkylcellulose
wherein the alkyl member is straight or branched of 1 to 7 carbons such as
hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose;
synthetic water-soluble cellulose-based lamina formers such as methyl
cellulose and
its hydraxyalkyl methylcellulose cellulose derivatives such as a member
selected from
the group consisting of hydroxyethyl methylcellulose, hydroxypropyl
methylcellulose, and hydroxybutyl methylcellulose; croscarmellose sodium;
other
cellulose polymers such as sodium carboxymethylcellulose; and other materials
blown to those skilled in the art. Other lamina-forming materials that can be
used for

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tlus purpose include polyvinyl alcohol), polyethylene oxide), gelatin, glucose
and
saccharides. The water soluble coating can comprise other pharmaceutical
excipients
that may or may not alter the way in which the water soluble coating behaves.
The
artisan of ordinary skill will recognize that the above-noted materials
include film-
forming polymers.
A water soluble coat or layer can also comprise hydroxypropyl
methylcellulose, which is supplied by Dow under its Methocel E-15 trademark.
The
materials can be prepared in solutions having different concentrations of
polymer
according to the desired solution viscosity. For example, a 2% W/V aqueous
solution
of MethocelTM E-15 has a viscosity of about 13-18 cps at 20°C.
For transdermal administration, the compounds may be combined with skin
penetration enhancers such as propylene glycol, polyethylene glycol,
isopropanol,
ethanol, oleic acid, N-methylpyrrolidone, or others known to those skilled in
the art,
which increase the permeability of the skin to the compounds, and permit the
compounds to penetrate through the skin and into the bloodstream. The
compound/enhancer compositions also may be combined additionally with a
polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/
vinylacetate, or others known to those skilled in the art, to provide the
composition in
gel form, which can be dissolved in solvent such as methylene chloride,
evaporated to
the desired viscosity, and then applied to backing material to provide a
patch.
For intravenous, intramuscular, or subcutaneous administration, the active
ingredients may be combined with a sterile aqueous solution which is
preferably
isotonic with the blood of the recipient. Such formulations may be prepared by
dissolving one or more solid active ingredients in water containing
physiologically
compatible substances such as sodium chloride, glycine, or others known to
those
skilled in the art, and/or having a buffered pH compatible with physiological
conditions to produce an aqueous solution, and/or rendering the solution
sterile. The
formulations may be present in unit dose containers such as sealed ampoules or
vials.
A solid dosage form of the invention can be coated with a flush coat as is
commonly done in the art to provide the desired shine, color, taste or other
aesthetic

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characteristics. Materials suitable for preparing the finish coat are well
known in the
art and found in the disclosures of many of the references cited and
incorporated by
reference herein.
Various other components, in some cases not otherwise listed above, can be
added to the present formulation for optimization of a desired active agent
release
profile including, by way of example and without limitation,
glycerylmonostearate,
nylon, cellulose acetate butyrate, d,l-poly(lactic acid), 1,6-hexanediamine,
diethylenetriamine, starches, derivatized starches, acetylated monoglycerides,
gelatin
coacemates, poly (styrene - malefic acid) copolymer, glycowax, castor wax,
stearyl
alcohol, glycerol palmitostearate, poly(ethylene), polyvinyl acetate),
polyvinyl
chloride), 1,3-butylene-glycoldimethacrylate, ethyleneglycol-dimethacrylate
and
methacrylate hydrogels.
It should be understood that compounds used in the art of pharmaceutical
formulation generally serve a variety of functions or purposes. Thus, whether
a
compound named herein is mentioned only once or is used to define more than
one
term herein, its purpose or function should not be construed as being limited
solely to
the named purposes) or function(s).
For preparing solid compositions such as tablets, the opioid antagonist, alone
or in conjunction with an opioid agonist, is mixed with a pharmaceutical
carrier or
excipient, such as conventional tableting ingredients and other pharmaceutical
diluents, such as water, to form a solid preformulation composition containing
a
homogeneous mixture of a compound or a non-toxic pharmaceutically acceptable
salt
thereof. When referring to these preformulation compositions as homogeneous,
it is
meant that the opioid antagonist, alone or in conjunction with an opioid
agonist, is
dispersed evenly throughout the composition so that the composition may be
readily
subdivided into equally effective unit dosage forms such as capsules, tablets,
caplets,
or pills. This solid preformulation composition is then subdivided into unit
dosage
forms of the type described above containing the above-stated dose of an
opioid
antagonist, alone or in combination with opioid agonist.

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Solid compositions of the opioid antagonist alone may be administered in
combination with a~.ly other therapeutic agent(s), including, but not limited
to, opioid
agonists.
Capsules, tablets, caplets, or pills of the novel pharmaceutical composition
can
be coated or otherwise compounded to provide a dosage form affording
the.advantage
of prolonged action. For example, the tablet or pill can comprise an Timer
dosage and
an outer dosage component, the latter being in the form of an envelope over
the
former. The two components can be separated by an enteric layer which serves
to
resist disintegration in the stomach and permits the imzer component to pass
intact
into the duodenum or to be delayed in release. A variety of materials can be
used for
such enteric layers or coatings, such materials including a number of
polymeric acids
and mixtures of polymeric acids with such materials as shellac, cetyl alcohol
and
cellulose acetate.
Controlled release (e.g., slow-release or sustained-release) dosage forms, as
well as immediate release dosage fornzs are specifically contemplated.
Controlled
release compositions in liquid forms in which a therapeutic agent may be
incorporated
for administration orally or by injection are also contemplated.
The pharmaceutical compositions or dosage forms of this invention may be
used in the form of a pharmaceutical preparation which contains one or more
opioid
antagonists alone or in combination with one or more opioid agonists or other
active
pharmaceutical ingredient.
It has been unexpectedly discovered that some opioid antagonists undesirably
bind sigluficantly to certain pharmaceutical excipients in an environment of
use.
Those pharmaceutical excipients generally cause an incomplete amount of the
opioid
antagonist to be released from an immediate release dosage form, within a
particular
time allotted for release in a dissolution test or in clinical use. For
example, when
naltrexone hydrochloride in solution was mixed with croscarmellose sodium in
suspension, the croscarmellose sodium bound more than 90% of the naltrexone
hydrochloride. Morphine sulfate also bound to this excipient. However, when
lactose, dibasic calcium phosphate, dextrose, or sucrose were tested in
combination

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with the above drugs, the drugs were not bound significantly by the
excipients.
Accordingly, some embodiments of the invention include specific combinations
of
opioid antagonist and pharmaceutical excipient, wherein the excipient does not
bind
the opioid antagonist to a significant degree in an environment of use. Other
embodiments include combinations of opioid agonist, opioid antagonists, and
pharmaceutical excipients, wherein the excipients binds the opioid agonist and
opioid
antagonist to effectively the same degree, so that they are released
concurrently,
sequentially and/or have substantially the same dissolution rates.
The combination dosage forms of the present invention can be formulated to
provide a concurrent release of the opioid agonist and opioid antagonist
generally
throughout at least a majority of the delivery profile for the formulation. As
used
herein, the terms "concurrent release" and "released concurrently" mean that
the
agonist and antagonist are released in is2 vitro dissolution assays in an
overlapping
manner. The respective beginnings of release of each agent can but need not
necessarily be simultaneous. Concurrent release will.occur when the majority
of the
release of the first agent overlap a majority of release of the second agent.
According
to one exemplary embodiment, release of the agonist and antagonist begins and
ends
at approximately the same time. In some embodiments of formulations comprising
an
opioid antagonist and an opioid agonist, the dissolution rates of the
antagonist and the
agonist are substantially the same. A desired portion of each active
pharmaceutical
ingredient may be released within a desired time. The desired portions may be,
for
example, 5%, 50% or 90%, or some other percentage. The desired time may be,
for
example, 10 minutes, 20 minutes, 30 minutes or 45 minutes.
Generally, the entire charge of each active pharmaceutical ingredient is
released in less than 120 min, less than 90 min, less than 60 min, less than
45 min,
less than 30 min, less than 20 min or less than 10 min. Preferably, the entire
charge
of each active pharmaceutical ingredient is released in less than 45 minutes.
According to a specific embodiment of the invention, 'each active
pharmaceutical ingredient is released as follows:

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Time (in minutes) Amount Released (% wt.)
0 0
>_35 and __<75
>_50 and __<90
5 15 >_75 and <_95
30 >_90
Coated tablets, beads, pellets or granules can be made to provide an immediate
and/or a concurrent release of an opioid antagonist and an opioid agonist.
Such
10 dosage forms are made according to the compositions and dosage forms
described
herein, for example as described in the examples. A coated solid substrate
will
independently include the opioid antagonist and/or the opioid agoust in the
solid
substrate or the coat. For example, specific embodiments include those
wherein: 1)
another active pharmaceutical ingredient, such as an opioid agonist, is in the
core and
the opioid antagonist is in the coat that at least partially surrounds the
core; 2) another
active pharmaceutical ingredient, such as an opioid agonist, and an opioid
antagonist
are both in the core; 3) another active pharmaceutical ingredient, such as an
opioid
agonist, amd opioid antagonist are both in a coat that at least partially
surrounds an
inet-t core; and 4) the opioid antagonist is in the core and another active
pharmaceutical ingredient, such as an opioid agonist, is in the coat that at
least
partially surrounds the core.
The term "unit dose" is used herein to mean a dosage form containing a
quantity of the therapeutic compounds, said quantity being such that one or
more
predetermined units may be provided as a single therapeutic administration.
Depending upon the specific combination and amounts of agonist and antagonist
included within the dosage form, an improved, additive or sylergistic
therapeutic
effect will be observed. An improved therapeutic effect is one wherein the
antagonist
enhances the therapeutic effect, such as analgesic effect, provided by the
agonist
alone. An additive therapeutic effect is one wherein each of the antagonist
and the
agonist possesses a common therapeutic effect, and the combination of the two
drugs

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provides an overall therapeutic effect that approximates the sum of their
individual
therapeutic effects. A synergistic therapeutic effect is one wherein the
combination of
the two drugs provides an overall therapeutic effect that is greater than the
sum of
their individual therapeutic effects.
FIG. 2 depicts a non-limiting embodiment of the invention: a pharmaceutical
composition of coated nonpareil solid substrates 1 and 2, such as pellets or
beads.
The coated pellet 1 comprises an inert nonpareil core 3 of one or more
pharmaceutical
excipients and a coat 4 of a low dose of an opioid antagonist and one or more
pharmaceutical excipients. The coated pellet 2 comprises an inert nonpareil
core 9 of
one or more pharmaceutical excipients and a coat 5 of a low dose of an active
pharmaceutical ingredient (in this case, an opioid agonist) and one or more
pharmaceutical excipients. The pharmaceutical excipients can be selected
independently at each occurrence. Likewise, the cores 3 and 9 can comprise the
same
or different ingredients. The two different types of coated nonpareils can be
filled
into a capsule, such as a hard gelatin capsule, or compressed into a tablet
core. The
coated nonpareils are optionally mixed with one or more other pharmaceutical
excipients prior to being filled into the capsule or compressed into the
tablet core.
The coated nonpareils 1 and 2 are made according to the process of Example
10 and generally by forming a mixture of at least two different coated
pellets, wherein
the first pellet is made by coating the opioid antagonist onto a first
nonpareil pellet
and the second pellet is made,by coating the opioid agonist onto a second
nonpareil
pellet.
When included in a capsule or tablet, the overall amount of each drug present
in the respective dosage form will depend upon the amount of drug needed or
useful
to provide the desired therapeutic response.
FIG. 3 depicts a pharmaceutical composition of a coated nonpareil bead 7 of
an inert nonpareil core 8 of one or more pharmaceutical excipients and a coat
6 of a
low dose of an opioid antagonist, a dose of another pharmaceutical ingredient
(in this
case, an opioid agonist) and one or more pharmaceutical excipients. The
pharmaceutical excipients(s) can be selected independently at each occurrence.
The

