Canadian Patents Database / Patent 2456322 Summary

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(12) Patent Application: (11) CA 2456322
(54) English Title: COMPOSITIONS AND METHODS TO PREVENT ABUSE OF OPIOIDS
(54) French Title: COMPOSITIONS ET METHODES DESTINEES A PREVENIR L'ABUS D'OPIOIDES
(51) International Patent Classification (IPC):
  • A61K 9/48 (2006.01)
  • A61K 9/16 (2006.01)
  • A61K 9/20 (2006.01)
  • A61K 9/50 (2006.01)
(72) Inventors :
  • BREDER, CHRISTOPHER (United States of America)
  • COLUCCI, ROBERT (United States of America)
  • OSHLACK, BENJAMIN (United States of America)
  • SACKLER, RICHARD (United States of America)
  • WRIGHT, CURTIS (United States of America)
(73) Owners :
  • EURO-CELTIQUE, S.A. (Luxembourg)
(71) Applicants :
  • EURO-CELTIQUE, S.A. (Luxembourg)
(74) Agent: BORDEN LADNER GERVAIS LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2002-08-06
(87) Open to Public Inspection: 2003-02-20
Examination requested: 2004-02-03
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country/Territory Date
60/310,515 United States of America 2001-08-06
60/310,516 United States of America 2001-08-06
60/310,537 United States of America 2001-08-06

English Abstract




Methods and compositions for preventing abuse of dosage forms of an opioid
analgesic and an opioid antagonist including at least one aversive agent in an
effective amount to deter an abuser from administering a tampered form of said
dosage form intravenously, intranasally, and/or orally.


French Abstract

La présente invention concerne des méthodes et des compositions destinées à prévenir l'abus de formes posologiques d'un analgésique opioïde et d'un antagoniste opioïde comprenant au moins un agent aversif en une quantité efficace pour empêcher un consommateur abusif de s'administrer une forme trafiquée de ladite forme posologique par voie intraveineuse, intranasale et/ou orale.


Note: Claims are shown in the official language in which they were submitted.




What is claimed is:
1. A oral dosage form comprising:
a therapeutically effective amount of an opioid analgesic;
an opioid antagonist; and
a tittering agent in an effective amount to impart a bitter taste to an abuser
upon
administration of said dosage, form after tampering.
2. The oral dosage form of claim 1, wherein the tittering agent is selected
from the
group consisting of flavor oils; flavoring aromatics; oleoresins; extracts
derived from
plants, leaves, flowers, fruit flavors; sucrose derivatives; chlorosucrose
derivatives;
quinine sulphate; denatonium benzoate; and combinations thereof.
3. The oral dosage form of claim l, wherein the tittering agent is a flavor
oil selected
from the group consisting of spearmint oil, peppermint oil, eucalyptus oil,
oil of
nutmeg, allspice, mace, oil of titter almonds, menthol and combinations
thereof.
4. The oral dosage form of claim 1, wherein the tittering agent is a fruit
flavor selected
from the group consisting of lemon, orange, lime, grapefruit, and mixtures
thereof.
5. The oral dosage form of claim l, wherein the tittering agent is de~:atonium
benzoate.
6. The oral dosage form of clam 1, wherein the tittering agent is in a
sequestered form.
7. The offal dosage form of claim 1,. wherein the antagonist is in a
sequestered form.
8. The oral dosage form of claim 1, wherein the antagonist and the tittering
agent are
both in sequestered forms.
9. The oral dosage form of claim 1, wherein said tittering agent is in an
amount of less
than about 50% by weight of the dosage form.
10. The oral dosage form of claim 1, wherein said tittering agent is in an
amount of less
than about 10% by weight of the dosage form.


63




11. The oral dosage form of claim l, wherein said battering agent is in an
amount of less
than about 5% by weight of the dosage form
12. The oral dosage form of claim 1, wherein said battering agent is in an
amount of from
about 0.1 to 1.0 percent by weight of the dosage form.
13. The oral dosage forms of claim l, further comprising a pharmaceutically
acceptable
excipient.
14. The oral dosage forms of claim 13, wherein said excipient is a sustained
release
excipient.
15. The oral dosage form of claim 13, said dosage form providing an analgesic
effect for
at least about 12 hours after oral administration to a human patient.
16. The oral dosage form of claims 1 wherein said battering agent is at least
partially
interdispersed with the opioid analgesic.
17. The dosage form of claim 1 having a ratio of opioid antagonist to opioid
agonist that
is analgesically effective when the combination is administered orally, but
which is
aversive in physically dependent human subjects when administered at the same
amount or at a higher amount than said therapeutically effective amount.
18. The dosage form of claim 17 wherein said ratio of opioid antagonist to
opioid agonist
maintains an analgesic effect but does not increase analgesic efficacy of the
opioid
agonist relative to the same therapeutic amount of opioid analgesic when
administered
to human patients without said opioid antagonist.
19. The oral dosage form of claim 1, wherein the antagonist is in an amount to
attenuate a
side effect of said opioid agonist selected from the group .consisting of anti-
analgesia,
hyperalgesia, hyperexcitability, physical dependence, tolerance, and a
combination of
any of the foregoing.


64




20. The oral dosage form of claim 1, wherein the amount of antagonist released
during
the dosing interval enhances the analgesic potency of the opioid agonist.
21. The oral dosage form of claim l, wherein the amount of the releasable
opioid receptor
antagonist is about 100 to about 1000 fold less than the amount of the opioid
agonist.
22. A method of treating pain comprising administering to a patient an oral
dosage form
of claim 1.
23. A method of preparing a pharmaceutical dosage form comprising combining a
therapeutically effective amount of an opioid analgesic; and an antagonist in
a dosage
form with an effective amount of a bittering agent to impart a bitter taste to
an abuser
upon administration of said dosage form after tampering.
24. The method of claim 23, wherein said tittering agent is at least partially
interdispersed with the opioid analgesic.
25. A method of preventing abuse of an oral dosage form of an opioid analgesic
comprising: '
preparing the dosage form with an analgesically effective amount of an opioid
analgesic; an. antagonist; and .
a tittering agent in an effective. amount to impart a bitter taste. to an
abuser upon
administration of said dosage form after tampering
26. ' A oral dosage form comprising:
a therapeutically effective amount of an opioid analgesic;
an opioid antagonist; and
an irritant in an effective amount to impart an irritating sensation to an
abuser upon
administration of said dosage form after tampering.
27. The oral dosage form of claim 26, wherein the irritant is selected from
the group
consisting of capsaicin, a capsaicin analog, and mixtures thereof.


65


28. ~The oral dosage form of claim 26, wherein the irritant is a capsaicin
analog selected
from the group consisting of resiniferatoxin, tinyatoxin,
heptanoylisobutylamide,
heptanoyl guaiacylamide, other isobutylamides or guaiacylamides,
dihydrocapsaicin,
homovanillyl octylester, nonanoyl vanillylamide, and mixtures thereof.

29. ~The oral dosage form of claim 26, wherein the irritant is capsaicin.

30. ~The oral dosage form of claim 26, wherein the irritant is vanillylamide.

31. ~The oral dosage form of clam 26, wherein the irritant is in a sequestered
form.

32. ~The oral dosage form of claim 26, wherein the antagonist is in a
sequestered form.

33. ~The oral dosage form of claim 26, wherein the antagonist and the irritant
are both in
sequestered forms.

34. ~The oral dosage form of claim 26, wherein the irritant is in an amount of
about
0.00125% to about 50% by weight of the dosage form.

35. ~The oral dosage form of claim 26, wherein the irritant is in an amount of
about 1 to
about 7.5% by weight of the dosage form.

36. ~The oral dosage form of claim 26; wherein the irritant is in an amount
of about 1 to
about 5% by weight of the dosage form.

37. ~The oral dosage forms of claim 26, further comprising a pharmaceutically
acceptable
excipient

38. ~The oral dosage forms of claim 37, wherein said excipient is a sustained
release
excipient.

39. ~The oral dosage form of claim 37, said dosage form providing an analgesic
effect for
at least about 12 hours after oral administration to a human patient.

66




40. ~The oral dosage form of claims 26, wherein said irritant is at least
partially
interdispersed with the opioid analgesic.

41. ~The dosage form of claims 26, having a ratio of opioid antagonist to
opioid agonist
that is analgesically effective when the combination is administered orally,
but which
is aversive in physically dependent human subjects when administered at the
same
amount or at a higher amount than said therapeutically effective amount.

42. ~The dosage form of claim 41, wherein said ratio of opioid antagonist to
opioid agonist
maintains an analgesic effect but does not increase analgesic efficacy of the
opioid
agonist relative to the same therapeutic amount of opioid analgesic when
administered
to human patients without said opioid antagonist.

43. ~The oral dosage form of claim 26 wherein the antagonist is in an amount
to attenuate
a side effect of said opioid agonist selected from the group consisting of
anti-
analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance,
and a
combination of any of the foregoing.

44. ~The oral dosage form of claim 26, wherein the amount of antagonist
released during
the dosing interval enhances the analgesic potency of the opioid agonist.

45. ~The oral dosage form of claim 26, wherein the amount of the releasable
opioid
receptor antagonist is about 100 to about 1000 fold less than the amount of
the opioid
agonist.

46. ~A method of treating pain comprising administering to a patient an oral
dosage form
of claims 26.

47. ~A method of preparing a pharmaceutical dosage form comprising combining a
therapeutically effective amount of an opioid analgesic; and an antagonist in
a dosage
form with an effective amount of a irritant to impart an irritating sensation
to an
abuser upon administration of said dosage form after tampering.

67




48. ~The method of claim 47, wherein said irritant is at least partially
interdispersed with
the opioid analgesic.

49. ~A method of preventing abuse of an oral dosage form of an opioid
analgesic
comprising:
preparing the dosage form with an analgesically effective amount of an opioid
analgesic; an opioid antagonist; and
an irritant in an effective amount to impart an irritating sensation to an
abuser upon
administration of said dosage form after tampering.

50. ~An oral dosage form comprising:
a therapeutically effective amount of an opioid analgesic, an opioid
antagonist and
one or more pharmaceutically acceptable excipients;~
said dosage form further including a gelling agent in an effective amount to
impart a
viscosity unsuitable for administration selected from the group consisting of
parenteral and nasal administration to a solubilized mixture formed when the
dosage
form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous
liquid.

51. ~The oral dosage form of claim 50, wherein said excipient comprises a
controlled
release material and the dosage form provides pain relief for at least about
12 hours
when orally administered to a human patient.

52. ~The oral dosage form of claim 50, wherein said gelling agent comprises a
controlled
release material and the dosage form provides pain relief for at least about
12 hours
when orally administered to a human patient.

53. ~The oral dosage form of claim 50, wherein said opioid analgesic is
selected from the
group consisting of levorphanol, meperidine, dihydrocodeine, dihydromorphine,
pharmaceutically acceptable salts thereof, and mixtures thereof.

54. ~The oral dosage form of claim 50, wherein said opioid analgesic is
morphine or a
pharmaceutically acceptable salt thereof.

68


55. ~The oral dosage form of claim 50, wherein said opioid analgesic is
hydromorphone or
a pharmaceutically acceptable salt thereof.

56. ~The oral dosage form of claim 50, wherein said opioid analgesic is
hydrocodone or a
pharmaceutically acceptable salt thereof.

57. ~The oral dosage form of claim 50, wherein said opioid analgesic is
oxycodone or a
pharmaceutically acceptable salt thereof.

58. ~The oral dosage form of claim 50, wherein said opioid analgesic is
codeine or a
pharmaceutically acceptable salt thereof.

59. ~The oral dosage form of claim 50, wherein said opioid analgesic is
oxymorphone or a
pharmaceutically acceptable salt thereof.

60. ~The oral dosage form of claim 50, wherein said ratio of said gelling
agent to said
opioid analgesic is from about 1:40 to about 40:1.

61. ~The oral dosage form of claim 50, wherein said ratio of said gelling
agent to said
opioid analgesic is from about 1:1 to about 30:1.

62. ~The oral dosage form of claim 50, wherein said ratio of said gelling
agent to said
opioid analgesic is from about 2:1 to about 10:1.

63. ~The oral dosage form of claim 50, wherein said gelling agent is selected
from the
group consisting of sugars, sugar derived alcohols, cellulose derivatives,
gums,
surfactants, emulsifying agents, and mixtures thereof.

64. ~The oral dosage form of claim 50, wherein said gelling agent is pectin.

65. ~The oral dosage form of claim 50, wherein said gelling agent is xanthan
gum.

66. ~The oral dosage form of claim 50, wherein said unsuitable viscosity is
attained when
about 1 to about 3 ml of aqueous liquid is mixed with the crushed dosage form.

69


67. ~A method of preventing abuse of an oral dosage form of a opioid analgesic
comprising:
preparing the dosage form with an analgesically effective amount of an opioid
analgesic; an opioid antagonist; and one or more pharmaceutically acceptable
excipients;
said dosage form further including a gelling agent in an effective amount to
impart a
viscosity unsuitable for administration selected from the group consisting of
parenteral and nasal administration to a solubilized mixture formed when the
dosage
form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous
liquid.

68. ~The method of claim 67, wherein said excipient comprises a controlled
release
material, and the dosage form provides effective pain relief for at least
about 12
hours when orally administered to a human patient.

69. ~The method of claim 67, wherein said gelling agent comprises a controlled
release
material, and the dosage form provides effective pain relief for at least
about 12 hours
when orally administered to a human patient.

70. ~The method of claim 67, wherein the addition of from about 0.5 to about
10 ml of said
aqueous liquid causes said solubilized mixture to have a viscosity of at least
about 60
cP.

71. ~The method of claim 67, wherein said opioid analgesic is selected from
the group
consisting of of morphine, hydromorphone, hydrocodone, oxycodone, codeine,
levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone,
pharmaceutically acceptable salts thereof and mixtures thereof.

72. ~The method of claim 67, wherein said gelling agent is selected from the
group
consisting of sugars or sugar derived alcohols, cellulose derivatives, gums,
surfactants, emulsifying agents, and mixtures thereof.

73. ~A controlled release oral dosage form comprising:



a therapeutically effective amount of an opioid analgesic; an opioid
antagonist; and
one or more pharmaceutically acceptable excipients;
said dosage form further including a gelling agent in an effective amount to
impart a
viscosity unsuitable for administration selected from the group consisting of
parenteral and nasal administration to a solubilized mixture formed when the
dosage
form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous
liquid
and thereafter heated;

said dosage form providing pain relief for at least about 12 hours when orally
administered to a human patient.

74. ~A method of preventing abuse of an oral controlled release dosage form of
a opioid
analgesic comprising:
preparing the dosage form with an analgesically effective amount of an opioid
analgesic; an opioid antagonist; and one or more pharmaceutically acceptable
excipients;
said dosage form further including a gelling agent in an effective amount to
impart a
viscosity unsuitable for administration selected from the group consisting of~
parenteral and nasal administration to a solubilized mixture formed when the
dosage
form is crushed and mixed with from about 0.5 to about 10 ml of an aqueous
liquid
and is thereafter heated;
said dosage form providing effective pain relief for at least about 12 hours
when
orally administered to a human patient.

75. ~A method of treating pain comprising:
administering to a patient a therapeutically effective amount of an opioid
analgesic; an
opioid antagonist; and pharmaceutically acceptable excipients such that the
dosage
form provides effective pain relief for at least about 12 hours when orally
administered to a human patient;
said dosage form further including a gelling agent in an effective amount to
impart a
viscosity unsuitable for administration selected from the group consisting of~
parenteral and nasal administartion to a solubilized mixture formed when the
dosage
form is crashed and mixed with from about 0.5 to about 10 ml of an aqueous
liquid.

76. The oral dosage form of claim 50, wherein the antagonist is in a
sequestered form.

71



77. The oral dosage form of claim 50, wherein the antagonist is in an amount
to attenuate
a side effect of said opioid agonist selected from the group consisting of
anti-
analgesia, hyperalgesia, hyperexcitability, physical dependence, tolerance,
and a
combination of any of the foregoing.

78. The oral dosage form of claim 50, wherein the amount of antagonist
released during
the dosing interval enhances the analgesic potency of the opioid agonist.

79. The oral dosage form of claim 50, wherein the amount of the releasable
opioid
receptor antagonist is about 100 to about 1000 fold less than the amount of
the opioid
agonist.

80. An oral dosage form comprising:
a therapeutically effective amount of an opioid analgesic;
an opioid antagonist; and a gelling agent in an effective amount to impart a
viscosity
unsuitable for nasal absorption of the drug upon administration to the nasal
passages
after tampering.

81. An oral dosage form comprising:
a therapeutically effective amount of an opioid analgesic;
an opioid antagonist; and a gelling agent in an effective amount to impart a
viscosity
unsuitable for parenteral administration after tampering.

72

Note: Descriptions are shown in the official language in which they were submitted.


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
COMPOSITIONS AND METHODS TO PREVENT ABUSE OF OPIOIDS
BACKGROUND OF THE INVENTION
Opioid analgesics are sometimes the subject of abuse. Typically, a particular
dose of
an opioid analgesic is more potent when administered parenterally as compared
to the same
dose administered orally. Therefore, one popular mode of abuse of oral opioid
formulations
involves the extraction of the opioid from the dosage form, and the subsequent
injection of
the opioid (using any "suitable" vehicle for injection) in order to achieve a
"high."
In the prior art, there have previously been attempts to control the abuse
potential
associated with opioid analgesics. For example, the combination of immediate
release
pentazocine and naloxone has been utilized in tablets availaUle in the United
States,
commercially available as Talwin°Nx from Sano~-Winthrop. Talwiri Nx is
indicated for the
relief of moderate to severe pain. Talwiri Nx contains immediate release
pentazocine
hydrochloride equivalent to 50 mg base and naloxone hydrochloride equivalent
to 0.5 mg
base. The amount of naloxone present in this combination has low activity when
taken
orally, and minimally interferes with the pharmacologic action of pentazocine.
However, this
amount of naloxone given parenterally has profo~md antagonistic action tr
narcotic
analgesics. Thus, the inclusion of naloxone is intended to curb a form of
misuse of oral
pentazocine which occurs when the dosage form is solubilized and injected.
Therefore, this
dosage .has lower potential for parenteral misuse than previous oral
pentazocine formulations.
A fixed combination therapy comprising tilidine (50 mg) and naloxone (4 mg)
has
been available in Germany for the management of severe pain since 1978
(Valorori N,
Goedecke). The rationale for the combination of these drugs is effective pain
relief and the
prevention of tilidine addiction through naloxone-induced antagonisms at the
morphine
receptor. A axed combination of buprenorphine and naloxone was introduced in
1991 in
New Zealand (Temgesic°Nx, Reckitt &. Cohnan) for the treatment of
pain.
Purdue Pharma L.P currently marlcets sustained-release oxycodone in dosage
forms
containing 10, 20, 40, and 80 mg oxycodone hydrochloride under the tradename
OxyContin.
U.S. Patent Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,295 disclose
sustained
release oxycodone formulations.
U.S. Patent No. 4,769,372 and 4,785,000 to Kreek describe methc :a of treating
patients suffering from chronic pain or chronic cough without provoking
intestinal
dysmotility by administering 1 to 2 dosage units comprising from about 1.5 to
about 100 mg


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
of opioid analgesic or antitussive and from about 1 to about 18 mg of an
opioid antagonist
having little to no systemic antagonist activity when administered orally,
from 1 to 5 times
daily. .
U.S. Patent No. 6,228,863 to Palermo et al. describes compositions and methods
of .
preventing abuse of opioid dosage foims.
WO 99/32119 to Kailco et al. describes compositions and methods of preventing
abuse of opioid dosage fours.
U.S. Patent No. 5,472,943 to Crain et al. describes methods of enhancing the
analgesic potency of bimodally acting opioid agonists by administering the
agonist with an
opioid antagonist.
Additionally, Shaw et al., U.S. Patent No. 3,980,766, relates to drugs which
are
suitable for therapy in the treatment of narcotic drug addiction by oral use,
e.g., methadone,
fornmlated to prevent injection abuse through concentration of the active
component in
aqueous solution by incorporating in a solid dosage or tablet form of such
drug an ingestible
solid having thickening properties which cause rapid increase in viscosity
upon concentration
of an aqueous solution thereof.
However, there still exists a need for a safe and effective treatment of pain
with opioid
analgesic dosage forms which are less subject to abuse than current therapies.
All documents cited herein, including the foregoing, are incorporated by
reference in
their entireties for all purposes.
OBJECTS AND SUMMARY OF TI3E INVENTION
It is an object of certain.embodiments of the invention to provide n oral
dosage form
of an opioid analgesic which is subject to less parenteral abuse than other
dosage forms.
It is an object of certain embodiments of the invention to provide an oral
dosage form
of an opioid analgesic which is subject to less intranasal abuse than other
dosage forms.
It is an object of certain embodiments of the invention to provide an oral
dosage form
of an opioid analgesic which is subject to less oral abuse than other dosage
forms.
It is a further object of certain embodiments of the invention to provide an
oral dosage
form of an opioid analgesic which is subject to less diversion than other
dosage forms.
It is a further object of certain embodiments of the invention to provide a
method of
treating pain in human patients with an oral dosage form of an opioid
analgesic while
reducing the abuse potential of the dosage form.
2


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It is a further object of certain embodiments of the invention to provide a
method of
manufacturing an oral dosage form of an opioid analgesic such that it has less
abuse potential.
These objects and others are achieved by the present invention, which is
directed in
part to an oral dosage fornz comprising an opioid analgesic; an opioid
antagonist; and at least
one aversive agent for reducing the abuse of the opioid analgesic.
In certain embodiments of the present invention, the oral dosage fornis of the
present
invention comprising an opioid analgesic; an opioid antagonist; and an
,aversive agent or
agents as a components) of the dosage form helps to prevent injection abuse by
decreasing
the "attractiveness" of the dosage form to a potential abuser.
In certain embodiments of the present invention, the dosage .=orni comprises
an
aversive agent such as a tittering agent to discourage an abuser from
tampering with the
dosage form and thereafter inhaling or swallowing the tampered dosage form.
Preferably, the
tittering agent is released when the dosage form is tampered with and provides
an unpleasant
taste to the abuser upon inhalation and/or swallowing of the tampered dosage
form.
In certain embodiments of the present invention, the dosage form comprises an
aversive agent such as an iiTitant to discourage an abuser from tampering with
the dosage
form and thereafter inhaling, injecting, or swallowing the tampered dosage
form. Preferably,
the irritant is release when the dosage form is tampered with and provides a
turning or
irritating effect to the abuser upon inhalation, injection, and/or swallowing
the tampered
dosage form.
In certain embodiments of the present invention, the dosage form comprises an
aversive agent such as a gelling agent to discourage an abuser from tampering
with the
dosage form and thereafter inhaling, injecting, or swallowing the tampered
dosage form.
Preferably; the gelling agent is released when the dosage form is tamper~,'i
with and provides
a gel-like quality to the tampered dosage form which slows the absorption of
the opioid
analgesic such that an abuser is less likely to obtain a rapid "high". In
certain preferred
embodiments, when the dosage form is tampered with and exposed to a small
amount (e.g.,
less than about 10 ml) of an aqueous liquid (e.g., water), the dosage form
will to unsuitable
for injection and/or inhalation. Upon the addition of the aqueous liquid, the
tampered dosage
form preferably becomes thick and viscous, rendering it unsuitable for
injection. The term
"unsuitable for injection" is defined for purposes of the present invention to
mean that one
would have substantial difficulty injecting the dosage form (e.g., due to pain
upon
administration or difficulty pushing the dosage form through a syringe) due to
the viscosity
imparted on the dosage form, thereby reducing the potential for abuse of the
opioid analgesic
3