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coated nonpareil can be filled into a capsule, such as a hard gelatin capsule,
or
compressed into a tablet core. The coated nonpareil is optionally mixed with
one or
more other pharmaceutical excipients prior to being filled into the capsule or
compressed into the tablet core.
The coated nonpareil bead 7 is made according to the process of Example 11
and generally by preparing a composition of the opioid antagoust, the opioid
agonist,
at least one polymer or film-forming material, and optionally a plasticizes
and
applying the composition to a nonpareil pellet.
FIG. 4 depicts a mixed granulation 10 of a first granulation 11 of an opioid
antagonist and a first blend of pharmaceutical excipients and a second
granulation 12
of another pharnaceutical ingredient (in this case, an opioid agonist) and a
second
blend of pharmaceutical excipients. The pharmaceutical excipients(s) can be
selected
independently at each occurrence. Likewise, the granulations 11 and 12 can
comprise
the same or different excipients. The two different granulations can together
be filled
into a capsule, such as a hard gelatin capsule, or compressed into a tablet
core. The
granulations are optionally mixed with one or more other pharmaceutical
excipients
prior to being filled into the capsule or compressed into the tablet core.
The mixed granulation 10 is generally made according to the process of
Example 13 and generally by fornzing a first granulation of an opioid
antagonist and a
first blend of pharmaceutical excipients, forming a second granulation of an
opioid
agonist and a second blend of pharmaceutical excipients, and mixing the first
and
second granulations.
FIG. 5 depicts a pharmaceutical composition of a second granulate 15
containing a mixture 16 of a first granulation 17, a low dose of the opioid
antagonist
and at least one pharmaceutical excipient, wherein the first granulation
comprises a
dose of another pharmaceutical ingredient (in this case, an opioid agonist)
and at least
one pharmaceutical excipient. The pharmaceutical excipients(s) can be selected
independently at each occurrence. Plural second granulates can be filled into
a
capsule, such as a hard gelatin capsule, or compressed into a tablet core. The
second

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granulates are optionally mixed with one or more other pharmaceutical
excipients
prior to being filled into the capsule or compressed into the tablet core.
The second granulate 15 is made according to the process of Example 14 and
generally by forming a first granulation 17 of another pharmaceutical
ingredient (in
this case, an opioid agonist) and at least one pharmaceutical excipient, and
mixing the
first granulation with a mixture 16 of the opioid antagonist and at least one
pharmaceutical excipient to form a second granulation.
FIG. 6 depicts a pharmaceutical composition 20 of a coated granulation of a
mixture of pharmaceutical excipients 23 coated with a binder composition 21 of
a
binder, the opioid antagonist, another pharmaceutical ingredient (in this
case, an
opioid agonist) and optionally one or more other pharmaceutical excipients 22.
The
pharmaceutical excipients(s) can be selected independently at each occurrence.
The
pharmaceutical composition can be filled into a capsule, such as a hard
gelatin
capsule, or compressed into a tablet core.
The pharmaceutical composition 20 is made according to the process of
Example 15 and generally by preparing a binder composition of a binder, the
opioid
agonist and the opioid antagonist and coating a mixture of pharmaceutical
excipients
with the binder composition to form a coated granulation. The coated
granulation is
then optionally mixed with one or more pharmaceutical excipients to form the
pharmaceutical composition 20.
Different methods of treatment will require different dosage strengths and
different ratios of agonist to antagonist in a dosage form. The compositions 2
and 10
have the advantage that pharmaceutical composition batches containing
substantially
different ratios of agonist to antagonist can be easily made simply by varying
the
amount of each coated nonpareil, or granulation, respectively, included in the
pharmaceutical composition without having to reformulate the respective coated
nonpareils 1 and 2 or granulations 11 and 12. Likewise the relative amount of
each
drug within its respective coated nonpareil, or granulation, can be varied to
make
pharmaceutical compositions of particular drug strengths.

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An advantage of a combination dosage form is that the presence of both active
pharmaceutical ingredients in a single unit dose form assures compliance with
the
desired dose ratio each time a dose is taken. Additional advantages may
include
reduced complexity, reduced potential for medication errors, and more
convenient
administration of multiple products concurrently, as well as reduction of the
amount
being ingested which may accommodate the accompaaiying synptoms that patients
have (for example, nausea, vomiting, inability or exacerbation of pain due to
swallowing).
For example, FIG. 7 depicts a graph of the relationship between drug ratio and
nonpareil loading into a 500 mg filled capsule. The coated nonpareil 1 can be
made
to contain 1 mg of opioid antagonist per 500 mg of coated nonpareil 1.
Likewise, the
coated nonpareil 2 can be made to contain 200 mg of opioid agonist (or another
pharmaceutical ingredient) per 500 mg of coated nonpareil 2. Therefore, when a
500
mg capsule is filled up to 90% wt. with nonpareil 2 and 10% wt. with nonpareil
1, the
capsule will contain 180 mg of opioid agonist and 0.1 mg of opioid antagoust,
and
the ratio of agonist to antagonist will be 1800. When a 500 mg capsule is
filled up to
50% wt. with nonpareil 2 and 50% wt. with nonpareil 1, however, the capsule
will
contain 100 mg of opioid agonist and 0.5 mg of opioid antagonist, and the
ratio of
agonist to antagonist will be 200. On the other hand, when a 500 mg capsule is
filled
with the same amounts of nonpareil 2 and nonpareil 1, but the nonpareil 1 is
made to
contain 0.5 mg of antagonist per 500 mg of nonpareil 1, then the capsule will
contain
100 mg of opioid agonist and 0.25 mg of opioid antagonist, and the ratio of
agonist to
antagonist will be 400. The exemplary relationships depicted in FIG. 7 are
generally
true for the formulations of FIGS. 2 and 4. These relationships will vary
according
the amount of each drug include in the formulation and the specific drugs
used.
The pharmaceutical compositions of FIGS. 3, 5 and 6, however, are useful for
providing a fixed ratio of opioid antagonist to opioid agonist (or another
active
pharmaceutical ingredient) regardless of the total drug strength of dosage
forms
containing those pharmaceutical compositions. For example, FIG. 8 depicts a
graph
of the relationship between the drug ratio and nonpareil loading into a S00 mg
filled

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capsule. The coated nonpareil 7 (shown in FIG. 3) can be made to contain 0.5
mg of
opioid antagonist per 500 mg of coated nonpareil 7 and 200 mg of opioid
agonist per
500 mg of coated nonpareil 7. Therefore, when a 500 mg capsule is filled 100%
wt.
with nonpareil 7, the capsule will contain 200 mg of opioid agonist and 0.5 mg
of
S opioid antagonist, and the drug ratio of agonist to antagonist will be 400.
When a 500
mg capsule is filled up to 50% wt. with nonpareil 7 and 50% wt. with a
pharmaceutical excipient, however, the capsule will contain 100 mg of opioid
agonist
and 0.25 mg of opioid antagonist, and the ratio of agonist to antagonist will
remain
400. If, however, the coated nonpareil 7 is made to contain 0.25 mg of opioid
antagonist per 500 mg of coated nonpareil 7 and 200 mg of opioid agonist per
500 mg
of coated nonpareil 7 and a 500 mg capsule is filled 100% wt. with nonpareil
7, the
capsule will contain 200 mg of opioid agonist and 0.25 mg of opioid
antagonist, and
the drug ratio of agonist to antagonist will be 800. In other words,
decreasing the
relative amount of the pharmaceutical compositions of FIGS. 3, 5 and 6
decreases the
total drug strength but does not alter the drug ratio.
Another embodiment provides a pharmaceutical composition of a coated first
granulate, wherein the granulate comprises the opioid agonist (or another
active
pharmaceutical ingredient) and a mixture of pharmaceutical excipients and the
coating
comprises the opioid antagonist and one or more pharmaceutical excipients.
This
granulate can be made according to the process of Example 16 and is generally
made
by coating a composition of the opioid agonist and a mixture of pharmaceutical
excipients and with a coating composition of the opioid antagonist and one or
more
pharmaceutical excipients.
The invention also provides a pharmaceutical composition of spray-dried
granules of the opioid antagonist, another active pharmaceutical ingredient
such as an
opioid agonist and at least one pharmaceutical excipient. These granules can
be made
according to the process of Example 17 and generally by spray-drying a
solution of
the opioid antagonist, the opioid agonist and at least one pharmaceutical
excipient to
form spray-dried granules.

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The dosage form can also comprise a soft gelatin capsule filled with a
suspension of the opioid antagonist in another active pharmaceutical
ingredient such
as an opioid agonist, and at least one nonaqueous velucle. This dosage can be
made
according to the process of Example 18 and generally by filling a soft gelatin
capsule
with a dispersion consisting essentially of the opioid antagonist, the opioid
agonist,
and at least one nonaqueous vehicle.
Compositions for inhalation or insufflation include solutions and suspensions
in pharmaceutically acceptable, aqueous or organic solvents, or mixtures
thereof, and
powders are also contemplated. The liquid or solid compositions may contain
suitable pharmaceutically acceptable excipients as set out above. The
compositions
commonly are administered by the oral or nasal respiratory route for local or
systemic
effect. Compositions in preferably sterile pharmaceutically acceptable
solvents may
be nebulized by use of inert gases. Nebulized solutions may be breathed
directly from
a nebulizing device or the nebulizing device may be attached to a face mask,
tent or
intermittent positive pressure breathing machine. Solution, suspension or
powder
compositions may be administered, preferably orally or nasally, from devices
which
deliver the formulation in an appropriate manner.
For the treatment of certain conditions it may be desirable to employ an
opioid
antagonist in conjunction with another pharmacologically active agent. For
example,
an opioid antagonist according to the present invention may be presented
together
with another therapeutic agent as a combined preparation for simultaneous,
separate,
or sequential use. Solid compositions of an opioid antagonist alone may be
administered in combination with any one or more other therapeutic agents,
including,
but not limited to, opioid agonists. Such combined preparations may be, for
exaanple,
in the form of a twin pack. In general, the currently available dosage forms
of the
other therapeutic agents for use in such combinations will be suitable.
An opioid antagonist alone, or in combination with another active
pharmaceutical ingredient, may be administered to the human subject by known
procedures including but not limited to oral, sublingual, intramuscular,
subcutaneous,
intravenous, intratracheal, transmucosal, or transdermal modes of
administration.