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in the dosage form. In certain embodiments, the gelling agent is present in
such an amount in
the dosage form that attempts at evaporation (by the application of heat) to
an aqueous
mixture of the dosage form in an effort to produce a higher concentration of
the therapeutic
agent, produces a highly viscous substance unsuitable for injection.
When nasally inhaling the tampered dosage forms the gelling agent can become
gel
like upon administration to the nasal passages due to the moisture of the
mucous membranes.
This also makes such formulations aversive to nasal administration, as the gel
will stick to the
nasal passage and minimize abs.oiption of the abusable substance.
In certain embodiments of the present invention, the dosage form comprises a
combination of any or all of the aforementioned aversive agents (e.g., a
tittering agent, an
irritant, and/or a gelling agent) to discourage an abuser from tampering v:
ath the dosage form
and thereafter inhaling, injecting, and/or swallowing the tampered dosage
form.
Embodiments specifically contemplated include tittering agent; gelling agent;
irritant;
tittering agent and gelling agent; tittering agent and irritant; gelling agent
and irntant;
tittering agent and gelling agent; tittering agent and irritant; gelling agent
and irntant; and
tittering agent and gelling agent and irritant.
In certain preferred embodiments, the dosage fornis are controlled release
oral dosage
forms comprising a therapeutically effective amount of an opioid analgesic and
an opioid
antagonist together with one or more of the aversive agents described above
such that the
dosage form provides effective pain relief for at least about 12 hours, or at
least about 24
hours, when orally administered to a human patient.
In certain embodiments of the present invention the opioid antagonist present
in the
dosage form is present in a substantially non-releasable form (i.e.,
"sequestered") when the
dosage ~ form is administered intact as directed. Preferably, because the
opioid antagonist is
present in the dosage form in a substantially non-releasable form, it dies not
substantially
block the analgesic effect of the opioid agonist when the dosage form is
orally administered
intact, and does not pose a risk of precipitation of withdrawal in opioid
tolerant or dependent
patients.
In certain embodiments of the present invention, the aversive agent present in
the
dosage form is present in a substantially non-releasable form (i.e.,
"sequestered") instead of,
or in addition to, the opioid antagonist being in a substantially non-
releasable form.
In other embodiments, the aversive agent may not to "sequestered" as disclosed
above wherein the aversive agent is not released or minimally released from an
intact dosage
form, tut may have a modified or sustained release so as not to dump the
aversive agent in a
4


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
particular section of the gastrointestinal tract; e.g. the stomach, where it
may cause an
unwanted effect such as excessive irntation. The aversive agent can be
combined with an
enteric carrier to delay its release or combined with a carrier to provide a
sustained release of
the aversive agent. However, it is contemplated in the present invention that
the aversive
agent will preferably not have any significant side effect (e.g.,
gastrointestinal side effect)
even if all of the aversive agent is immediately ieleased upon oral
administration of an intact
dosage form as directed. The aversive agents) can also be in the dosage form
in releasable
fonm and non-releasable forni in any combination. For example, a dosage form
can have a
tittering agent, irritant, gel or combination thereof in releasable form and
non-releasable form
as disclosed in U.S. Patent Application entitled "Compositions And Methods To
Prevent
Abuse Of Opioids" filed August 6, 2002. Likewise, the antagonist of the
present invention
may be in releasable form, non-releasable form or a combination of releasable
form and non-
releasable fornl as , disclosed in U.S. Patent Application entitled
"Pharnlaceutical
Formulations Containing ' Opioid Agonist, Releasable Antagonist, and
Sequestered
Antagonist" filed August 6, 2002 and hereby incorporated by reference in its
entirety, in
combination with one of the aversive agents disclosed herein.
For example, the antagonist of the present invention can to an antagonist with
minimal oral activity such as naloxone in releasable or "non-sequestered"
forni. The
inclusion of such an.antagonist would be a deterrent to parenteral abuse of
the dosage fornl
and the aversive agents of the present invention (i.e., tittering agent.
irritant, gelling agent)
would to a deterrent to oral and nasal abuse of the dosage form. In addition,
the dosage form
can contain a "sequestered" antagonist such as a bioavailable antagonist to
further deter the
oral and nasal abuse of the dosage form upon administration of a tampered
dosage form.
The term "aversive agent" is defined for purposes of the present invention to
mean a
tittering agent, an irritant, or a gelling agent.
The term "tampered dosage form" is defined for purposes of the present
invention to
mean that the dosage form has been manipulated by mechanical, thermal, and/or
chemical
means which changes the physical properties of the dosage form, e.g., to
liberate the opioid
agonist for immediate release if it is in sustained release form, or to make
the opioid agonist
available for inappropriate use such as administration by an alternate route,
e.g., parenterally.
The tampering can be, e.g., by means of crushing, shearing, grinding, chewing,
dissolution in
a solvent, heating, (e.g., greater than about 45° C), or any
combination thereof.
The term "substantially non-releasable form" for purposes of the present
invention
refers to an opioid antagonist and/or aversive agent that is not released or
substantially not


CA 02456322 2004-02-03
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released at one hour after the intact dosage form containing an opioid
agonist, an opioid
antagonist and at least one aversive agent is orally administered (i.e.,
without having been
tampered with). Formulations comprising an opioid antagonist in a dosage form
in a
substantially non-releasable fornl are described in U.S. Application Serial
No. 091781,081,
entitled "Tamper Resistant Oral Opioid Agonist Formulations", filed February
8, 2001, the
disclosure of which is hereby incorporated by reference in its entirety. For
purposes of the
present invention, the amount released after oral administration of the intact
dosage form may
be measured in-vitro via the dissolution at 1 hour of the dosage form in 900
ml of Simulated
Gastric Fluid LISlllg a USP Type II (paddle) apparatus at 75 rpm at 37°
C. Such a dosage form
is also referred to as comprising a "sequestered antagonist" and/or a
"sequestered aversive
agent" depending on the agent or agents which are not released or
substantially not released.
In certain preferred embodiments of the invention, the substantially non-
releasable form of
the antagonist and/or the aversive agent is resistant to laxatives (e.g.,
mineral oil) used to
manage delayed colonic transit and resistant to achlorhydric states.
Preferably, the aversive
agent is not released or not substantially released 4, 8, 12 and/or 24 hours
after oral
administration.
The phrase "at least partially blocking the opioid effect", is defined for
purposes of
the present invention to mean that the opioid antagonist at least
significantly blocks the
euphoric effect of the, opioid antagonist, thereby reducing the potential for
abuse of the opioid
agonist in the dosage forni.
The phrase "analgesic effectiveness" is defined for purposes of the present
invention
as a satisfactory reduction in or elimination of pain, along with a tolerable
level of side
effects, as determined by the human patient.
The phrase "not substantially blocking the analgesic effect of an opioid
agonist" for
purposes of the present invention means that the opioid antagonist does not
block the effects
of the opioid agonist in sufficient degree as to render the dosage form the:
apeutically less
effective for providing analgesia.
The term "sustained release" is defined for purposes of the present invention
as the
release of.the opioid analgesic from the oral dosage form at such a rate that
blood (e.g.,
plasma) concentrations (levels) are maintained within the therapeutic range
but below toxic
levels over an extended period of time , e.g., from about 12 to about 24 hours
as compared to
an immediate release product. Preferably the sustained release is sufficient
to provide a
twice-a-day or a once-a-day formulation.
6


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
The term "particles" of opioid antagonist, as used herein, refers to granules,
spheroids,
beads or pellets comprising the opioid antagonist. In certain preferred
embodiments, the
opioid antagonist particles are about 0.2 to about 2 mm in diameter, more
preferably about
0.5 to about 2 mm in diameter.
The term "parenterally" as used herein includes subcutaneous injections,
intravenous
injections, intramuscular injections, intrasternal injections, infusion
techniques, or other
methods of injection known in the art.
The term "inhaled" as used herein includes traps-mucosal, traps-bronchial, and
trans-
nasal abuse.
The terns "tittering agent" as used herein includes a compound used to impart
a bitter
taste, titter flavor, etc., to an abuser administering a tampered dosage form
of the present
invention.
The term "in-itant" as used herein includes a compound used to :~~npart an
irritating,
e.g., turning or uncomfortable, sensation to an abuser administering a
tampered dosage forni
of the present invention. '
The term "gelling agent" as used herein includes a compound or composition
used to
impart gel-like or thickening quality to a tampered dosage form upon the
'addition of moisW re
or liquid.
DETAILED DESCRIPTION OF THE INVENTIOiV~
The aversive agents of the present invention are preferably for use in
connection with
oral dosage forms including opioid analgesics and opioid antagonists, which
provide valuable
analgesia but which may be abused. This is particularly true for controlled
release opioid
analgesic products which have a large dose 'of a desirable opioid analgesic
intended to be
released over a period of time in each dosage unit. Dmg abusers typically may
take a
controlled-release product and crush, shear, grind, chew, dissolve and/or
heat, extract or
otherwise damage the product so that the full contents of the dosage fomn
become available
for immediate absorption by injection, inhalation, and/or oral consumption.
In certain embodiments, the present invention comprises a method for
preventing or
deterring of the abuse of opioid analgesics by the inclusion of an opioid
antagonist and at
least one aversive agent in the dosage forni with the opioid analgesic.
In certain embodiments of the present invention wherein the dosage form
includes an
aversive agent comprising a tittering agent, various tittering agents can to
employed
including, for example and without limitation, natural, artificial and
synthetic flavor oils and
7


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
flavoring aromatics and/or, oils, oleoresins and extracts derived from plants,
leaves, flowers,
fruits, and so forth, and combinations~thereof. Nonlimiting representative
flavor oils include
spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace,
oil of bitter
almonds, menthol and the like. Also useful tittering agents are artificial,
natural and
synthetic fruit flavors such as citrus oils including lemon, orange, lime,
grapefruit, and fruit
essences and so forth. Additional tittering agents include sucrose derivatives
(e.g., sucrose
octaacetate), chlorosucrose derivatives, quinine sulphate, and the like The
preferred tittering
agent for use in the present invention is Denatonium Benzoate NF-Anhydrous,
sold under the
name BitrexTM (Macfarlan Smith Limited, Edinburgh, UK).
With the inclusion of a tittering agent in the formulation, the intake of the
tampered
with dosage form produces a titter taste upon inhalation or oral
administration which in
certain embodiments spoils or hinders the pleasure of obtaining a high from
the tampered
dosage form, and preferably prevents the abuse of the dosage form. '
A tittering agent may be added to the formulation in an amout~~. of less than
about
50% by weight preferably less than about 10% by weight, most preferably less
than about 5% ,
by weight of the dosage form, and most preferably in an amount ranging from
about 0.1 to
1.0 percent by weight of the dosage form depending on the particular tittering
agents) used.
A dosage form including a tittering agent preferably discourages improper
usage of the
tampered dosage form by imparting a disagreeable taste or flavor to the
tampered dosage
form.
In certain embodiments of the present invention wherein the dosage form
includes an
aversive agent comprising an irritant, various irritants can be employed
including, for
example and without limitation capsaicin, a capsaicin analog with similar type
properties as
capsaicin, and the like. Some capsaicin analogues or derivatives include for
example and
without limitation, resiniferatoxin, tinyatoxin, heptanoylisobutylamide,
heptanoyl
guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin,
homovanillyl
octylester, nonanoyl , vanillylamide, or other compounds of the class known as
vanilloids.
Resiniferatoxin is described, for example, in U.S: Pat. No. 5,290,816
(Blumberg), issued Mar.
1, 1994. U.S. Pat. No. 4,812,446 (Brand), issued Mar. 14, 1989, describes
capsaicin analogs
and methods for t$eir preparation. Further, U.S. Pat. No. 4,424,205 (LaHann
et~al.), issued
Jan. 3, 1984, cite Newman, "Natural and Synthetic Pepper-Flavored Substances"
published in
1954 as listing pungency of capsaicin-like analogs. Ton et al., . British
Journal of
Pharmacology, 10, pp. 175-182 (1955) discuss pharmacological actions of
capsaicin and its
analogs.
8