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When a combination of these compounds are administered, they may be
administered
together in the same composition, or may be administered in separate
compositions.
If the opioid antagonist and another active pharmaceutical ingredient are
administered
in separate compositions, they may be administered by similar or different
modes of
administration, or may be administered simultaneously with one another, or one
shortly before or after the other.
Commercial formulations currently used to administer the opioid antagonist or
opioid agonist can be modified as described to provide a pharmaceutical
composition
and formulation accordiilg to the invention. Commercial oral dose forms of
opioid
agonists for human administration include: codeine, dihydrocodeine (e.g.,
SYNALGOS-DC~ from Wyeth-Ayerst Pharmaceuticals), fentanyl (e.g., ACTIQ~
from Abbott Laboratories), hydrocodone (e.g., VICODIN~ and VICOPROFEN~
from Knoll Laboratories; NORCO~ from Watson Laboratories; HYCODANO from
Endo Pharmaceuticals; NORCET~ from Abara; ANEXSIA~, HYDROCET~, and
LORCET-HD~ from Mallinckrodt; LORTAB~ from UCB Pharma; HY-PHEN~
from Ascher; CO-GESIC~ from Schwarz Pharma; ALLAY~ from Zenith Goldline),
hydromorphone (e.g., DILAUDID~ from Knoll), levorphanol (e.g., LEVO-
DROMORAN~ from ICN Pharmaceuticals), meperidine (e.g., DEMEROL~ from
Sanofi Pharmaceuticals), methadone (e.g., METHADOSE~ from Mallinckrodt; and
DOLOPHINE~ HCl from Roxane Laboratories), morphine (e.g., KADIAN~ from
Faulding Laboratories; MS CONTIN~ from Purdue Frederick; ORAMORPH~ SR
from Roxane), oxycodone (e.g., PERCOCET~ and PERCODAN~ from Endo;
OXYCET~ from Mallinckrodt; OXYCONTIN~ from Purdue Frederick; TYLOX~
from Ortho-McNeil Pharmaceutical; ROXICODONE~, ROXILOX~ and
ROXICET~ from Roxane), pentazocine (e.g., TALACEN~ and TALWIN~ from
Sanofi Pharmaceuticals), propoxyphene (e.g., DARVOCET-N~ and DAVRON~
from Eli Lilly & Co.; DOLENE~ from Lederle; WYGESIC~ from Wyeth-Ayerst),
and tramadol (e.g., ULTRAM~ from Ortho-McNeil Pharmaceutical). Commercial

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liquid dose forms of opioid agonists for human administration include:
hydrocodone
(e.g., HYDROPHANE~ from Halsey), hydromorphone (e.g., DILAUDID~ from
Knoll), meperidine (e.g., DEMEROL~ from Sanofi), methadone (e.g.,
DOLOPHINE~ from Roxane), oxycodone (e.g., HYCOM1NE~ from Knoll;
ROXILOX~ from Roxane), and propoxyphene (e.g., DARVON-N~ from Eli Lilly).
Commercial parenteral dose forms for human administration include: alfentanil
(e.g.,
ALFENTA~ from Akorn), buprenorphine (e.g., BUPRENEX~ from Reckitt &
Colman Pharmaceuticals), butorphanol (e.g., STADOL~ from Apothecon), dezocine
(e.g., DALGAN~ from Astrazeneca), fentanyl, hydromorphone (e.g., DILAUDID-
HPO from Knoll), levallorphan (e.g., LORFAN~ from Roche), levorphanol (e.g.,
LEVO-DROMORAN~ from ICN), meperidine (e.g., DEMEROL~ from Sanofi),
methadone (e.g., DOLOPHINE~ HCI from Roxane), morphine (e.g,
ASTRAMORPH~ from Astrazeneca; DUR.AMORPH~ and INFLTMORPH~ from
Elkins-Sinn), oxymorphone (e.g., NLTMORPHAN~ from Endo), nalburphine (e.g.,
NUBAIN~ from Endo Pharmaceutical), and pentazocine (TALWIN~ from Abbott).
Commercial transdermal dose forms of opioid agonists for human administration
include fentanyl (e.g., DURAGESIC~ from Janssen). Cormnercial suppository dose
forms of opioid agonists for human administration include oxymorphone (e.g.,
NUMORPHAN~ from Endo).
The present invention also includes pharmaceutical kits comprising an opioid
antagoiust together with any other therapeutic agent, including but not
limited to, an
opioid agonist, where the antagonist is in an amount as specified above. In
the kit, the
opioid antagonist and the opioid agonist or other therapeutic agent may each
be
presented in separate containers of any type, for example, bottles or packages
(e.g.,
for capsules, tablets, pills or patches) as compounds, andlor in separate
containers as
compounds in combination with a pharmaceutically acceptable excipient or
Garner.
Alternatively, the opioid antagonist and the opioid agonist or other
therapeutic agent
may be combined together in one or more containers such as bottles or packages
with
or without an excipient or carrier. Thus, for example, the invention also
includes

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pharmaceutical kits comprising a container of any type, such as a package,
bottle,
envelope, blister pack, bag, or pouch, syringe, inhaler or tube, consisting
essentially of
the opioid antagonist and a separate container consisting essentially of the
opioid
agonist or other therapeutic agent, each container containing, if desired, an
excipient
or other carrier.
The pharmaceutical compositions may be administered to human
subjects/patients in need of such treatment in dosage forms, for example,
witlun the
ranges described herein, that will provide acceptable pharmaceutical efficacy.
It will
be appreciated that the specific dose required for use in any particular
application will
vary from patient to patient, not only with the particular compound or
composition
selected, but also with the route of administration, the nature of the
condition being
treated, the age, condition, pain tolerance, and other idiosyncrasies of the
patient,
concurrent medication or special diets then being followed by the patient, and
other
factors which those skilled in the art will recognize, with the appropriate
dosage
ultimately being at the discretion of the attendant physician.
In preferred embodiments, when the opioid antagonist is administered alone,
the amount of the opioid antagonist administered is an amount effective to
enhance or
maintain the analgesic potency of the opioid agonist and/or attenuate or
maintain the
adverse side effects of the opioid agonist and/or attenuate tolerance,
withdrawal,
dependence and/or addiction. This amount is readily determinable by one
skilled in
the art.
The present invention is described in the following examples, which are set
forth to aid in the understanding of the invention and should not be construed
to limit
in any way the invention as defined in the claims wluch follow thereafter.
Pharmaceutical active and inactive ingredients used in the preparation of
example
formulations were compendia) in the USP/NF, when there was an existing
monograph.

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EXAMPLE 1
The drug product is manufactured to contain multiple active components that
include the opioid antagonist in one unit dose (e.g., a single capsule or
tablets or pill
or patch). Alternatively, the drug product is manufactured to contain only one
active
component that is the opioid antagonist (e.g., naltrexone). Naltrexone
hydrochloride
(naltrexone) were manufactured as described herein and administered as a
separate
capsule in dosage forms according to the invention.
The description, structure and physical/chemical characteristics of the drug
substance Naltrexone Hydrochloride, USP is as follows:
Generic Name: Naltrexone Hydrochloride
Chemical Name: 17-cyclopropylmethyl-4,Sa-epoxy-3,14-
dihydroxymorphinan-6-one hydrochloride
Molecular Formula: C2oH23N04~HCl
Molecular Weight: 377.86
(See, e.g., USP description for details on the physical and chemical
properties
of naltrexone hydrochloride.)
Naltrexone Capsules
Naltrexone capsules were manufactured in representative concentrations of
0.01 mg, 0.1 mg and 1.0 mg naltrexone HCl by the process illustrated in FIGS.
lA-1B
and described below.
Com onents Per Ca sule
Per Batch
0.01 mg Naltrexone Capsules
Naltrexone Hydrochloride, 0.01 mg 0.013 g
USP
ade 2
Microcrystalline cellulose,346.24 mg 432.80 g
NF
rade 3
Magnesium stearate, NF 1.75 m 2.19
ade'"
Hard gelatin capsule shells1 1250
(opaque white/white, size
0), NF
grade 5

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0.1 mg Naltrexone Capsules
Naltrexone Hydrochloride,0.10 mg 0.13 g
USP
ade 2
Microcrystalline cellulose,346.15 mg 432.69 g
NF
ade 3
Ma esium stearate, NF 1.75 m 2.19
ade
Hard gelatin capsule shells1 1250
(opaque white/white, size
0), NF
grade 5
Corn onents Per Ca sule Per Batchl
1.0 m Naltrexone Ca sules
Naltrexone Hydrochloride,1.00 mg 1.25 g
USP
ade ~
Microcrystalline cellulose,345.25 mg 431.57 g
NF
rade 3
Ma nesium stearate, NF 1.75 m 2.18
grade
Hard gelatin capsule shells1 1250
(opaque white/white, size
0), NF
ade 5
1 Amounts listed are for a 1250 capsule batch. Other batch sizes may be
used with equivalent formula, using similar equipment and processing.
2 Supplied in 10 g. bottles by Mallinckrodt Chemicals, Inc., P.O. Box
5439, St. Louis, MO 63147.
3 Supplied as Avicel~ PH102 by FMC Corporation, Pharmaceutical
Division, 1735 Market St. Philadelphia, PA 19103.
4 Supplied by Whittaker, Clark & Danield, Inc. 1000 Coolidge St., South
Plainfield, NJ 07080
5 Supplied by Capsugel~, Division of Warner-Lambent Co., 535 N.
Emerald Rd., Greenwood, SC 29646

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Com onents Per Ca sule Per Batch
Placebo Ca sules
Microcrystalline cellulose,346.25mg 415.5 g
NF
grade2
Ma esium stearate, NF 1.75 m 2.1
ade
Hard gelatin capsule shells1 1200 ,
(opaque white/white, size
0), NF
ade4
1 Amounts listed are for a 1200 capsule batch. Other batch sizes may
be used with equivalent formula, using similar equipment and
processing.
2 Supplied as Avicel~ PH102 by FMC Corporation, Pharmaceutical
Division, 1735 Market St. Philadelphia, PA 19103.
3 Supplied by Whittaker, Clark & Danield, Inc. 1000 Coolidge St.,
South Plainfield, NJ 07080
The manufacturing schematic of FIGS. 1A and 1B was employed to
manufacture naltrexone capsules useful for human administration. A description
of
the steps of the manufacturing process for naltrexone and placebo capsules
follows:
For three selected concentrations (0.01 mg, 0.1 mg, 1.0 mg) of naltrexone
capsules, a series of blends were made and combined to create the specified
concentrations for filling. Additional blends were made and combined to create
concentrations less than 0.01 mg, such as 0.001 mg. Further blends can be made
at
less thaaz 0.001 mg, including 0.0001 mg or less.
Placebo Blend
A placebo blend was made according to the following process.
Referring first to FIG. 1A, magnesium stearate 50 was placed through a clean,
60 mesh stainless sieve and the sifted stearate 52 was collected directly into
a blender
bowl. A small portion of microcrystalline cellulose 54 was placed through the
same
sieve and collected over the sifted stearate 52, then mixed well for at least
1 minute.
This was repeated with another small portion of cellulose. The remaining
cellulose
was placed through the sieve and mixed well for 15 minutes. The resulting
blend 56
was checked for visible contaminants.