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
With the inclusion of an irritant (e.g., capsaicin) in the dosage for~~, when
the dosage
fornl is tampered with, the capsaicin imparts a burning or discomforting
quality to the to the
abuser to preferably discourage the inhalation, injection, or oral
administration of the
tampered dosage form, and preferably to prevent the abuse of the dosage form.
Suitable
capsaicin compositions include capsaicin (trans 8-methyl-N-vanillyl-6-
noneamide) or
analogues thereof in a concentration between about 0.00125% and 50% by weight,
preferably
between about 1 and about 7.5% by weight, and most preferably, between about 1
and about,
5% by weight.
In certain embodiments of the present invention wherein the dosage form
includes an
aversive agent comprising a gelling agent, various gelling agents can be
employed including,
for example and without limitation, sugars or sugar derived alcohols, such as
mamiitol, .
sorbitol, and the like, starch and , starch derivatives, cellulose
derivatives, such as
microcrystalline cellulose, sodium caboxymethyl cellulose, methylcellulose,
ethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl
methylcellulose,
attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacant.'_,
gum acacia, guar
gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum
silicate, the
carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol,
polyethylene oxide,
polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant/wetting
agent systems,
emulsifiers, other polymeric materials, and mixtures thereof, etc. In certain
preferred
embodiments, the gelling agent is xanthan gum. In other preferred embodiments,
the gelling
agent of the present invention is pectin. The pectin or pectic substances
useful for this
invention include not only purified or isolated pectates but also crude
natural pectin sources,
such as apple, citrus or sugar beet residues which have been subjected, when
necessary, to
esterification or de-esterification, e.g., by alkali or enzymes. Preferably,
the pectins used in
this invention are derived from citrus fruits such as lime, lemon, grapefruit,
and orange.
With the inclusion of a gelling agent in the dosage form, when the dosage form
is
tampered with, the gelling agent preferably imparts a gel-like quality to the
tampered dosage
form which preferably spoils or hinders the pleasure of obtaining a rapid high
from the
tampered dosage form due to the gel like consistency in contact with the
mucous membrane,
and in certain embodiments, prevents the abuse of the dosage form by
minimizing absorption,
e.g. in the nasal passages. A gelling agent may be added to the formulation in
a ratio of
gelling agent to opioid agonist of from about 1:40 to about 40:1 by weight,
preferably from
about 1:1 to about 30:1 by weight, and more preferably from about 2:1 to about
10:1 by
weight of the opioid agonist.
9


CA 02456322 2004-02-03
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In certain other embodiments, the dosage form forms a viscous gel after the
dosage
form is tampered with, dissolved in an aqueous liquid (from about 0.5 to auout
10 ml and
preferably from 1 to about 5 ml), causing the resulting mixture to have a
viscosity of at least
about 10 cP. Most preferably, the resulting mixture will have a viscosity of
at least about 60
cP.
In certain other embodiments, the dosage form forms a viscous gel after the
dosage
form is tampered with, dissolved in an aqueous liquid (from about 0.5 to about
10 ml and
preferably from 1 to about 5 ml) and then heated (e.g., greater than about
45°C), causing the
resulting mixture to have a viscosity of at least about 10 cP. Must
preferably, the resulting
mixture will have a viscosity of at least about 60 cP.
In certain embodiments, the dosage form may include one or more of .the
aforementioned aversive agents. For .safety reasons, the amount of the
bittering agent,
irritant, or gelling agent in the formulation of the present invention should
not be toxic to
humans.
Opioid antagonists useful in the present invention include, for example and
without
limitation, naltrexone, naloxone, nalmefene, nalide, nalmexone, nalorphine,
nalorphine
dinicotinate, cyclazocine, levallorphan, pharmaceutically acceptable salts
thereof, and
mixhmes thereof. In certain preferred embodiments, the opioid antagonist is
naloxone or
naltrexone. In certain embodiments, the amount of the opioid
antagonistincluded in the
dosage form, may be about 10 ng to 275 mg.
Naloxone is an opioid antagonist which is almost void of agonist effects.
Subcutaneous doses of up to 12 mg of naloxone produce no discernable
subjective effects,
and 24 mg naloxone causes only slight drowsiness. Small doses (0.4-0.8 mg) of
naloxone
given intramuscularly or intravenously in man prevent or promptly reverse the
effects of
morphine-lilce opioid agonist. One mg of naloxone intravenously has been
reported to
completely block the effect of 25 mg of heroin. The effects of naloxone are
seen almost
immediately after intravenous administration. The drug is absorbed after oral
administration,
but has been reported to be metabolized into an inactive form rapidly in its
frst passage
through the liver such that it has been reported to have significantly lower
potency than as
when parenterally administered. Oral dosages of more than 1g have been
reported to be
ahnost.completely metabolized in less than 24 hours. It has been reported that
25% of
naloxone administered sublingually is absorbed. Weinberg, et al., Sublingual
Absorption of
selected Opioid Analgesics, Clin Pharmacol Ther. (1988); 44:335-340.


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
Other opioid antagonists, for example, cyclazocine and naltrexone, both of
which
have cyclopropyhnethyl substitutions on the nitrogen, retain much of them
efficacy by the
oral route and their durations of action are much longer, approaching 24 hours
after their oral
administration.
hi the treatment of patients previously addicted to opioids, naltrexone has
been used
in large oral doses (over 100 mg) to prevent euphorigenic effects of opioid
agonists.
Naltrexone has been reported to exert strong preferential blocking action
against fuu over
delta sites. Naltrexone is known as a synthetic congener of oxymorphone with
no opioid
agonist properties, and differs in structure from oxymorphone by the
replacement of the
methyl group located on the nitrogen atom of oxymorphone with a
cyclopropylmethyl group.
The hydrochloride salt of naltrexone is soluble in water up to about 100
mglcc. The
pharmacological and pharmacokinetic properties of naltrexone have been
evaluated in
multiple animal and clinical studies. See, e.g., Gonzalez JP, et al.
Naltrexone: A review of its
Pharmacodynamic and Phannacokinetic Properties and Therapeutic Efficacy in the
Management of Opioid Dependence. Dnacgs 1988; 35:192-213, hereby incorporated
by
reference. Following oral administration, naltrexone is rapidly absorbed
(,.within 1 hour) and
has an oral bioavailability ranging from 5-40%. Naltrexone's protein binding
is
approximately 21 % and the volume of distribution following single-dose
administration is
16.1 L/kg.
Naltrexone is commercially available in tablet form (Revia°°,
DuPont) for the '
treatment of alcohol dependence and for the blockade of exogenously
administered opioids.
See, e.g., Revia (naltrexone hydrochloride tablets). PlZ,ysiciaiz's
DeskRefereiace Slst ed.,
Montvale, NJ. "Medical Economics" 1997; 51:957-959. A dosage of SO mg Revia
blocks
the pharmacological effects of 25 mg IV administered heroin for up to 24
hours.
It is known that when coadministered with morphine, heroin or other opioids on
a
chronic basis, naltrexone blocks the development of physical dependence to
opioids. It is
believed that the method by which naltrexone blocks the effects of heroin is
by competitively
binding at the opioid receptors. Naltrexone has been used to treat narcotic
addiction by
complete blockade of the effects of opioids. It has been found that the most
successful use of
naltrexone for a narcotic addiction is with narcotic addicts having good
prognosis, as part of a
comprehensive occupational or rehabilitative program involving
behavioral,control or other
compliance enhancing methods. For treatment of narcotic dependence with
naltrexone, it is
desirable that the patient be opioid-free for at least 7-10 days. The initial
dosage of
naltrexone for such purposes has typically been about 25 mg, and if no
withdrawal signs
11


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
occur, the dosage may be increased to 50 mg per day. A daily dosage of 50 mg
is considered
to produce adequate clinical blockade of the actions of parenterally
administered opioids.
Naltrexone has also been used for the treatment of alcoholisir as an adjunct
with social and
psychotherapeutic methods.
In certain embodiments, the aversive agent and/or the opioid antagonist
included in
the dosage form may be in a substantially non-releasable form. Where the
opioid antagonist
is in a substantially non-releasable form, the substantially non-releasable
form of the opioid
antagonist comprises an opioid antagonist that is formulated with one or more
pharmaceutically acceptable hydrophobic materials, such that the antagonist is
not released or
substantially not released during its transit through the gastrointestinal
tract yvhen
administered orally as intended, without having been tampered with.
Additionally; in certain embodiments, wherein the aversive agent is in a
substantially
non-releasable form, the substantially non-releasable form of the aversive
agent comprises an
aversive agent that is formulated with one or more pharmaceutically acceptable
materials
acceptable hydrophobic materials, such that the aversive agent is not released
or substantially
not released during its transit through the gastrointestinal tract when
administered orally as
intended, without having been tampered with.
In certain embodiments of the present invention, the substantially non-
releasable form
of the opioid antagonist is vulnerable to mechanical, thermal and/or chemical
tampering, e.g.,
tampering by means of crushing, shearing, grinding, chewing and/or dissolution
in a solvent
in combination with heating (e.g., greater than about 45°C) of the oral
dosage form. When
the dosage form is tampered with, the integrity of the substantially non-
releasable form of the
opioid antagonist will be compromised, and the opioid antagonist will be made
available to
be released. In certain embodiments, when the dosage form is chewed, crushed
or dissolved
and heated in a solvent, and administered orally, intranasally, parenterally
or sublingually, the
analgesic or euphoric effect of the opioid is reduced or eliminated. In
certain embodiments,
the effect of the opioid agonist is at least partially blocked by the opioid
antagonist. In
certain other embodiments, the effect of the opioid agonist is substantially
blocked by the
opioid antagonist.
Additionally, the substantially non-releasable form of the aversive agent is
vulnerable
to mechanical, thermal and/or chemical tampering, e.g., tampering by means of
crushing,
shearing, grinding, chewing and/or dissolution in a solvent in combination
with heating (e.g.,
greater than about 45°C) of the oral dosage form. When the dosage form
is tampered with,
the integrity of the substantially non-releasable form of the aversive agent
will be
~12


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
compromised, and the aversive agent will be made available to be released. In
certain
embodiments, when the dosage form is chewed, crushed or dissolved and heated
in a solvent,
the release of the aversive agent hinders, deters or prevents the
administration of the
tampered dosage form orally, intranasally, parenterally and/or Sublingually.
In certain embodiments of the present invention, ratio of the opioid agonist
to the
substantially non-releasable forni of an opioid antagonist in the oral dosage
fornl'is such that
the effect of the opioid agonist is at least partially blocked when the dosage
form is chewed,
cW shed or dissolved in a solvent and heated, and administered orally,
intranasally,
parenterally or sublingually. Since the oral dosage form of certain
embodiments described
herein, when administered properly as intended, would not substantially
release the opioid
antagonist andlor the aversive agent, the amount of such antagonist and/or
aversive agent
may be varied more widely than if the opioid antagonist andlor aversive agent
is available to
be released into the gastrointestinal system upon oral administration. For
safety reasons, the
amount of the antagonist and/or aversive agent present in a substantially non-
releasable form
should not be harmful to humans even if fully released. The ratio ~of
particular opioid agonist
to antagonist can be determined without undue experimentation by one skilled
in the art.
In certain embodiments of the present invention, the ratio of the opioid
agonist and
the opioid antagonist, present in a substantially non-releasable form, is
about 1:1 to about
50:1 by weight, preferably about 1:1 to about 20:1 by weight. In certain
preferred
embodiments, the ratio is about 1:1 to about 10:1 by weight. In a preferred
embodiment of
the invention, the opioid agonist comprises oxycodone or hydrocodone and is
present in the
amount of about 15-45 mg and the opioid antagonist comprises naltrexone and is
present in
an amount of about 0.5 to about lOmg, preferably about 0.5 to about 5 mg.
In an alternative embodiment, the opioid antagonist of the present invention
may be
included in the dosage form, such that it is analgesically effective when
orally administered,
but which upon parenteral administration, does not produce analgesia, euphoria
or physical
dependence. In this particular embodiment, preferably the opioid antagonist is
naloxone
which is in an amount which is not orally effective, but is parenterally
effective, as described
in U.S. Patent No. 3,773,955, the disclosure of which is hereby incorporated
by reference in
its entirety. In this embodiment the naloxone is released from the dosage form
when orally
administered, but does not abolish the oral activity of the opioid analgesic
included in the
dosage form.
Alternatively, the opioid antagonist of the present invention is' released
from the
dosage form upon oral administration and may be included in the dosage form in
an amount
13


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
as described in WO 99/32119, the disclosure of which is hereby incorporated by
reference in
its entirety, (i) which does not cause a reduction in the level of analgesia
elicited from the
dosage form upon oral administration to a non-therapeutic level and (ii) which
provides at
least a mildly negative, "aversive" experience in physically dependent
subjects - (e.g.,
precipitated abstinence syndrome) when the subjects attempt to take at least
twice the usually
prescribed' dose at a time (and often 2-3 times that dose or more), as
compared to a
comparable dose of the opioid without the opioid antagonist present.
Preferably, the amount
of antagonist included in the oral dosage form is less~positively reinforcing
(e.g., less "liked")
to a non-physically dependent opioid addict than a comparable oral dosage form
without the
antagonist included. Preferably, the formulation provides effective analgesia
when orally
administered. In certain preferred embodiments, the oral dosage form comprises
an orally
therapeutically effective dose of an opioid agonist, and an opioid antagonist
in a ratio that
provides a combination product which is analgesically effective when the
combination is
administered orally, but which is aversive in physically dependent human
subjects when
administered at the same dose or at a higher dose than said therapeutically
effective dose.
Based on a preferred ratio of naltrexone in an amount from about 0.5 to about
4 mg
per 15 mg of hydrocodone as described in WO 99/32119, the approximate .ratio
of naltrexone
to lmg of certain opioids inset forth in Table A:
Table A: Weight Ratio of Naltrexone per Dose Opioid
Opioid Weight Ratio Naltrexone
per
1 m O ioid


Oxycodone 0.037 to 0.296


Codeine 0.005 to 0.044


Hydrocodone 0.033 to 0.267


Hydromorphone0.148 to 1.185


Levorphanol 0.278 to 2.222


Meperidine 0.0037 to 0.0296


Methadone 0.056 to 0.444


Morphine 0.018 to 0.148


14


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
Based on the more preferred ratio of about 0.75 mg to about 3 mg naltrexone
per 15
mg hydrocodone of naltrexone as described in WO 99/32119, the approximate
ratio of
naltrexone to lmg of certain opioids is set forth in Table B below:
'Table B: Weight Ratio of Naltrexone uer Dose Ouioid
Opioid Weight Ratio Naltrexone


Oxycodone 0.056 to 0.222


Codeine 0.0083 to 0.033


Hydrocodone 0.050 to 0.200


Hydromorphone0.222 to 0.889


Levorphanol 0.417 to 1.667


Meperidine 0.0056 to 0.022


Methadone 0.083 to 0.333
~


Morphine 0.028 to 0.111


In certain embodiments, the present invention is directed in part to an oral
dosage
form comprising an orally analgesically effective amount of an opioid agonist
and an opioid
antagonist in a ratios as described above along with one or more aversive
agents as described
herein.
In certain alternative embodiments, when the opioid antagonist is naloxorie,
the opioid
agonist and antagonist (e.g., naloxone) included in the present dosage forms
may be .in
preferred ratios as described in U.S. Patent No. 4,457,933 to Gordon et al.,
the disclosure of
which is hereby incorporated by reference in its entirety, such that both the
oral and
parenteral abuse potentials of the opioid agonist is diminished without
appreciably affecting
the oral analgetic activity of the opioid agonist.
In certain alternative embodiments, the opioid antagonist may be included in
the
dosage form in an amount such that the opioid antagonist attenuates side
effects of the opioid
agonist, said side effects being anti-analgesia, hyperalgesia,
hyperexcitability, physical
dependence, tolerance, and combinations of any of the foregoing. For example,
in certain
preferred embodiments, the amount of the opioid antagonist is from about 100
to about 1000
fold less that the amount of the opioid agonist. Certain preferred amounts of
opioid
antagonist to agonist in accordance with this embodiment are described, for
example, in U.S.


CA 02456322 2004-02-03
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Patent Nos. 5,472,943; 5,512,578; 5,580,876; 5,767,125; RE36,547; and
6,096,256 all to
Crain-et al., the disclosures of which are herein incorporated by reference in
their entireties.
All known combinations of releasable opioid antagonists with opioid agonists
such
as those described in U.S. Patent No. 3,773,955 (Pachter, et al.); U.S. Patent
No. 3,493,657
(Lewenstein, et al.) U.S. Patent No. 4,457,933 (Gordon, et al.); U.S. Patent
No. 4,582,835
(Lewis) U.S. Patent Nos. 5,512,578; 5,472,943; 5,580,876; and 5,767,125
~Crain) and U.S.
Patent No. 4,769,372 and 4,785,000 (Kreek) caii be combined with the aversive
agents
disclosed herein and all of these references are hereby incorporated by
reference.
All commercial products of opioid agonist and releasable antagonists can be
combined with an aversive agent disclosed herein. For example, Talwin NX can
be
formulated with an aversive agent, e.g., a battering agent to reduce oral
abuse as well as
parenteral abuse of the opioid therein.
The opioid agonists useful in the present invention include, but are not
limited to,
alfentanil, allylprodine, alphaprodine, anileridine, berizylmorphine,
bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, desomorphine,
dextromoramide, dezocine,
diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,
eptazocine,
ethoheptazine, ethylmethylthiambutene, eth~lmorphine, etonitazene, etorphine,
dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone,
hydromorphone,
hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenaylmorphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine,
myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,
nonnorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,
pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide,
propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine,
tramadol, mixtures
of any of the foregoing, salts of any of the foregoing, and the like: In
certain embodiments,
the amount of the opioid agonist in the claimed opioid composition may be
about 75 ng to
about 750 mg.
In certain preferred embodiments, the opioid agonist is selected from the
group
consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine,
levorphanol,
meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives
thereof,
dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol,
levorphanol, or salts
thereof or mixhnes thereof. In certain preferred embodiments, the opioid
agonist is
oxycodone or hydrocodone.
16


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In embodiments in which the opioid analgesic comprises hydrocodone, dosage
forms
may include analgesic doses from about 2 mg to about 50 mg of hydrocodone
bitarirate. In
embodiments in which the opioid analgesic comprises hydromorphone the dosage
forni may
include from about 2 mg to about 64 mg hydromorphone hydrochloride. In
embodiments in
which the opioid analgesic comprises morphine, the dosage form may include
from about 2.5
mg to about 800 mg morphine sulfate, by weight. In embodiments in which the
opioid
analgesic comprises oxycodone, the dosage form may include from about 2.5 mg
to about
320 mg oxycodone hydrochloride. The dosage fornz may contain more than one
opioid
analgesic to provide a therapeutic effect. Alternatively, the dosage form may
contain molar
equivalent amounts of other salts of the opioids useful in the present
invention.
Although hydrocodone and oxycodone are effective in the management of pain,
there
has been an increase in their abuse by individuals who are psychologically
dependent on
opioids or who misuse opioids for non-therapeutic reasons. Previous experience
with other
opioids has demonstrated a decreased abuse potential when opioids are
administered in
combination with a narcotic antagonist especially in patients who are ex-
addicts. Weinhold
LL, et al. Buprenorphine Alone and in Combination with Naltrexone in Non-
Dependent
Humans, Dnsg and Alcolaol Depende~ace 1992; 30:263-274; Mendelson J., et al.,
Buprenorphine and Naloxone Interactions in Opiate-Dependent Volunteers, CZarI.
Plaarnz
TIZes-. 1996; 60:105-114; both of which are hereby incorporated by reference.
These
combinations, however, do not contain the opioid antagonist that is in a
substantially non-
releasable form. Rather, the opioid antagonist is released in the
gastrointestinal system when
orally administered and is made available for absorption, relying on the
physiology of the
host to differentially metabolize the agonist and antagonist and negate the
agonist effects.
Hydrocodone is a semisynthetic narcotic analgesic and antitussive with
multiple
central nervous system and gastrointestinal actions. Chemically, hydrocodone
is 4,5-epoxy-
3-methoxy-.17-methyhnorphinan-6-one, and is also known as dihydrocodeinone.
Like other
opioids, hydrocodone may be habit forming and may produce drug dependence of
the
morphine type. In excess doses hydrocodone, like other opium derivatives, will
depress
respiration.
Oral hydrocodone is also available in Europe (Belgium, Germany, Greece, Italy,
Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral
formulation is
also available in Germany as an antitussive agent. For use as an analgesic,
hydrocodone
bitartrate is commercially available in the United States only as a fixed
combination with
17


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non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) for relief of
moderate or
moderately severe'pain.
A common dosage form of hydrocodone is in combination with acetaminophen, and
is commercially available, e.g., as Lortab~ in the U.S. from UGB Pharma, Inc.
as 2.5/500 mg,
5/500 mg, 7.5/500 mg and 10/500 mg hydrocodone/acetaminophen tablets. Tablets
are also
available in the ratio of 7.Smg hydrocodone~bitarlrate and 650mg
acetaminophen; and 7.Smg
hydrocodone bitartrate and 750mg acetaminophen. Hydrocodone in combination
with aspirin
is given in an oral dosage form to adults generally in 1-2 tablets every 4-6
hours as needed to
alleviate pain. The tablet form is Smg hydrocodone bitartrate and 224mg
aspirin with 32mg
caffeine; or Smg hydrocodone bitartrate and SOOmg aspirin. A relatively new
formulation
comprises hydrocodone bitartrate and ibuprofen. Vicoprofeno, commercially
available in the
U.S. from Knoll Laboratories, is a tablet containing 7.5 mg hydrocodone
bitarLrate and 200
mg ibuprofen. The present invention is contemplated to encompass all such
formulations,
with the inclusion of the opioid antagonist particles coated with a coating
that renders the
antagonist substantially non-releasable.
Oxycodone, chemically known as 4,5-expoxy-14-hydroxy-3-methoxy-17-
methylmorphinan-6-one, is an opioid agonist whose principal therapeutic action
is analgesia.
Other therapeutic effects of oxycodone include anxiolysis, euphoria and
feelings of
relaxation. The precise mechanism of its analgesic action is not known, but
specific CNS
opioid receptors for endogenous compounds with opioid-like activity have been
identified
throughout the brain and spinal cord and play a role in the analgesic effects
of this drug.
Oxycodone is commercially available in the United States, e.g., as Oxycontin~
from
Purdue Pharma L.P. as controlled-release tablets for oral administration
containing 10 mg, 20
mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxyIRTM, also fror~> Purdue
Pharma
L.P., as immediate-release capsules containing 5 mg oxycodone hydrochloride.
The present
invention is contemplated to encompass all such formulations, with the
inclusion of an opioid
antagonist and one or more aversive agents.
PREPARATION OF AVERSIVE AGENT
IN A SUBSTANTIALLY NON-RELEASABLE FORM:
In certain embodiments of the present invention, an a~rersive agent in a
substantially
non-releasable form may be prepared by combining the aversive agent with one
or more of a
pharmaceutically acceptable hydrophobic material. For example, aversive agent
particles
18