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1.0 mg Naltrexone Blend
The entire quantity of naltrexone 58 was placed through a clean, 60 mesh
stainless sieve and the sifted naltrexone 60 was collected directly into a
blender bowl.
A small portion of the placebo blend 56 was placed through the same sieve and
collected over the naltrexone, then mixed well for at least 1 minute. This was
repeated with another small portion of placebo blend. The remaining placebo
blend
was placed through the sieve and mixed well for 15 minutes. The result was the
1.0
mg naltrexone blend 62. The blend was checked for visible contaminants. The
blend
62 was either further diluted as described in the next paragraph or used to
fill capsules
(as described further below) if a 1.0 mg dosage form was desired as the final
product.
0.1 mg Naltrexone Blend
A specified amount of the 1.0 mg naltrexone blend 62, made as described
above, was placed into a blender bowl. A small portion of placebo blend 56 was
placed over the 1.0 mg naltrexone blend 62, then mixed well for at least 1
minute.
This was repeated with another small portion of the placebo blend 56. The
remaining
portion of the placebo blend 56 required to provide a 10:1 dilution was added
and
mixed well for 15 minutes. The result was the 0.1 mg naltrexone blend 64. The
blend
64 was checked for visible contaminants. The blend 64 was either further
diluted as
described in the next paragraph or used to fill capsules (as described further
below) if
a 0.1 mg dosage was desired as the final product.
0.01 mg Naltrexone Blend
A specified amount of the 0.1 mg naltrexone blend 64, made as described
above, was placed into a blender bowl. A small portion of placebo blend 56 was
placed over the 0.1 mg naltrexone blend 64, then mixed well for at least 1
minute.
This was repeated with another small portion of the placebo blend 56. The
remaining
portion of the placebo blend 56 required to provide a 10:1 dilution were added
and
mixed well for 15 minutes. The result was the 0.01 mg naltrexone blend 66. The
blend 66 was checlced for visible contaminants.

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Analogous dilution has been carried out with a specified amount of the 0.01
mg naltrexone blend to achieve a 0.001 mg naltrexone blend 76 (as shown in
FIGS.
1A and 1B). Further dilutions are also contemplated, if a smaller dose is
desired.
Filling Capsules
With reference to FIG. 1B (a continuation of FIG. 1A), the following filling
procedure was used to put each naltrexone dosage form 62, 64, and 66 into
capsules.
1250 empty capsule shells 6~ were loaded onto filling trays. The caps were
separated
from the bodies - shown as step 70.
The amount of the 1.0 mg naltrexone blend 62 needed to fill 1250 capsules
(including 1% overage) was determined. This amount of specified concentration
naltrexone blend was weighed and transferred to the capsule machine. The
capsules
70 were filled with the entire quantity of naltrexone blend, applying three
pressings
for each filling operation. The capsules were sealed to form filled capsules
72. The
capsules 72 were de-dusted and polished. The filled capsules 72 were tested
for
weight variation, and only those capsules 72 within specified range were
accepted as
the final product - 1.0 mg naltrexone capsules 74. The capsules 74 were
collected
into secure, labeled, double polyethylene bags.
In a similar fashion, the 0.1 mg naltrexone blend 64 and the 0.01 mg
naltrexone blend were put into capsules and finished, again as illustrated in
FIG. 1B.
A process of serial dilution and blending was used to manufacture lower
concentration strength naltrexone capsules. Additionally, reduction in the
capsule fill
weight has been used to accomplish proportional reductions in naltrexone
capsule
strength as necessary, for example, to manufacture O.OOOlmg naltrexone
capsules.
To form placebos, the placebo blend 56 was used in place of the naltrexone
blend 62 to fill capsules, which were again finished in the same manner.
EI~A.MPLE 2
This example demonstrates the clinical use and evaluation of solid oral dosage
forms, including some of the dosage forms of Example 1. Pharmaceutical
compositions and dosage forms of naltrexone prepared according to the
procedure

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stated in Example 1 were achninistered in human clinical trials with morphine,
tramadol or hydrocadone/acetaminophen.
A study of morphine alone and in combination with naltrexone is described in
Example 1 of U.S. Application No. 60/202,265, filed May 5, 2000, incorporated
by
reference herein. A summary of exemplary study results follows.
The clinical study was designed to compare the analgesic activity of three
different doses of naltrexone (NTX) in combination with morphine sulfate
(hereafter
called morphine or MS) 60 mg, versus MS 60 mg alone. The test subj ects had
moderate to severe postsurgical dental pain. The test products were MS 60 mg
with
naltrexone (NTX) 1 mg, MS 60 mg with NTX 0.1 mg, and MS 60 mg with NTX 0.01
mg. A single oral dose of one of the treatments was administered when the
subject
was suffering moderate to severe postoperative pain. The Study Population was
201
male and female outpatients with moderate to severe pain following extraction
of two
or more impacted third molars.
For the data analysis, certain pain parameters were computed as follows. The
extent to which pain changes at each time point was measured by pain relief
scores
(PR, with 0=none, 1=a little, 2=some, 3=a lot, 4=complete), and pain intensity
difference scores (PID, the difference between baseline and the current time,
with the
pain intensity scale consisting of 0=none, 1=mild, 2=moderate, 3=severe). The
extent
to which pain changes over the entire test period was measured by the total
pain relief
score (TOTPAR-8), sum of pain intensity differences (SPID-8), maximum pain
relief
score (MAXPAR), peak pain intensity difference (PEAI~PID), and global
evaluation
(0=poor, 1=fair, 2=good, 3=very good, 4=excellent). TOTPAR-8 and SPID-8 are
defined as the sum of PR and PID, respectively, for the entire 8-hour
observation
period, weighted by the time difference between adjacent points (i.e., area
under the
curve using the trapezoidal rule). MAXPAR and PEAKPID are defined as the
maximum of PR and PTD, respectively. The efficacy.and safety evaluations
included
global pain evaluation, time to rescue, percent of patients remedicating with
rescue
medication, time to onset of meaningful pain relief, time to onset of first
perceptible
pain relief and visual analog scale (VAS), and adverse event assessments.

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The placebo treatment group had the lowest mean Total Pain Relief scores.
All 4 of the active treatment groups exhibited mean Total Pain Relief scores
that were
numerically higher than placebo. The combination treatments had a reverse dose-
response relation in the mean Total Pain Relief scores, i.e., the highest dose
of NTX
had the lowest mean Total Pain Relief scores and the lowest dose of NTX had
the
highest mean Total Pain Relief scores. This pattern (low-dose (0.01 mg NTX) >
mid-
dose (1.0 mg NTX) was observed for all pain relief variables throughout the
study.
The mean Total Pain Relief scores for the 0.01-mg NTX and 0.1-mg NTX
combination treatments were higher than that for the MS alone treatment,
whereas the
1.0-rng NTX combination treatment mean was comparable to or lower than that
for
the MS alone treatment.
The placebo treatment had the lowest mean 4-hour Sum of Pain Intensity
Differences scores. All 4 of the active treatment groups exhibited improved
profiles
in mean Sum of Pain Intensity Differences relative to placebo. The mean Sum of
Pain
Intensity Differences scores for the 0.01-mg NTX and 0.1-mg NTX combination
treatments were higher than that for the MS alone treatment, whereas the 1.0-
mg NTX
combination treatment was comparable to that for the MS alone treatment. The
patterns of the 6-hour and 8-hour Sum of Pain Intensity Differences scores
were
similar to those at 4 hours.
The median time to onset of meaungful pain relief was shortest in the 0.01-
mg NTX (low-dose) combination treatment group. The placebo treatment had the
lower number of subjects who reached meaningful pain relief.
The majority of adverse side effects reported wexe categorized as digestive
(nausea or vomiting) or nervous system (dizziness or sormolence).
A study of tramadol alone and in combination with naltrexone is described in
Example 10 of U.S. Application Serial Nos. 09/756,331, filed January 8, 2001,
which is
a continuation of 09/566,071, filed May 5, 2000 and PCT/LTS00/12493 [W0/00
67739]
filed May 5, 2000, the entire disclosures of which are hereby incorporated by
reference. A summary of exemplary study results follows.

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In this study in human subjects with pain, tramadol hydrochloride (tramadol)
was administered alone or in combination with various amounts (doses) of an
opioid
antagonist, naltrexone. In this study, one obj ective was to determine whether
an
opioid antagonist such as naltrexone hydrochloride (hereafter referred to in
this
example as naltrexone or NTX) enhances the a~lalgesic properties of tramadol
hydrochloride (hereafter referred to in this example as tramadol or T) in
human
subjects/patients with pain following dental surgery. An additional objective
was to
evaluate whether an opioid antagonist such as NTX attenuated (e.g., reduced,
blocked
or prevented) tramadol's adverse side effects in humans.
Human subjects were randomized into one of the following five treatment
groups:
~ Group l: T (50 mg) with NTX (1 mg)
~ Group 2: T (50 mg) with NTX (0.1 mg)
~ Group 3: T (50 mg) with NTX (0.01 mg)
~ Group 4: T (50 mg) with Placebo
~ Group 5: Placebo with Placebo
All subjects with moderate to severe pain received one dose of study
medication. Subjects received two capsules to take by mouth, one tramadol or
placebo, the other naltrexone or placebo.
A pain assessment was performed pre-treatment. Following the dental
surgery, the subject's pain level was assessed by a trained observer. The
subject
reported the initial pain intensity by both (1) verbalizing one pain category
(0 = none,
1 = mild, 2 = moderate or 3 = severe), and (2) using a Visual Analog Scale
(VAS) of
0 -100 mm where 0 = no pain and 100 = worst pain imaginable, by placing a
single
slash on the scale. A pain assessment was also performed post-treatment.
The efficacy and safety evaluations included pain intensity, pain relief,
global
pain evaluation, evaluation of time to meaningful pain relief (stop watch),
visual scale
analog (VAS), and adverse event assessments. For the data analysis, certain
pain
parameters were computed as generally described above.

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The placebo treatment group had the lowest mean 4-hour Total Pain Relief
scores. All 4 of the active treatment groups exhibited mean 4-hour Total Pain
Relief
scores that were numerically higher than placebo. The combination treatments
had a
reverse dose-response relation in the mean 4-hour Total Pain Relief scores,
i.e., the
highest dose of NTX had the lowest mean 4-hour Total Pain Relief scores and
the
lowest dose of NTX had the highest mean 4-hour Total Pain Relief scores. The
mean
4-hour Total Pain Relief scores for the 0.01-mg NTX and 0.1-mg NTX combination
treatments were higher than that for the T alone treatment, whereas the 1.0-mg
NTX
combination treatment mean was lower than that for the T alone treatment.
The placebo treatment had the lowest mean 4-hour Sum of Pain Intensity
Differences scores. All 4 of the active treatment groups exhibited improved
profiles
in mea~.z 4-hour Sum of Pain Intensity Differences relative to placebo. The
mean 4-
hour Stun of Pain Intensity Differences scores for the 0.01-mg NTX and 0.1-mg
NTX
combination treatments were higher than that for the T alone treatment,
whereas the
1.0-mg NTX combination treatment was lower than that for the T alone
treatment.
The patterns of the 6-hour and 8-hour Sum of Pain Intensity Differences scores
were
similar to those at 4 hours.
The 4, 6, and 8 hour Visual Analog Scale Sum of Pain Intensity Differences
results were as follows. The placebo treatment had the lowest mean 4-hour VAS-
Sum
of Pain Intensity Differences. The 4 active treatment groups exhibited mean
VAS-
Sum of Pain Intensity Differences scores that were higher than that for the
placebo.
The mean 4-hour VAS-Sum of Pain Tntensity Differences for the 3 NTX
combination
treatments was higher than that for T alone. The profiles of 6-hour and 8-hour
VAS-
Sum of Pain Intensity Differences scores were similar to those at 4 hours.
The placebo treatment had the lowest number of subjects who reached
meaningful pain relief. In addition, all the combination treatment groups had
higher
numbers of subjects reaching meaningful pain relief than did the group that
received
T alone.
Whereas the hourly pain relief scores for the placebo treatment were generally
flat, those for the active treatment groups were generally improving over
time. There

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was separation between the placebo and the active treatment groups that
continued
throughout the 8-hour study period.
The majority of adverse events reported were categorized as gastrointestinal
disorders (nausea or vomiting) or nervous system disorders (dizziness,
headache or
sedation).
A study of morphine alone and in combination with naltrexone is described in
Example 2 of U.S. Application Ser. No. 60!245,110, filed November 1, 2000,
incorporated by reference herein. A summary of exemplary study results
follows.
In a dose ranging study, doses of morphine sulfate (60 mg) in combination
with naltrexone hydrochloride (0.1 mg, 0.01 mg, or 0.001 mg) were administered
for
moderate to severe pain in patients following dental surgery. This study was
performed to investigate the analgesic efficacy (onset, peak, duration, and
total effect)
of morphine alone, naltrexone alone, three different doses of naltrexone in
combination with morphine and placebo.
The 300 subject study was designed with six treatment groups: A) placebo
(50 pts); B) morphine 60 mg (50 pts); C) naltrexone 0.01 mg (50 pts); D)
morphine 60
mg and naltrexone 0.1 mg (50 pts); E) morphine 60 mg and naltrexone 0.01 mg
(50
pts); F) morphine 60 mg and naltrexone 0.001 mg (50 pts). In this study, in
the
treatment of moderate to severe pain following extraction of 3 or 4 full or
partial bony
impacted third molars, a single oral dose of one of the treatments was
administered
when the patient was suffering moderate to severe postoperative pain. The
observation period for efficacy was 8 hours post treatment, and for safety was
24
hours post treatment.
The efficacy and safety evaluations included pain intensity, pain relief,
global
pain evaluation, evaluation of time to meaningful pain relief (stopwatch),
visual
analog scale (VAS), and adverse event assessments. For the data analysis,
certain
pain parameters were computed as generally described above.
The 0.01 mg NTX alone and placebo treatment groups had the lowest mean 4
hour Sum of Pain Intensity Difference (SPID) scores. All 4 of the active
treatment
groups with MS alone or in combination with NTX exhibited improved profiles in

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mean SPm relative to NTX alone or placebo. The mean 4 hour SP1D scores for the
0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for
the
MS alone treatment, whereas the 0.001 mg NTX combination treatment was
comparable to that for the MS alone treatment. The patterns of the 6 hour and
8 hour
SPA scores were similar to those at 4 hours.
The 0.01 mg NTX alone aaZd placebo treatment groups had the lowest mean
Total Pain Relief scores. All 4 of the active treatment groups exhibited mean
Total
Pain Relief scores that were numerically higher than the 0.01 mg NTX alone and
placebo ia-eatment groups. The combination treahnents had a dose-response
relation
in the mean Total Pain Relief scores, i.e., the highest dose of NTX had the
highest
mean Total Pain Relief scores and the lowest dose of NTX had the lowest mean
Total
Pain Relief scores. This pattern (high-dose (0.1 mg NTX) > mid-dose (0.01 mg
NTX)
> low-dose (0.001 mg NTX) was generally observed for pain relief variables
throughout the study. The mean Total Pain Relief score for the 0.01 mg NTX and
the
0.1 NTX combination treatment groups were higher than that for the MS alone
treatment, whereas the 0.001 mg NTX combination treatment mean was comparable
to or lower than that for the MS alone treatment.
The NTX alone and placebo treatment groups had the highest number of
subjects who had "poor" global evaluation scores. The profiles of the global
evaluations scores are based on subjects' evaluations.
The median time to onset of meaningful pain relief was shortest in the 0.1 mg
NTX combination treatment group.
The median time to onset of analgesia was shortest in the 0.1 mg NTX
combination treatment group.
The baseline pain intensity scores and visual analog scale scores were
generally comparable across treatment groups.
The majority of adverse events reported were categorized as digestive (nausea
or vomiting) or nervous system (dizziness or somnolence).
A study of hydrocodone with acetaminophen (instead of morphine) alone and
in combination with naltrexone is described in Example 3 of U.S. Application
Ser.

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No. 60/245,110, filed November 1, 2000, incorporated by reference herein. A
summary of exemplary study results follows.
In a dose ranging study, doses of hydrocodone (5 mg) with acetaminophen
(500 mg) and naltrexone (0.1 mg, 0.01 mg, and 0.001 mg) were administered for
moderate to severe pain following dental surgery. The study was performed to
investigate the analgesic efficacy of hydrocodone with acetaminophen alone,
four
different doses of naltrexone in combination with hydrocodonelacetaminophen,
and
placebo.
The 300 subject study was designed with six treatment groups: A) placebo (50
pts); B) HC 5 mg/APAP 500 mg and placebo (50 pts); C) HC 5 mg/APAP 500 mg
and NTX 1.0 mg (50 pts); D) HC 5 mg/APAP 500 mg and NTX 0.1 mg (50 pts); E)
HC 5 mg/APAP 500 mg and NTX 0.01 mg (50 pts); F) HC 5 mg/APAP 500 mg and
NTX 0.001 mg (50 pts). In this study, in the treatment of moderate to severe
pain
following extraction of 3 or 4 full or partial bony impacted third molars, a
single oral
dose of one of the treatments was administered when the patient was suffering
moderate to severe postoperative pain. The observation period for efficacy was
8
hours post treatment and for safety was 24 hours post treatment.
The efficacy and safety evaluations included pain intensity, pain relief,
global
pain evaluation, evaluation of time to meaningful pain relief (stopwatch),
visual
analog scale and adverse event assessments. For the data analysis, certain
pain
parameters were computed as generally described above.
The placebo treatment group had the lowest mean 4 hour Sum of Pain
Intensity Difference (SPID) scores. All 5 of the active treatment groups with
HC/APAP alone or in combination with NTX exhibited improved profiles in mean
SPID relative to placebo. The mean 4 hour SPID score for the 0.001 mg NTX
combination treatment Was higher than that for the HC/APAP alone treatment,
whereas the other NTX combination treatments were comparable to or lower than
that
for the HC/APAP alone treatment. The patterns of the 6 hour and 8 hour SPID
scores
were similar to those at 4 hours.

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The placebo treatment group had the lowest mean Total Pain Relief scores.
All 5 of the active treatment groups with HC/APAP alone or in combination with
NTX exhibited mean Total Pain Relief scores that were numerically higher than
placebo. The mean Total Pain Relief score for the 0.001 mg NTX combination
treatment was higher than that for the HC/APAP alone treatment, whereas the
other
NTX combination treatment means were comparable to or lower than that for the
HC/APAP alone treatment.
The placebo treatment group had the highest number of subjects who had
"poor'° global evaluation scores. The 0.001 mg NTX combination
treatment group
had the highest number of subjects with a total of "excellent", "very good'"
and "good"
global evaluation scores. The profiles of the global evaluation scores are
based on
subj ects' evaluations.
The median time to onset of meaningful pain relief was shortest in the 0.001
mg NTX (lowest-dose) combination treatment group. The placebo and the 0.01 mg
NTX combination treatment groups had the lowest number of subjects who reached
meaningful pain relief.
The baseline pain intensity scores and visual analog scale scores were
generally comparable across treatment groups.
The majority of adverse events reported were categorized as digestive (nausea
or vomiting) or nervous system (dizziness or sedation).
Another study of morphine alone and in combination with naltrexone was
conducted. In this dose ranging study, doses of morphine sulfate (30 mg, 60
mg, and
90 mg) in combination with naltrexone hydrochloride (0.1 mg) were administered
for
moderate to severe pain in male patients following dental surgery. Tlus study
was
performed to investigate the efficacy of combinations of different doses of
morphine
with naltrexone 0.1 mg, relative to placebo and relative to morphine alone, to
evaluate
the dose-response effects of morphine when administered alone and when
coadministered with naltrexone 0.1 mg, and to examine the consistency of
effect of
naltrexone 0.1 mg across different doses of morphine, when coadministered with
morphine.

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The 210 subject study was designed with seven treatment groups: A) placebo
(30 pts); B) morphine 30 mg (30 pts); C) morphine 60 mg (30 pts); D) morphine
90
mg (30 pts); E) morphine 30 mg and naltrexone 0.1 mg (30 pts); F) morphine 60
mg
and naltrexone 0.1 mg (30 pts); G) morphine 90 mg and naltrexone 0.1 mg (30
pts).
In this study, in the treatment of moderate to severe pain following
extraction of 3 or
4 full or partial bony impacted third molars, a single oral dose of one of the
treatments
was administered when the patient was suffering moderate to severe
postoperative
pain. The observation period for efficacy was 8 hours post treatment and for
safety
was 24 hours post treatment.
The efficacy and safety evaluations included PID, SPID-4, SPID-6 and SPID-
8, PEAKPID, VAS-PID at each assessment, VAS-SPID-4, -6, and -8, PEAK.-VAS
P~, pain relief (PR) score, TOTPAR-4, -6, and -8, MAXPAR, global evaluation,
time to onset of analgesia, time to re-medication, percent of patients re-
medicating by
4, 8, 24 hours, and adverse event assessments. For the data analysis, certain
pain
parameters were computed as generally described above.
The mean PID scores for the placebo treatment group were generally flat
while the mean PID scores generally improved over time for the active
treatment
groups (30 mg MS, 60 mg MS and 90 mg MS alone or in combination with 0.1 mg
NTX). The mean scores for the morphine alone and morphine/naltrexone
combination treatment groups were higher than the mean PID scores for the
placebo
group at each hourly assessment time from 1-8 hours. Highest pain relief as
measured
by PID scores was observed for the 90 mg MS/0.1 mg NTX combination treatment
group.
The placebo treatment group had the lowest mean 4 hour Sum of Pain
Intensity Difference (SPID) scores. All 6 of the active treatment groups with
30 mg,
60 mg or 90 mg MS alone or in combination with 0.1 mg NTX exhibited improved
profiles in mean SPID relative to placebo. The mean 4 hour SPID score for the
90 mg
MS/0.1 mg NTX combination treatment was the highest among all treatment
groups.
The mean SPID scores fox the 30 mg, 60 mg and 90 mg MS alone treatment groups
were comparable. In contrast, the mean SPID scores for the 30 mg MS/0.1 mg
NTX,