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may be coated with coating that substantially prevents the release of the'
aversive agent, the
coating comprising the hydrophobic materials(s). Another example would be an
aversive
agent that is dispersed in a matrix that renders the aversive agent
substantially non-releasable,
the matrix comprising the hydrophobic materials(s). In certain embodiments,
the
pharmaceutically acceptable hydrophobic material comprises a cellulose polymer
selected
from the group consisting of ethylcellulose, cellulose acetate, cellulose
propionate (lower,
medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate,
cellulose acetate phthalate and cellulose triacetate. An example of
ethylcellulose is one that
has an ethoxy content of 44 to 55%. Ethylcellulose may be used in the form of
an alcoholic
solution. In certain other embodiments, the hydrophobic material comprises
polylactic acid,
polyglycolic acid or a co-polymer of the polylactic and polyglycolic acid.
In certain embodiments, the hydrophobic material may comprise a cellulose
polymer
selected from the group consisting of cellulose ether, cellulose ester,
cellulose ester ether, and
cellulose. The cellulosic polymers have a degree of substitution, D.S., on the
anhydroglucose
unit, from greater than zero and up to 3 inclusive. By degree of substitution
is meant the
average number of hydroxyl groups present on the anhydroglucose unit
comprising the
cellulose polymer that are replaced by a substituting group. Representative
materials include
a polymer selected from the group consisting of cellulose acylate, cellulose
diacylate,
cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose
triacetate, mono, di, and
tricellulose alkanylates, mono, di, and tricellulose aroylates, and mono, di,
and tricellulose
alkenylates. Exemplary polymers include cellulose acetate having a D.S. and an
acetyl
content up to 21%; cellulose acetate having an acetyl content up to 32 to
39.8%; cellulose
acetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%; cellulose
acetate having a
D.S. of 2 to 3 and an acetyl content of 35 to 44.8%.
More specific cellulosic polymers include cellulose propionate having a D.S.
of 1.8
and a propyl content of 39.2 to 45 and a hydroxyl content of 2.8 to 5.4%;
cellulose acetate
butyrate having a D.S. of 1.8, an acetyl content of 13 to 15% and a butyryl
content of 34 to
39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a
butyryl content of 17
to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylate having a.
D.S. of 2.9 to 3
such as cellulose triacetate, cellulose trivalerate, cellulose trilaurate,
cellulose tripalmitate,
cellulose trisucciriate, and cellulose trioctanoate; cellulose diacylates
having a D.S. of 2.2 to
2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose
dioctanoate, cellulose
dipentanoate, and coesters of cellulose such as cellulose acetate butyrate,
cellulose acetate
octanoate butyrate and cellulose acetate propionate.
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Additional cellulose polymers useful for preparing an aversive agent in a
substantially
non-releasable form include acetaldehyde dimethyl cellulose acetate, cellulose
acetate
ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate
dimethylaminocellulose acetate.
Acrylic polymers useful for preparation of the aversive agent in a
substantially non-
releasable form include, but are not limited to, acrylic resins comprising
copolymers
synthesized from acrylic and methacrylic acid esters (e.g., the copolymer of
acrylic acid
lower alkyl ester and methacrylic acid lower alkyl ester) containing about
'0.02 to 0.03 mole
of a tri (lower alkyl) ammonium group per mole of the acrylic and methacrylic
monomers
used. An example of a suitable acrylic iesin is a polymer manufactured by Rohm
Pharma
GmbH and sold under the Eudragit° RS trademark. Eudragit RS30D is
preferred. Eudragit
RS is a water insoluble copolymer of ethyl acrylate (EA), methyl.methacrylate
(MM) and
trimethylammoniumethyl methacrylate chloride (TAM) in which the molar ratio of
TAM to
the remaining components (EA and MM) is 1:40. Acrylic resins such as Eudragit
RS may
be used in the form of an aqueous suspension.
In certain embodiments of the invention, the acrylic polymer may be selected
from the
group consisting of acrylic acid and methacrylic acid copolymers, methyl
methacrylate
copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic
acid),
poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl
methacrylate),
polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide,
aminoalkyl
methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate co-
polymers.
When the aversive agent in a substantially non-releasable form comprises
aversive
agent particles coated with a coating that renders the aversive agent
substantially non-
releasable, and when a cellulose polymer or an acrylic polymer is used for
preparation of the
coating composition, suitable plasticizers, e.g., acetyl triethyl citrate
and/or acetyl tributyl
citrate may also be admixed with the polymer. The coating may also contain
additives such
as coloring agents, talc and/or magnesium stearate, which are well known in
the coating art.
The coating composition may be applied onto the aversive agent particles by
spraying
it onto the particles using any suitable spray equipment known in the art. For
example, a
bluster fluidized-bed system may be used in which.an air jet, injected from
underneath,
fluidizes the coated material and effects drying while the insoluble polymer
coating is
sprayed on. The thickness of the coating will depend on the characteristics of
the particular
coating composition being used. However, it is well within the ability of :one
skilled in the


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
art to deterniine by routine experimentation the optimum thickness of a
particular coating
required for a particular dosage form of the present invention.
The pharniaceutically acceptable hydrophobic material useful for preparing an
aversive agent in a substantially non-releasable form includes a biodegradable
polymer
comprising a poly(lactic/glycolic acid) ("PLGA"), a polylactide, a
polyglycolide, a
polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes,
polysaccharides,
proteinaceous polymers, polyesthers, polydioxanone, polygluconate, polylactic-
acid-
polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesther or
mixtures or
blends of any of these.
In certain embodiments, biodegradable polymer comprises a poly(lactic/glycolic
acid), a copolymer of lactic and glycolic acid, having molecular weight of
about 2,000 to
about 500,000 daltons. The ratio of lactic acid to glycolic acid is from about
100:0 to about
25:75, with the ratio of lactic acid to glycolic acid of 65:35 being
preferred.
Poly(lactic/glycolic acid) may be prepared by the procedure set forth in U.S.
Patent
No. 4,293,539 (Ludwig et al.), the disclosure of which is hereby incorporated
by reference in
its entirety. In brief, Ludwig prepares the copolymer by condensation of
lactic acid and
glycolic acid in the presence of a readily removable polymerization catalyst
(e.g., a strong
acid ion-exchange resin such as Dowex HCR-W2-H). The amount of catalyst is not
critical
to the polymerization, but typically is from about 0.01 to about 20 parts by
weight relative to
the total weight of combined lactic acid and glycolic acid. The polymerization
reaction may
be conducted without solvents at a temperature from about 100°C to
about 250°C for about
48 to about 96 hours, preferably under a reduced pressure to facilitate
removal of water and
by-products. Poly(lactic/glycolic acid) is then recovered by filtering the
molten reaction
mixture in an organic solvent such as dichloromethane or acetone and then
filtering to
remove the catalyst.
Once the aversive agent in a substantially non-releasable form is prepared, it
may be
combined with an opioid agonist and the opioid antagonist (which may also be
in a
substantially non-releasable form as described herein), along with
conventional excipients
known in the art, to prepare the oral dosage form of the present invention. It
is contemplated
that a tittering agent or capsaicin would be the most likely aversive agents
to be included in a
sequestered formulation. The polymers and other ingredients above may also be
utilized to
formulate the aversive agents to slow release or delay release as disclosee~
zbove.
In certain preferred embodiments of the invention, the oral dosage form is a
capsule
or a tablet. When being formulated as a tablet, the aversive agent and opioid
agonist and
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opioid antagonist may be combined with one or more inert, non-toxic
pharmaceutical
excipients which are suitable for the manufacture of tablets. Such excipierts
include, for
example, an inert diluent such as lactose; granulating and disintegrating
agents such as
cornstarch; binding agents such as starch; and lubricating agents such as
magnesium stearate.
The oral dosage form of the present invention may be formulated to provide
immediate release of the opioid agonist contained therein. In other
embodiments of the
invention, however, the oral dosage form provides sustained-release of the
opioid agonist.
In certain embodiments, the oral dosage forms providing sustained release of
the
opioid agonist may be prepared by admixing the aversive agent in a
substantially non-
releasable form with the opioid agonist and the opioid antagonist and
desirable
pharmaceutical excipients to provide a tablet, and then coating the tablet
with a sustained-
release tablet coating.
In certain embodiments of the invention, sustained release opioid agonist
tablets may
be prepared by admixing the substantially non-releasable form of an aversive
agent with an
aversive agent in a matrix that provides the tablets with sustained-releasing
properties.
DOSAGE FORMS
The opioid analgesic/opioid antagonist formulation in combination with one or
more
aversive agents can be formulated as an immediate release formulation or
controlled release
oral formulation in any suitable tablet, coated tablet or multiparticulate
formulation known to
those skilled in the art. The controlled release dosage form may include a
controlled release
material which is incorporated into a matrix along with the opioid analgesic
and the opioid
antagonist. In addition, the aversive agent may be separate from the ma'.-ix,
or incorporated
into the matrix.
The controlled release dosage form may optionally comprise particles
containing or
comprising the opioid analgesic, wherein the particles have diameter from
about 0.1 mm to
about 2.5 mm, preferably from about 0.5 mm to about 2 mm. The opioid
antagonist may be
incorporated into these particles, or may be incorporated into a tablet or
capsule containing
these particles. Additionally, the aversive agent may be incorporated into
these particles, or
may be incorporated into a tablet or capsule containing these particles.
Preferably, the
particles are film coated with a material that permits release of the opioid
analgesic at a
controlled rate in an environment of use. The film coat is chosen so as to
achieve, in
combination with the other stated properties, a desired in-vitro release rate.
The controlled
release coating formulations of the present invention should be capable of
producing a strong,
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continuous film that is smooth and elegant, capable of supporting pigmen+s and
other coating
additives, non-toxic, inert, and tack-free.
In certain embodiments, the dosage forms of the present invention comprise
normal
release matrixes containing the opioid analgesic, opioid antagonist, and the
aversive agent.
COATED BEADS
In certain embodiments of the present invention a hydrophobic material is used
to
coat inert pharmaceutical beads such as nu panel 18/20 beads comprising an
opioid analgesic,
and a plurality of the resultant solid controlled release beads may thereafter
be placed in a
gelatin. capsule in an amount sttfftcient to provide an effective controlled
release dose when
ingested and contacted by an enviromnental fluid, e.g., gastric fluid or
dissolution media.
' Tlte beads comprising the opioid analgesic may further comprise the opioid
antagonist andfox
one or more aversive agents, or the opioid antagonist and or one or more
aversive agents may
be prepared as separate beads end then combined. in a dosage form including
the controlled
.release beads comprising a:n opioid analgesic, or the opioid antagonist .:
.nd/or one or more
aversive agents ' may be mixed in the dosage form with . the controlled
release beads
comprising the opioid analgesic. In preferred embodiments where the opioid
analgesic and
the aversive agent are mixed in a capsule as different beads, the beads have
an exact or
similar appearance in order to deter an abuser from manually separating the
beads prior to
abuse in order to avoid the aversive substance. In tablet dosage forms, 'the
aversive agent, is
preferably aaot included as a distinct layer which can be easier to separate
from the active
agent, although the preseni invention does, encompass these embodiments.
The controlled release bead formulations of the present invention slowly
release the
opioid analgesic, e.g., when ingested and exposed to gastric fluids., and then
to intestinal
fluids. The controlled release proftle of tile formulations of the invention
can be altered, for
example, Uy varying the amount of. overcoating with the hydrophobic ~~aterial,
altering the
mariner in wl:icha plasticizer is added to the hydrophobic material, by
varying the amount of
plasticizer relative to hydrophobic material. by the inclusion of additional'
ingredients or
excipients, by altering the method of manufachme, etc. The dissolution p=Mile
of tlze,ultimate
product may also be modified, for example, by irucreasing or decreasing the
thickness of the.
retardant coating. ' . ' ' '
'Spheroids or beads coated with an opioid analgesic are prepared, e.g., by
dissolving
the opioid analgesic in water and then spraying the solution onto a substrate,
for example, nu
pariel .18/20 beads, using a bluster insert. Thereafter, the opioid antagonist
and/or aversive
23. '


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agent is optionally added to the beads prior to coating. Optionally,
additional ingredients are
also added prior to coating the beads. For example, a product which includes
hydroxypropyhnethylcellulose, etc. (e.g., Opadry°, commercially
available from Colorcon,
Inc.) may be added to the solution and the solution mixed (e.g., for about 1
hour) prior to
application of the same onto the beads. The resultant coated substrate, in
this example beads,
may then be optionally overcoated with a barrier agent, to separate the opioid
analgesic from
the hydrophobic controlled release coating. An example of a suitable barrier
agent is one
which comprises hydroxypropylmethylcellulose. However, any film-former known
in the art
may be used. It is preferred that the barrier agent does not affect the
dissolution rate of the
final product.
The beads may then be overcoated with an aqueous dispersion of the hydrophobic
material. The aqueous dispersion of hydrophobic material preferably further
includes an
effective amount of plasticizer, e.g. triethyl citrate. Pre-formulated aqueous
dispersions of
ethylcellulose, such as Aquacoat~ or Surelease~, may be used. If Surelease~ is
used, it is not
necessary to separately add a plasticizer. Alternatively, pre-formulated
aqueous dispersions of
acrylic polymers such as Eudragit° can be used.
Plasticized hydrophobic material may be applied onto the substrate comprising
the
opioid analgesic by spraying using any suitable spray equipment known in the
art. In a
preferred method, a Wurster fluidized-bed system is used in which an air jet,
injected from
underneath, fluidizes the core material and effects drying while the acrylic
polymer coating is
sprayed on. A sufficient amount of the hydrophobic material to obtain a
predetermined
controlled release of said opioid analgesic when the coated substrate is
exposed to aqueous
solutions, e.g. gastric fluid, is preferably applied, taking into account the
physical
characteristics of the opioid analgesic, the manner of incorporation of the
plasticizer, etc.
After coating with the hydrophobic material, a further overcoat of a film-
former, such as
Opadry~, is optionally applied to the beads. This overcoat is provided, if at
all, in order to
substantially reduce agglomeration of the beads.
The release of the opioid analgesic from the controlled release formulation of
the
present invention can be further influenced, i.e., adjusted to a desired rate;
by the addition of
one or more release-modifying agents, or by providing one or more passageways
through the
coating. The ratio of hydrophobic material to water soluble material is
determined by, among
'other factors, the release rate required and the solubility characteristics
of the materials
selected.
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The release-modifying agents which function as pore-formers may be organic or
inorganic, and include materials that can be dissolved, extracted or leached
from the coating
in the environment of use. The pore-fomners may comprise one or more
hydrophilic materials
such as hydroxypropylmethylcellulose.
The controlled release coatings of the present invention can also include
erosion-
promoting agents such as starch and gums.
The controlled release coatings of the present invention can also include
materials
useful for making microporous lamina in the environment of use, such as
polycarbonates
comprised of linear polyesters of carbonic acid in which carbonate groups
reoccur in the
polymer chain.
The release-modifying agent may also comprise a semi-permeable polymer.
In certain preferred embodiments, the release-modifying age?:', is selected
from
hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of
the foregoing.
The controlled release coatings of the present invention may also include an
exit
means comprising at least one passageway, orifice, or the like. The passageway
may be
formed by such methods as those disclosed in U.S. Patent Nos. 3,845,770;
3,916,889;
4,063,064; and 4,088,864 . The passageway can have any shape such as round,
triangular,
square, elliptical, irregular, etc.
MATRIX FORMULATIONS
In certain embodiments of the present invention, the sustained release
formulation is
achieved via a matrix optionally having a controlled release coating as set
forth herein. The
present invention may also utilize a sustained release matrix that affords in-
vitro dissolution
rates of the opioid analgesic and or antagonist within desired ranges and
releases the opioid
analgesic and/or antagonist in a pH-dependent or pH-independent manner.
A non-limiting list of suitable sustained-release materials which may be
included in a
sustained-release matrix according to the invention includes hydrophilic
and/or hydrophobic
materials, such as gums, cellulose ethers, acrylic resins, protein derived
materials, waxes,
shellac, and oils such as hydrogenated castor oil and hydrogenated vegetable
oil. However,
any pharmaceutically acceptable hydrophobic, or hydrophilic sustained-release
material which
is capable of imparting sustained-release of the opioid analgesic may be used
in accordance
with the present invention. Preferred sustained-release polymers include
alkylcelluloses such
as ethylcellulose, acrylic and methacrylic acid polymers and copolymers; and
cellulose


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
ethers, especially hydroxyalkylcelluloses (especially
hydroxypropylmethylcellulose) and
carboxyallcylcelluloses. Preferred acrylic and methacrylic acid. polymers and
copolymers
include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl
methacrylates,
ethyl acrylate, trimethyl ammonioethyl methacrylate, cyanoethyl methacrylate,
aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid
alkylamine copolymer, poly(methylmethacrylate), poly(methacrylicacid)
(anhydride),
polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and
glycidyl
methacrylate copolymers. Certain preferred embodiments utilize mixtures of any
of the
foregoing sustained-release materials in the matrix of the invention.
The matrix also may include a binder. In such embodiments, the binder
preferably
contributes to the sustained-release of the oxycodone or pharmaceutically
acceptable salt
thereof from the sustained-release matrix.
If an additional hydrophobic binder material is included, it is preferably
selected from
natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the
same. Examples
include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is
not meant to be
exclusive. In certain preferred embodiments, a combination of two or more
hydrophobic
binder materials are included in the matrix formulations.
Preferred hydrophobic binder materials which may be used in accordance with
the
present invention include digestible, long chain (C$-CSO, especially C12-C4o),
substituted or
unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl
esters of fatty acids,
mineral and vegetable oils, natural and s3mthetic waxes and polyalkylene
glycols.
Hydrocarbons having a melting point of between 25° and 90°C are
preferred. Of the long-
chain hydrocarbon binder materials, fatty (aliphatic) alcohols are preferred
in certain
embodiments. The oral dosage form may contain up to 80% (by weight) of at
least one
digestible, long chain hydrocarbon.
In certain embodiments, the hydrophobic binder material may comprise natural
or
synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or
preferably
cetostearyl alcohol), fatty acids, including but not limited to fatty acid
esters, fatty acid
glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons,
normal waxes,
stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having
hydrocarbon
backbones. Suitable waxes include, for example, beeswax,. glycowa°,
castor wax and
carnauba wax. For purposes of the present invention, a wax-like substance is
defined as any
material which is normally solid at room temperature and has a melting point
of from about
26


CA 02456322 2004-02-03
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30 to about 100°C. In certain preferred embodiments, the dosage form
comprises a sustained
release matrix comprising an opioid analgesic; opioid antagonist; onw or more
aversive
agents; and at least one water soluble hydroxyalkyl cellulose, at least one
C12-C36, preferably
Ci4-Cz2, aliphatic alcohol and, optionally, at least one polyalkylene glycol.
The hydroxyalkyl
cellulose is preferably a hydroxy (C~ to CG) alkyl cellulose, such as
hydroxypropylcellulose,
hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The
amount of the at,
least one hydroxyalkyl cellulose in the present oral dosage form may be
determined, inter
alia, by the precise rate of opioid analgesic release required. The aliphatic
alcohol may be, for
example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly
preferred
embodiments of the present oral dosage form, however, the at least one
aliphatic alcohol is
cetyl alcohol or cetostearyl alcohol. The amount of the aliphatic alcohol in
the present oral
dosage form may be determined, as above, by the precise rate of opioid
analgesic release
required. It may also depend on whether at least one polyalkylene glycol is
present in or
absent from the oral dosage form. Ln the absence of at least one polyalkylene
glycol, the oral
dosage form preferably contains between about 20% and about 50% (by wt) of the
aliphatic
alcohol. When a polyalkylene glycol is present in the oral dosage form, then
the combined
weight of the aliphatic alcohol and the polyalkylene glycol preferably
constitutes between
about 20% and about 50% (by wt) of the total dosage form.
In one preferred embodiment, the ratio of, e.g., .the at least one
hydroxyalkyl cellulose
or acrylic resin to the at least one aliphatic alcohol/polyalkylene glycol
determines, to a
considerable extent, the release rate of the opioid analgesic from the
formulation. In certain
embodiments, a ratio of the hydroxyalkyl cellulose to the aliphatic
alcohol/polyalkylene
glycol of between 1:1 and 1:4 is ,preferred, with a ratio of between 1:2 and
1:3 being
particularly preferred.
In certain embodiments, the polyalkylene glycol may be, for example,
polypropylene
glycol, or polyethylene glycol which is preferred. The average 'molecular
weight of the at
least one polyalkylene glycol is preferably between 1,000 and 15,000,
especially between
1,500 and 12,000.
Another suitable sustained-release matrix comprises an alkylcellulose
(especially
ethylcellulose), a Cla to C3~ aliphatic alcohol and, optionally, a
polyalkylene glycol.
In addition to the above ingredients, a sustained-release matrix may also
contain
suitable quantities of other materials, e.g., diluents, lubricants, binders,
granulating aids and
glidants that are conventional in the pharmaceutical art.
27


CA 02456322 2004-02-03
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In order to facilitate the preparation of a solid, sustained-relea~P oral
dosage form
according to this invention there is provided, in a further aspect of the
present invention, a
process for the preparation of a solid, sustained-release oral dosage form
according to the
present invention comprising incorporating an opioid analgesic in a sustained-
release matrix.
Incorporation in the matrix may be effected, for example, by:
(a) forniing granules comprising at least one hydrophobic and/or hydrophilic
material
as set forth above (e.g., a water soluble hydroxyalkyl cellulose) together
with the opioid
analgesic, opioid antagonist, and at least one aversive agent;
(b) mixing the at least one hydrophobic and/or hydrophilic material-containing
granules with at least one C~2-C3~ aliphatic alcohol, and
(c) optionally, compressing and shaping the granules.
The granules may be formed by any of the procedures well-known to those
skilled in
the art of pharmaceutical formulation. For example, in one preferred method,
the granules
may be formed by wet granulating the hydroxyalkyl cellulose, opioid analgesic,
opioid
antagonist, and one or more aversive agents with water. In a pa ticularly
preferred
embodiment of this process, the amount of water added during the wet
granulation step is
preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the
dry weight of
the opioid analgesic. Optionally, the opioid analgesic, opioid antagonist,
and/or the one or
more aversive agents are added extragranularly.
A sustained-release matrix can also be prepared by, e.g., melt-granulation or
melt-
extrusion techniques. Generally, melt-granulation techniques involve melting a
normally
solid hydrophobic binder material, e.g., a wax, and incorporating a powdered
drug therein. To
obtain a sustained release dosage form, it may be necessary to incorporate a
hydrophobic
sustained-release material, e.g. ethylcellulose or a water-insoluble acrylic
polymer, into the
molten wax hydrophobic binder material. Examples of sustained-release
formulations
prepared via melt-granulation techniques are found, e.g., in U.S. Patent No.
4,861,598.
The additional hydrophobic binder material may comprise one or more water-
insoluble wax-like thermoplastic substances possibly mixed with one or more
wax-like.
thermoplastic substances being less hydrophobic than said one or more v, titer-
insoluble wax-
like substances. In order to achieve sustained release, the individual wax-
like substances in
the fornlulation should be substantially non-degradable and insoluble in
gastrointestinal fluids
during the initial release phases. Useful water-insoluble wax-like binder
substances may be
those with a water-solubility that is lower than about 1:5,000 (w/w).
28