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60 mg MSJ0.1 mg NTX and 90 mg MSl0.1 mg NTX combination treatment groups
demonstrated a dose response, with the 90 mg MS/0.1 mg NTX combination
treatment group having the highest mean SPID-4 scores, and the 30 mg MS/0.1
NTX
combination treatment group having the lowest mean SPID-4 scores of the
combination treatment groups.
The placebo treatment group had the lowest mean Total Pain Relief scores.
111 6 of the active treatment groups with 30 mg, 60 mg or 90 mg MS alone or in
combination with 0.1 mg NTX exhibited mean Total Pain Relief scores that were
numerically higher than placebo. The mean Total Pain Relief score for the 90
mg
MS/0.1 mg NTX combination treatment was the highest among all treatment
groups.
The mean Total Pain Relief scores for the 30 mg, 60 mg and 90 mg MS alone
treatment groups were comparable. In contrast, the mean Total Pain Relief
scores for
the 30 mg MS/0.1 mg NTX, 60 mg MS/0.1 mg NTX and 90 mg/MS 0.1 mg NTX
combination treatment groups demonstrated a dose response, with the 90 mg
MS/0.1
mg NTX combination treatment group having the highest mean Total Pain Relief
scores, and the 30 mg MS/0.1 NTX combination treatment group having the lowest
mean Total Pain Relief scores of the combination treatment groups.
The mean PEAKPID scores varied among treatment groups, and were greater
for all 6 active treatment groups compared to the placebo group. Compared to
all
other groups, the mean PEAI~PID scores were highest for the 90 mg MS/0.1 mg
NTX
combination treatment group.
The mean pain relief score for the placebo treatment was less than those for
the active treatment groups (30 mg, 60 mg, 90 mg MS alone or in combination
with
0.1 mg NTX) which improved over time. There was separation between the placebo
and the active treatment groups that continued throughout the 8 hour study
period.
Highest pain relief scores were observed for the 90 mg MS/0.1 mg NTX
combination
group.
The mean MAXPAR scores varied among treatment groups. The mean
MAXPAR score was highest for the 90 mg MS/0.1 mg NTX combination treatment

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group compared to all other groups. The meaai scores for all 6 active
treatment groups
were greater than the mean score for the placebo group.
The placebo treatment group had the highest number of subjects who had
"poor" global evaluation scores. The 90 mg MS/0.1 mg NTX combination treatment
group had the highest number of subjects with a total of "excellent", "very
good" and
"good" global evaluation scores. The profiles of the global evaluation scores
are
based on subjects' evaluations.
The median time to onset of analgesia was shortest in the 90 mg MS/0.1 mg
NTX combination treatment group.
The placebo group had the shortest median time to remedication and the 90
mg MS/0.1 mg NTX combination treatment group had the longest median time to
remedication. More than 70% of subjects at 4 hours in the 90 mg MS/0.1 mg NTX
combination group and more than 60% of subjects in the same combination group
at 8
hours did not require rescue medication.
The baseline pain intensity scores and visual analog scale scores were
generally comparable across treatment groups.
The majority of adverse events reported were categorized as digestive (nausea
or vomiting) or nervous system (dizziness or somnolence).
E~~AMPLE 3
This example describes the preparation of a dosage form comprising
naltrexone hydrochloride (referred to as "naltrexone" or "NTX" in these
examples)
which was used in clinical evaluations. This example also describes the
measurement
of the dissolution of that dosage form.
The dosage form for the clinical evaluation and the dissolution tests of this
example were provided by preparing hard gelatin capsules comprising an opioid
antagonist and excipients according to Example 1. The capsules contained
naltrexone
HCl and two and pharmaceutical excipients. The tables below indicate the
qualitative
composition of the NTX capsules.

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Components of Naltrexone HCl Capsules
Component Description
Naltrexone HCI, USP Active Pharmaceutical Ingredient
Microcrystalline Cellulose, Disintegrant/Filler
NF
Magnesium Stearate, NF Lubricant
Hard Gelatin Capsule Unit Dose Form
The NTX capsules were prepared by filling the empty capsule shells with a
powder blend of NTX, microcrystalline cellulose, and magnesium stearate. The
fill
weight was constant for each strength of NTX capsules produced.
Unless otherwise specified, and subject to the particular conditions and
parameters disclosed for the particular examples, the dissolution tests in
Example 3
and the other examples were performed using the dissolution test in U.S.
Phannacopeia 24 (2000) Physical Test <711> (which is incorporated herein by
reference), employing Apparatus 2 (Paddle Stirnng Element).
Dissolution testing was performed on two capsules per dissolution vessel in a
media of 500 ml of 0.1 N hydrochloric acid (HCl). The testing media
temperature
was maintained at about 37.0°C (+/- 0.5°C), and the paddle speed
was 50 rpm.
Sample aliquots of the testing media were withdrawn at various time points,
and the
quantity of naltrexone (and/or another ingredient whose dissolution was to be
tested)
was determined. The release of the tested ingredient is reported as percentage
released versus time.
The table below summarizes the results obtained for the dissolution tests on
the NTX capsules. These results are the mean values of six tests.
Dissolution of Naltrexone Hydrochloride from Example 3
Time (man) NTX Released (%)
0 0
5 94.2
10 91.4
The dosage form provided for rapid dissolution of over 90% of the theoretical
amount of naltrexone with about 5-10 minutes.

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EXAMPLE 4
This example describes the preparation of a dosage form comprising morphine
sulfate pentahydrate (MS) for clinical evaluation. This example also describes
the
measurement of the dissolution of that dosage form. The dosage form for
clinical
evaluation and for the dissolution tests of this example were hard gelatin
capsules.
The MS capsules were prepared by placing 1 to 4 tablets of a commercially
available
mg MS immediate release tablet into a hard gelatin capsule. A mixture of
microcrystalline cellulose and magnesium stearate was then added to bring the
capsule to volume and facilitate processing. The table below indicates the
qualitative
10 composition of the MS capsules.
Components of Morphine Sulfate Capsules
Com onent Descri tion
Morphine Sulfate, Pentahydrate Active Pharmaceutical Ingredient
(as a 15 mg Commercial MS
Tablet)
1-4 tablets
Microcrystalline Cellulose, Disinte rant/Filler
NF
Ma esium Stearate, NF Lubricant
Hard Gelatin Capsule Unit Dose Fonn
The ih vity°o dissolution rates in this example were determined
using the
Apparatus 2 (Paddle Stirring Element) in U.S. Pharmacopeia 24 (2000), using
the
same conditions and parameters as described in Example 3.
15 For dissolution testing, one 60 mg MS capsule was placed in the testing
media. The table below summarizes the results obtained for the dissolution
tests on
the MS capsules. These results are the mean values of six tests.
Dissolution of Morphine Sulfate, Pentahydrate from Example 4
Time (min) MS Released (%)
0 0
5 78.2
10 89.4
These dissolution results show that this dosage form provides immediate
release of morphine sulfate pentahydrate.

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EXAMPLE 5
This example describes the preparation of a dosage form comprising
oxycodone hydrochloride. This example also describes the measurement of the
dissolution of that dosage form. The following general procedure was used to
prepare
capsules containing different strengths of oxycodone hydrochloride (referred
to in this
example as oxycodone) supplied as Roxicodone~ (Roxane Laboratories, Inc.).
Roxicodone~ tablets are available in 5.0 mg (oxycodone hydrochloride) strength
tablets. Each Roxicodone~ tablet is claimed to have a theoretical drug content
of 5.0
mg oxycodone hydrochloride, although the actual amount may vary within an
acceptable range, for example by about 10%.
A 5.0 mg oxycodone hydrochloride capsule was made by mixing
microcrystalline cellulose (229.2 mg) with magnesium stearate (1.2 mg) to form
a
blend. The blend and one Roxicodone~ tablet were loaded separately into the
body
component of a hard gelatin capsule shell. The capsule was then closed with
the cap
component of the shell. The filled capsule weighed approximately 426.0 mg.
A 15.0 mg oxycodone hydrochloride capsule was made by mixing
microcrystalline cellulose (135.5 mg) with magnesium stearate (0.7 mg) to form
a
blend. The blend and three Roxicodone0 tablets were loaded separately into the
body
component half of a hard gelatin capsule shell. The capsule was then closed
with the
cap component of the shell. The filled capsule weighed approximately 533.0 mg.
The filled capsules containing 15.0 mg oxycodone were subjected to
dissolution tests equivalent to the dissolution test set forth in the USP 24
Monograph
for oxycodone hydrochloride tablets, except that the testing medium was a USP
grade
buffer having a pH of 4.5, and a paddle speed of 75 rpm was used.
Additionally,
chromatographic separation of the oxycodone from the colorant in the gelatin
capsule
was necessary to overcome interference in the ultraviolet absorbance spectrum.
The
USP 24 Monograph for oxycodone hydrochloride tablets refers to the general
dissolution test set forth in U.S. Pharmacopeia 24.
The following table summarizes the dissolution results obtained for the 15 mg
oxycodone strength capsules based on 12 samples tested.

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Dissolution Of Oxycodone Hydrochloride From Example 5
Time (min) Oxycodone Released (%)
0 0
87
99
.
102
These dissolution results show that this dosage form provides immediate
release of oxycodone hydrochloride.
Dissolution tests were also attempted at 50 rpm, but the paddle method did not
5 provide enough agitation and coning occurred. At this lower paddle speed of
50 rpm,
the overfill excipients from the capsule formed a cone at the bottom of the
dissolution
vessel and prevented the tablet from dissolving properly. The occurrence of
coning
justifies modification of the dissolution test parameters. To overcome the
coung, the
paddle speed was increased to 75 rpm, which is still within acceptable USP
10 dissolution criteria.
EXAMPLE 6
This example describes the preparation of a dosage form comprising tramadol
hydrochloride (referred to in this example as "tramadol") which was used in
clinical
evaluations. This example also describes the measurement of the dissolution of
that
15 dosage form. The following general procedure was used to prepare capsules
containing different strengths of tramadol hydrochloride supplied as Ultram0
(Johnson RW). Ultram~ tablets are available in 50.0 mg (tramadol
hydrochloride)
strength tablets. Each Ultram~ tablet is claimed to have a theoretical drug
content of
50.0 mg tramadol hydrochloride, although the actual amount of each may vary
within
20 an acceptable range, for example by about 10%.
A 50.0 mg tramadol hydrochloride capsule was made by mixing
microcrystalline cellulose (167.16 mg) with magnesium stearate (0.84 mg) to
form a
blend. The blend and one Ultram~ tablet were loaded separately into the body
component of a hard gelatin capsule shell. The capsule was then closed with
the cap
25 component of the shell. The filled capsule weighed approximately 491.3 mg.

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The filled capsules were subjected to dissolution tests using Apparatus 2
(Paddle Stirring Element) in U.S. Phannacopeia 24. Analysis of tramadol
capsules
was accomplished by performing dissolution on the filled capsules in 900 ml of
0.1 N
hydrochloric acid. The media temperature was maintained at about 37.0°C
(+/-
0.5°C), and the paddle speed was 75 rpm. The following table summarizes
the
dissolution data obtained for the 50 mg tramadol hydrochloride strength
capsules
based on 6 samples having been tested.
Dissolution Of Tramadol Hydrochloride From Example 6
TIME (MIN) ' TRAMADOL RELEASED (%)
0 0
5 8
60
93
30 106
Once again, coning was observed for dissolution tests performed at 50 rpm
10 which resulted in an unreliable test. To overcome the coning, the paddle
speed was
increased to 75 rpm, which is still within acceptable USP dissolution
criteria.
These dissolution results show that this dosage form provides immediate
release of tramadol hydrochloride and that the excipients employed do not
significantly bind an opioid agonist in an aqueous environment.
15 EXAMPLE 7
This example describes a general procedure used to make a pharmaceutical
composition comprising an opioid antagonist on coated nonpareil beads or
pellets,
such as coated pellet 1 shown in FIG 2. This example describes a dosage form
consisting essentially of an opioid antagonist. A binder solution of at least
a binder,
an organic and/or aqueous solvent and an opioid antagonist is prepared. A
suitable
binder is hydroxypropyl methylcellulose ("HPMC"), plasticized with triacetin,
e.g.,
Opadry~ brand commercial coating from Colorcon, W c. The binder solution is
coated onto inert nonpareil pellets to form a coated pellet. The coating is
conducted
in a fluidized bed apparatus configured in a bottom-spray orientation with a
Wurster

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column insert. A plasticizer may be added to the coating dispersion to
increase the
flexibility of the coating. The thickness (weight) of the coat on the
nonpareil pellets
can be varied as desired but generally falls in the range of about 2-50% wt.
of the total
pellet weight. The coated pellets weigh less than about 10 mg and have a
diameter or
length of about 0,1-5.0 mm. These coated pellets may comprise the following
ingredients in the approximate amounts indicated.
Composition of Coated Pellets
INGREIDIENT AMOUNT (% wlw)
O ioid anta onist (NTX 0.1
O adiyOO Clear 5.0
Non-pareil sugar cores 94.9
The nonpareil cores used in the coated pellet and bead formulations generally
comprise a pharmaceutically inert material such as lactose, sucrose, and
starch.
The coated pellets may be loaded into hard gelatin capsules or compressed
into tablets.
EXAMPLE 8
This example describes a general procedure used to make a pharmaceutical
composition comprising a coated granulation similar to that shown in FIG. 6,
except
than the opioid antagonist is the only active pharmaceutical ingredient
employed in
this example. This example describes a dosage form consisting essentially of
an
opioid antagonist. A granulating-solution is made by mixing an opioid
antagonist,
one or more binders, and water in a vessel equipped with a high shear mixer. A
suitable granulating solution comprises the following ingredients in the
approximate
amounts indicated.

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Granulating Solution
INGREDIENT AMOUNT (% w/w)
O ioid anta onist T 0.5
HPMC ES 5.0
PEG 8000 1.2
Purified water .s. to 100 ml
A first blend of inert pharmaceutical excipients (such as those in the table
below) is then granulated with a granulating solution in a fluidized bed unit
to form a
granulated wet mass that is sized by passing it through a No. 12 sieve. The
sized
granules are subsequently dried, thereby forming the coated granulation, which
is then
passed through a No. 30 mesh screen.
Granulation Blend
INGREDIENT AMOUNT (% w/w)
HPMC 4.5
Lactose, hydrous 73
Dibasic calcium hos hate 22.5
The granules are then mixed with magnesium stearate (0.5% wt.) and low-
substituted hydroxypropylcelluose ("L-HPC") (3.0% wt.) and blended for an
additional 5 min. The blend is then compressed into tablets on a rotary tablet
press.
EXAMPLE 9
This example describes a general procedure used to make a soft gelatin
capsule dosage form comprising a drug suspension. A suspension is made by
mixing
a non-aqueous vehicle such as miglyol, PEG, glycerin, propylene glycol, or
vegetable
oil with solids such as an opioid antagonist and optionally at least one other
pharmaceutical excipient. The solids added to the non-aqueous vehicle are
generally
powdered or particulate and can include beads, pellets and granules, for
example. A
suitable suspension comprises the following ingredients in the approximate
amounts
indicated.
INGREDIENT AMOUNT (% w/w)
O ioid anta onist (NTX) 0.05
Talc 10
Miglyol 812 .s. to 100

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EXAMPLE 10
This example describes a general procedure used to male the pharmaceutical
composition of FIG. 2, which comprises a mixture of two different coated
nonpareil
beads or pellets. This example describes a dosage form comprising an opioid
antagonist and another active pharmaceutical ingredient (in this case, an
opioid
agonist). A combination capsule dosage form containing both naltrexone and
morphine sulfate pentahydrate for concurrent release of both drugs was
prepared. The
excipients used in this example were found not to bind morphine or naltrexone
significantly in an aqueous environment.
A first binder solution comprising at least a binder, an organic andlor
aqueous
solvent and an opioid antagonist is prepared. The first binder solution is
coated onto
inert nonpareil pellets to form a first coated pellet. A suitable binder is
plasticizied
HPMC, such as Opadry~ Clear. The coating was conducted in a fluidized bed
apparatus configured in a bottom-spray orientation with a Wurster column
insert.
The spray rate of the coating solutions was adjusted during processing to
maintain the
following approximate equilibrium conditions during processing; inlet
temperature
70°-80°C, exhaust temperature 42°-47°C.
Composition of first Coated Pellets
INGREDIENT' AMOUNT (% w!w)
O ioid anta onist TX 0.1
O adry~ Clear 5.0
Non-pareil sugar cores 94.9
In a similar fashion, a second binder solution comprising at least a binder,
an
organic and/or aqueous solvent and an opioid agonist is prepared. The second
binder
solution is coated onto other inert nonpareil pellets to form a second coated
pellet. A
plasticizer may be added to the coating dispersion to increase the flexibility
of the
coating.
Aqueous coating solutions with the compositions listed above were used to
manufacture capsules containing drug coated non-pareil beads that rapidly and
concurrently release opioid agonist and opioid antagonist from the dosage
form.

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Composition of second Coated Pellets
INGREDIENT AMOUNT (% wlwn
O ioid a onist MS) 7.5
O a ~ Clear 7.5
Non- areil su ar cores 85.0
Predetermined amounts of the first and second pellets are mixed thereby
forming a mixture of the pellets. The thickness (weight) of the coat on the
nonpareil
pellets can be varied as desired but generally falls in the range of about 1-
70% wt. of
the total pellet weight. The coated pellets weigh less than about 10 mg and
have a
diameter or length of about 0.1-5.0 mm.
Capsules made according to this example contained the following ingredients
in the approximate amounts indicated.
INGREDIENT Mass Fraction Quantity
w/w (mg)
O ioid A onist Beads, consistin 400
of:
Opioid Agonist (morphine sulfate6.667 30.0
entah drate)
Binder (e. ., lasticized HPMC) 6.667 30.0
Non-Pareil Sugar Cores 75.556 340.0
O ioid Anta onist Beads, consistin 50
of
O ioid Anta onist (NTX) 0.011 0.05
Binder (e. ., lasticized HPMC 0.556 2.5
Non-Paa-eil Su ar Cores 10.544 47.45
Total Net Content Wei ht 100.000 450.0
Hard Gelatin Ca sule, Size 0 1 ca sule
The nonpareil cores used in the coated pellet and bead formulations of the
invention generally comprise a pharmaceutically inert material such as
lactose,
sucrose, and/or starch.
A mixture of coated pellets was loaded into hard gelatin capsules and
subjected to dissolution tests using Apparatus 2 (Paddle Stirnng Element) in
U.S.
Pharmacopeia 24, except that a variety of different agitation rates were used.
The

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testing media was 500 ml of 0.1 N HCI, at a constant media temperature of
37°C (+/-
0.5°C). The agitation rates of the paddles for the dissolution tests
were 50, 75 or 100
rotations per minute. The tables below summarize the results obtained for the
dissolution tests at the respective paddle speeds. The results reported at
each time for
each paddle speed are the mean values of six tests.
Dissolution profile at 50 rpm.
Time (min) MS Released (%) NTX Released (%)
0 0 0
55.3 60.4
72.1 72.0
82.1 98.7
45 89.5 95.1
Dissolution profile at 75 rpm.
Time (min) MS Released (%) NTX Released (%)
0 0 0
5 53.6 63.2
10 66.7 74.5
20 81.2 86.4
30 85.2 91.0
45 98.2 95.2
60 97.1 96.8
Dissolution profile at 100 rpm.
Time (min) MS Released (%) NTX Released (%)
0 0 0
5 68.6 69.6
10 84.8 82.6
20 97.2 91.6
30 101.2 95.4
45 102.7 96.1
60 103.1 98.1
10 These dissolution results show that this combination dosage form provides
concurrent release of an opioid agonist and an opioid antagonist and that the
excipients employed do not significantly bind an opioid agonist or an opioid
agonist
in an aqueous environment. These dissolution results show that in this
combination

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dosage form, the dissolution profiles were substantially the same at each
agitation
rate, percentages of the opioid agonist and the opioid antagonist are
substantially the
same when tested at 75 rpm and 100 rpm at 5 minutes, 10 minutes, 20 minutes,
30
minutes, 45 minutes, and 60 minutes. The dosage form of this example also
provides
immediate release of both active pharmaceutical ingredients at greater than
about 90%
dissolution at 45 minutes.
EXAMPLE 11
This example demonstrates a general procedure used to make the
pharmaceutical composition of FIG. 3 comprising a single type of coated
nonpareil
pellet, wherein the coat comprises an opioid antagonist and another active
pharmaceutical ingredient (in this case, an opioid agonist). A first binder
solution
comprising at least a binder, an organic and/or aqueous solvent, a
plasticizer, an
opioid agonist and an opioid antagonist is prepared. The first binder solution
is
coated onto inert nonpareil pellets to form coated pellets. The thickness
(weight) of
the coat on the nonpareil pellets can be varied as desired but generally falls
in the
range of about 2-80 % wt., normally between 10-50%, of the total pellet
weight. The
pellets weigh about less than 10 mg and have a diameter or length of about 0.2-
2.0
mm. These coated pellets comprise the following ingredients in the approximate
amounts indicated.
Coating Composition
INGREDIENT AMOUNT ( % w/w)
Opioid antagonist (NTX) 0.01
Opioid agonist (MS) 6
HPC 4.5
PEG 8000 0.4
Purified water q.s. to 100
EXAMPLE 12
This example demonstrates a combination tablet dosage form containing both
naltrexone salt and morphine salt for concurrent release and immediate release
of both
active pharmaceutical ingredients. The combination tablet comprises an opioid
SUBSTITUTE SHEET (RULE 26)

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antagonist and another active pharmaceutical ingredient (in this case, an
opioid
agonist). The excipients used in this example were found not to bind morphine
or
naltrexone significantly (e.g., to an extent that interferes with the
therapeutic effect or
concurrent release) in an aqueous environment. The tablet disintegrates within
about
5 min after exposure to an aqueous buffer at 37°C and provides rapid
dissolution of
the active pharmaceutical ingredients. Tablets made according to this example
contained the following ingredients in the approximate amounts indicated.
Components of MS/NTX Concurrent Release Tablets
Component Description Content
(m /tablet)
Mo hine Sulfate, Pentah drate API 30.00
Naltrexone HCl API 0.05
Lactose Monoh drate Filler 92.51
Dibasic calcium Phos hate, DihydrateFiller 50.76
Low-Substituted h drox ro lcelluloseDisinte ant 16.87
Hydrox ro y1 methylcellulose Binder 2.81
2910
Talc Glidant 6.00
Magnesium stearate (comperdial Lubricant 1.00
designations are not used elsewhere)
The tablets were made according to the following general procedure. A high
shear, wet granulation method was employed to prepare the bulk powders for
tableting.
Granulating solution
INGREDIENT AMOUNT IN SOI~UTION(% w/w)
Opioid antagonist (NTX) 0.265
Hydroxypropyl Methylcellulose 5.0
2910
Purified water q.s. to 100 ml
A dry material blend of an opioid agonist and the following pharmaceutical
excipients was prepared in a high shear granulator.

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Granulation Blend
INGREDIENT AMOUNT IN BLEND (% wlw)
Opioid agonist (MS) 16.95
Hydroxypropyl Methylcellulose 1.06
2910
Low Substituted Hydroxypropyl 1.06
Cellulose (L-HPC)
Lactose Monohydrate, Spray 52.26
Dried
Dibasic calcium phosphate 28.68
While mixing, the binder solution was added slowly to the dry material blend
to prepare the granulation. The wet granulation was sized by passing it
through a 20
mesh screen. The sized wet granulation was dried in a fluid-bed apparatus
until the
dried mass had a moisture content of less than about five percent. The dried
granulation was passed through a 20 mesh screen. The following non-granulated
excipients were blended into the dried granulation using a double cone
blender.
Non-granulated Excipients
INGREDIENT AMOUNT IN FINAL
EXCIPIENTS (% w/w)
Talc 27.27
L-HPC 68.18
Magnesium Stearate 4.55
The final powder blend was then compressed on a rotary tablet press using 7
mm round, biconcave tooling. The compressed tablet compacts were collected,
and
the aqueous based coatings applied in a tablet-coating unit.
The tablets were coated with a clear seal coat of plasticized HPMC (Opadry~)
based aqueous coating solution and a colored topcoat of plasticized HPMC
(Opadry~) based aqueous coating dispersion.

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The tablets were determined to disintegrate in less than 3 minutes in
deionized
water at 37°C (+/- 2°C) using the disintegration test in U.S.
Pharmacopeia 24 (2000)
Physical Tests <701> (which is incorporated herein by reference).
The dissolution of the MS and NTX from the uncoated and coated tablet cores
was evaluated using Apparatus 2 (Paddle Stirring Element) in U.S. Phannacopeia
24,
with 500 mL of O.1N HCl as the dissolution media. Two tablets were placed in
500
mL of dissolution media at 37°C (+/- 0.5°C). The paddle
agitation rate was 50 rpm,
and the percentages of dissolved MS and NTX were determined from samples of
the
testing medium.
The tables below summarize the results of the dissolution tests on the
uncoated
tablet cores and the coated tablet cores prepared as described above. FIG. 9
shows the
dissolution profile of the coated tablet cores.
Dissolution of MS and NTX from Uncoated, Concurrent Release Tablets
Time (min) % MS Released % NTX Released
0 0 0
10 82.4 97.7
95.1 95.6
96.4 119.8
~45 96.2 103.3
Dissolution of MS and NTX from Coated, Concurrent Release Tablets
Time (min) % MS Released % NTX Released
0 0 0
10 82.9 89.3
20 90.0 90.3
30 94.1 92.9
45 96.3 95.5
15 Accordingly, this embodiment of the invention provides an immediate release
solid oral tablet comprising an opioid antagonist and an opioid agonist. The
active
pharmaceutical ingredients are released concurrently. Furthermore, the
dissolution
percentages of the opioid agonist and the opioid antagonists in this dosage
form are
substantially the same at each time (except at 30 min. for the uncoated
tablets). These
20 dissolution results show that this combination dosage form provides
concurrent

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release of an opioid agonist and an opioid antagonist and that the excipients
employed
do not significantly bind an opioid agonist in an aqueous environment.
EXAMPLE 13
This example demonstrates a general procedure used to make the
pharmaceutical composition of FIG. 4 comprising a mixture of two different
types of
granulations. One granulation comprises an opioid antagonist and the other
granulation comprises another active pharmaceutical ingredient (in this case,
an
opioid agonist).
A first granulation is made by blending an opioid antagonist and a first blend
of pharmaceutical excipients with a granulating solution to form a wet mass
that is
passed through a sieve to form wet granules that are subsequently dried. A
suitable
first granulation comprises the following ingredients in the approximate
amounts
indicated.
First Granulation
INGREDIENT AMOUNT (% wlw)
O ioid anta onist (NTX) 0.5
HPMC ES 5
Lactose, hydrous 54.5
EncompressT"" 40
Likewise, a second granulation is made by blending an opioid agonist and a
second blend of pharmaceutical excipients with a granulating solution to form
a wet
mass that is passed through a sieve to form wet granules that are subsequently
dried.
A suitable second granulation comprises the following ingredients in the
approximate
amounts indicated.

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Second Granulation
INGREDIENT AMOUNT (% w/w)
O ioid a onist (MS 10
HPMC ES 4.5
L-HPC 2
Lactose, hydrous q.s. to 100
The first and second granulations are subsequently blended to form the
mixture. The granulations pass through a No. 20 mesh screen. Granulations of
both
active pharmaceutical ingredients are passed through a No. 20 mesh screen and
blended with a disintegrant (e.g., L-HPC, 3% wt.) and a lubricant (e.g.,
magnesium
stearate, 0.5% wt.) for 10 min in a twin-shell blender prior to compression on
a rotary
tablet press.
EXAMPLE 14
IO This example demonstrates a general procedure used to make the
pharmaceutical composition of FIG. 5 comprising a combination granulation. The
combination granulation comprises an opioid antagonist and another active
pharmaceutical ingredient (in this case, an opioid agonist).
A first granulation is made by blending an opioid antagonist and a first blend
of pharmaceutical excipients with a granulating solution to form a wet mass
that is
passed through a No. 12 sieve to form wet granules that are subsequently
dried. The
final granulation passes through a No. 20 mesh screen. A suitable first
granulation
comprises the following ingredients in the approximate amounts indicated.
First Granulation
INGREDIENT AMOUNT (% w/w)
O ioid antagonist (NTX) 0.5
HPMC ES 3.75
Sucrose 5
Lactose 80
Dicalcium phosphate 10

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A second granulation is made by blending an opioid agonst, a second blend of
pharmaceutical excipients and the first granulation with a granulating
solution to form
a wet mass that is passed through a sieve to form wet granules that are
subsequently
dried. A suitable second granulation comprises the following ingredients in
the
approximate amounts indicated.
Second Granulation
INGREDIENT AMOUNT (% w/w)
First Granulation 20
O ioid Agonist (Hydrocodone 4.0
bitartrate)
HPMC ES 4.5
L-HPC 1.5
Lactose, hydrous q.s. to 70
EXAMPLE 15
This example demonstrates a general procedure used to make the
pharmaceutical composition of FIG. 6 comprising a coated granulation which
comprises an opioid antagonist and another active pharmaceutical ingredient
(in this
case, an opioid agonist). A granulating solution is made by blending an opioid
agonist, an opioid antagonist, a binder and a solvent in a vessel equipped
with a high
shear mixer. A suitable granulating solution comprises the following
ingredients in
the approximate amounts indicated.
Granulating solution
INGREDIENT AMOUNT (% w/w)
O ioid anta onist (NTX) 0.1
O ioid a onist (hydrocodone 10
bitartrate)
HPMC ES 5.5
PEG 8000 1.0
Purified water q.s. to 100
A first blend of inert pharmaceutical excipients is then granulated with the
granulating solution in a fluidized bed unit to form a wet mass that is passed
through a
No. 12 sieve to form wet granules which are subsequently dried, thereby
forming the
coated granulation.

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The final granulation is then mixed with one or more pharmaceutical
excipients to form a pharmaceutical mixture comprising the following
ingredients in
the approximate amounts indicated. The final granulation passes through a No.
20
mesh screen.
Granulation
INGREDIENT ~ AMOUNT (% wlw)
Weight of solids from granulating 15
solution
Lactose 39
Encom ress 41.5
L-HPC 4
Ma esium stearate 0.5
EXAMPLE 16
This example demonstrates a general procedure similar to the one used to
make the pharmaceutical composition of Example 15 except that the opioid
agonist is
not included in the granulating solution and is instead included with the
pharmaceutical excipients being granulated.
A granulating-solution is made by mixing an opioid antagonist, a binder and a
solvent in a vessel equipped with a high shear mixer. A suitable granulating-
solution
comprises the following ingredients in the approximate amounts indicated.
Granulating solution
INGREDIENT AMOUNT (% wlw)
O ioid anta onist (NTX) 0.5
HPMC E5 5.0
PEG 8000 1.2
Purified water .s. to 100 ml
A first blend of inert pharmaceutical excipients is then granulated with the
granulating solution in a fluidized bed unit to form a wet mass that is passed
through a
No. 12 sieve to form wet granules which are subsequently dried, thereby
forming the
coated granulation, and passed through a No. 30 mesh screen. A suitable
granulation
comprises the following ingredients in the approximate amounts indicated.

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Granulation
INGREDIENT AMOUNT (% w/w)
O ioid a onist oxycodone bitartrate 5.0
HPMC 4.5
Lactose, hydrous 68
Dibasic calcium hos hate 22.5
The coated granulation is mixed with magnesium stearate (0.5% wt.) and L
HPC (3.0% wt.) and blended for an additional 5 min. The blend is then
compressed
into tablets on a rotary tablet press.
EXAMPLE 17
This example demonstrates a general procedure used to make a
pharmaceutical composition comprising spray-dried granules. A solution of an
opioid
antagonist, another active pharmaceutical ingredient, such as an opioid
agonist, and at
least one pharmaceutical excipient is spray-dried in a BUCHITM spray-dryer at
a rate
of about 10 ml/min while using an inlet temperature of 90°C and an
outlet
temperature of 50°C. The spray-dried granules are collected and have a
particle size
of less than about 20 mesh. Suitable spray-dried granules comprise the
following
ingredients in the approximate amounts indicated.
INGREDIENT AMOUNT (% w/w)
Opioid agonist (oxycodone 10
hydrochloride)
O ioid anta onist (NTX 0.2
HPMC E5 3
Sucrose: lactose (1:I) .s. to 86.8
While specific parameters for operation of the spray-dryer are detailed above,
operation of the spray-dryer can be conducted as needed and the parameters for
operation of the apparatus can be varied as needed to prepare a product
according to
this example.
The granules are dried and blended with magnesium stearate (0.5% wt.) and
L-HPC (3.0% wt.) and blended for an additional 4-6 min. The blend is then
compressed into tablets on a rotary tablet press or is filled into hard
gelatin capsules.

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EXAMPLE 18
This example demonstrates a general procedure used to make a soft gelatin
capsule dosage form containing a drug suspension. A suspension is made by
mixing a
non-aqueous vehicle such as miglyol, PEG, glycerin, propylene glycol, or
vegetable
oil with an opioid antagonist, another active pharmaceutical ingredient such
as an
opioid agonist, and optionally at least one other pharmaceutical excipient.
The solids
added to the non-aqueous vehicle are generally powdered or particulate and can
include beads, pellets and granules, for example. A suitable suspension
comprises the
following ingredients in the approximate amounts indicated.
INGREDIENT AMOUNT (% w/w)
Opioid agonist (MS) 20
O ioid anta onist (NTX) 0.05
Talc 10
Mi lyol 812 .s to 100
Although the invention herein has been described with reference to particular
embodiments, it is to be understood that these embodiments are merely
illustrative of
various aspects of the invention. Thus, it is to be understood that numerous
modifications may be made in the illustrative embodiments and other
arrangements
may be devised without departing fiom the spirit and scope of the invention.