CA 02456322 2004-02-03
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The preparation of a suitable melt-extruded matrix according to the present
invention
may, for example, include the steps of blending the opioid analgesic, opioid
antagonist, and at
least one aversive agent, together with a sustained release material and
preferably a binder
material to obtain a homogeneous mixture. The homogeneous mixture is then
heated to a
temperature sufficient to at least soften the mixture sufficiently to extl-ude
the same. The
resulting homogeneous mixture is then extruded, e.g., using a twin-screw
extruder, to form
strands. The extrudate is preferably cooled and cut into multiparticu.'~tes by
any means
known in the art. The matrix multiparticulates are then divided into unit
doses. The extrudate
preferably has a diameter of from about 0.1 to about 5 mm and provides
sustained release of
the oxycodone or pharmaceutically acceptable salt thereof for a time period of
at least about
24 hours.
An optional process for preparing the melt extruded formulations of the
present
invention includes directly metering into an extruder a hydrophobic sustained -
release
material, the opioid analgesic, opioid antagonist, one or more aversive
agents, and an optional
binder material; heating the homogenous mixture; extruding the homogenous
mixture to
thereby form strands; cooling the strands containing the homogeneous mixture;
cutting the
strands into matrix multiparticulates having a size from about 0.1 mm to about
12 mm; and
dividing said particles into unit doses. In this aspect of the invention, a
relatively continuous
manufacturing procedure is realized.
Optionally, the opioid antagonist and/or the one or more aversive agents may
be
prepared as separate multiparticulates (without the opioid agonistj and
thereafter the
multiparticulates may be combined with multiparticulates comprising opioid
analgesic
(without the antagonist and/or the one or more aversive agents) in a dosage
form.
Plasticizers, such as those described above, may be included in melt-extruded
matrices. The plasticizer is preferably included as from about 0.1 to about
30% by weight of
the matrix. Other pharniaceutical excipients, e.g., talc, mono or poly
saccharides, lubricants
and the like may be included in the sustained release matrices of the present
invention as
desired. The amounts included will depend upon the desired characteristic to
be achieved.
The diametei of the extntder aperture or exit port can be adjusted to vary the
thickness
of the extruded strands. Furthermore, the exit part of the extruder need not
be round; it can be
oblong; rectangular, etc. The exiting strands can be reduced to particles
using a hot wire
cutter, guillotine, etc.
A melt extruded matrix multiparticulate system can be, for example, in the
fore of
granules, spheroids or pellets. depending upon the .extruder exit orifice. For
purposes of the
29


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present invention, the terms "melt-extruded matrix multiparticulate(s)" and
"melt-extruded
matrix multiparticulate system(s)" and "melt-extruded matrix, particles" shall
refer to a
plurality of units, preferably within a range of similar size and/or shape and
containing one or
more active agents and one or more excipients, preferably including a
hydrophobic sustained
release material as described herein. Preferably the melt-extruded matr.;x
multiparticulates
will be of a range of from about 0.1 to about 12 mm in length and have a
diameter of from
about 0.1 to about 5 nnm. In addition, it is to be understood that the melt-
extnided matrix
multiparticulates can be any geometrical shape within this size range. In
certain
embodiments, the extrudate may simply be cut into desired lengths and divided
into unit
doses of the therapeutically active agent without the need of a spheronization
step.
In one preferred embodiment, oral dosage forms are prepared that include an
effective
amount of melt-extruded matrix multiparticulates within a capsule. For
example, a plurality
of the melt-extruded matrix multiparticulates may be .placed in a gelatin
capsule in an amount
sufficient to provide an effective sustained release dose when ingested and
contacted by
gastrointestinal fluid.
In another embodiment, a suitable amount of the ' multiparticulate extrudate
is
compressed into an oral tablet using conventional tableting equipment using
standard
techniques. Techniques and compositions for making tablets (compressed and
molded),
capsules (hard and soft gelatin) and pills are also.described in Remin~tc'n's
Pharmaceutical .
Sciences, (Arthur Osol, editor), 1553-1593 (1980).
In yet another preferred embodiment, the extnidate can be shaped into tablets
as set
forth in U.S. Patent hlo. 4,957,681 (Klimesch, et. al.).
Optionally, the sustained-release matrix multiparticulate systems, tablets, or
capsules
can be coated with a sustained release coating such as the sustained release
coatings
described herein. Such coatings preferably include a sufficient amount of
hydrophobic and/or
hydrophilic sustained-release material to obtain a weight gain level from
about 2 to about 25
percent, although the overcoat may be greater depending upon, e.g., the
desired release rate.
The coating can optionally contain one or more of the aversive agents. In such
embodiments,
an optional second overcoat can be applied as to minimize the perception of
the aversive
agent when a dosage form of the present inventions administered intact.
The dosage forms of the present invention may further include combinations of
melt-
extruded matrix multiparticulates containing an opioid analgesic; an opioid
antagonist; one or
more aversive agents; or mixtures thereof. Furthermore, the dosage forms can
also include an
amount of an immediate release opioid analgesic for prompt therapeutic effect.
The


CA 02456322 2004-02-03
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immediate release opioid analgesic may be incorporated, e.g., as separate
multiparticulates
within a gelatin capsule, or may be coated on the surface of, e.g., melt
extnided matrix
multiparticulates.
The sustained-release profile of the melt-extruded formulations .~i the
invention can
be altered, for example, by varying the amount of sustained-release material,
by varying the
amount of plasticizes relative to other matrix constituents, by varying the
amount of
hydrophobic material, by the inclusion of additional ingredients or
excipients, by altering the
method of manufacture, etc.
In other embodiments of the invention, melt-extruded formulations are prepared
without the inclusion of the opioid analgesic; opioid antagonist; one or more
aversive agents;
or mixtures thereof; which is added thereafter to the extrudate. Such
formulations typically
will have the opioid analgesic; opioid antagonist; one or more aversive
agents; or mixtures
thereof blended together with the extruded matrix material, and then the
mixture would be
tableted in order to provide a slow release formulation. Such formulations may
be
advantageous, for example, when the opioid analgesic; opioid antagonist; one
or more
aversive agents; or mixtures thereof included in the formulation is sensitive
to temperatures
needed for softening the hydrophobic material andlor the retardant material.
Typical melt-extrusion production systems suitable for use in accordance with
the
present invention include a suitable extruder drive motor having variable
speed and constant
torque control, start-stop controls, and a meter. In addition, the production
system will
include a temperature control console which includes temperature sensors,
cooling means~and
temperature indicators throughout the length of the extruder. In addition, the
production
system will include an extruder such as a twin-screw extruder which consists
of two counter-
rotating intermeshing screws enclosed within a cylinder or barrel having an
apertvae or die at
the exit thereof. The feed materials enter through a feed hopper and are moved
through the
barrel by the screws and are forced through the die into strands which are
thereafter conveyed
such as by a continuous movable belt to allow for cooling and being directed
to a pelletizer or
other suitable device to render the extruded ropes into the matrix
multiparticulate system. The
pelletizer can consist of rollers, fixed knife, rotating cutter and the like.
Suitable instruments
and systems are available from distributors such as C.W. Brabender
Instruments, Inc. of
South Hackensack, New Jersey. Other suitable apparaW s will be apparent to
those of ordinary
skill in the art.
A further aspect of the invention is related to the preparation of melt-
extruded matrix
multiparticulates as set forth above in a manner which controls the amount of
air included in
31


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the extruded product. By controlling the amount of air included in the
extrudate, the release
rate of the opioid analgesic, opioid antagonist" one or more aversive agents"
or mixtures
thereof may be altered.
Thus, in a further aspect of the invention, the melt-extruded product is
prepared in a
manner which substantially excludes air during the extrusion phase of the
process. This may
be accomplished, for example, by using a Leistritz extruder having a vacuum
attachment. The
extruded matrix multiparticulates prepared according to the invention using
the Leistritz
extnider under vacuum provides a melt-extruded product having different
physical
characteristics. In particular, the extrudate is substantially non-porous when
magnified, e.g.,
using a scanning electron microscope which provides an SEM .,scanning electron
micrograph). Such substantially non-porous formulations may provide a faster
release of the
therapeutically active agent, relative to the same formulation prepared
without vacuum.
SEMs of the matrix multiparticulates prepared using an extruder under vacuum
appear very
smooth, and the multiparticulates tend to be more robust than those
multiparticulates
prepared without vacuum. It has been observed that in at least certain
formulations, the use of
extrusion under vacuum provides an extruded matrix multiparticulate product
which is more
pH-dependent than its counterpart fornmlation prepared without vacuum.
Alternatively, the melt-extruded product is prepared using a Werner-Pfleiderer
twin
screw extruder.
In certain embodiments, a spheronizing agent is added to a granulate or matrix
multiparticulate and then spheronized to produce sustained release spheroids.
The spheroids
are then optionally overcoated with a sustained release coating by methods
such as those
described above.
Spheronizing agents which may be used to prepare the matrix multiparticulate
formulations of the present invention include any art-known spheronizing
agent. Cellulose
derivatives are preferred, and microcrystalline cellulose is especially
preferred. A suitable
microcrystalline cellulose is, for example, the material sold as Avicel PH 101
(TradeMark,
FMC Corporation). The spheronizing agent is preferably included as about 1 to
about 99% of
the matrix multiparticulate by weight.
In certain embodiments, in addition to the opioid analgesic, opioid
antagonist, one or
more aversive agents, and spheronizing agent, the spheroids may also contain a
binder.
Suitable binders, such as low viscosity, water soluble polymers, will be well
known to those
skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl
cellulose, such
as hydroxy propyl cellulose, are preferred. Additionally (or alternatively)
the spheroids may
32


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
contain a water insoluble polymer, especially an acrylic polymer, an acrylic
copolymer, such
as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
In certain embodiments, a sustained release coating is applied to the
sustained release
spheroids, granules, or matrix multiparticulates. In such embodiments, the
sustained-release
coating may include a water insoluble material such as (a) a wax, either alone
or in admixture..
with a fatty alcohol; or (b) shellac or zero. The coating is preferably
derived from an aqueous
dispersion of the hydrophobic sustained release material.
In certain embodiments, it is necessary to overcoat the sustained release
spheroids,
granules, or matrix multiparticulates comprising the opioid analgesic, opioid
antagonist, one
or more aversive agents, and sustained release carrier with a sufficient
amount of the aqueous
dispersion of, e.g., alkylcellulose or acrylic polymer, to obtain a weight
gain level from about
2 to about 50%, e.g., about 2 to about 25%, in order to obtain a sustained-
release formulation.
The overcoat may be lesser or greater depending upon, e.g., the desired
release rate, the
inclusion of plasticizes in the aqueous dispersion and the manner of
incorporation of the
same. Cellulosic materials and polymers, including alkylcelluloses, are
sustained release
materials well suited for coating the sustained release spheroids, granules,
or matrix
multiparticulates according to the invention. Simply by way of example, one
preferred
alkylcellulosic polymer is ethylcellulose, although the artisan will
appreciate that other
cellulose andlor alkylcellulose polymers may be readily employed, singly or in
any
combination, as all or part of a hydrophobic coating according to the
invention.
One commercially-available aqueous dispersion of ethylcellulose is Aquacoat~
(FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat~ is prepared by
dissolving the
ethylcellulose in a water-immiscible organic solvent and then emulsifying the
same in water
in the presence of a surfactant and a stabilizer. After homogenization to
generate submicron
droplets, the organic solvent is evaporated under vacuum to form a
pseudolatex. The
plasticizes is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior
to using the same as a coating, it is necessary to intimately mix the
Aquacoat~ with a suitable
plasticizes prior to use.
Another aqueous dispersion of ethylcellulose is commercially available as
Surelease~
(Colorcon, Inc., West Point, Pennsylvania, U.S.A.). This product is prepared
by incorporating
plasticizes into the dispersion during the manufacturing process. A hot melt
of a polymer,
plasticizes (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a
homogeneous
mixture, which is then diluted with an alkaline solution to obtain an aqueous
dispersion
33


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which can be applied directly to the sustained release spheroids, granules, or
matrix
multiparticulates.
In other preferred embodiments of ' the present invention, the sustained
release
material comprising the sustained-release coating is a pharmaceutically
acceptable acrylic
polymer, including but not limited to acrylic acid and methacrylic acid
copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,
poly(acrylic
acid), poly(methacrylic acid), methacrylic acid alkylarnide copolymer,
poly(methyl
methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide,
aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and
glycidyl
methacrylate copolymers.
In certain preferred embodiments, the acrylic polymer is comprised of one or
more
ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well,
known in
the art, and are described in the National Formulary (NF) XVII as fully
polymerized
copolymers of acrylic and methacrylic acid esters with a low content of
quaternary
ammonium groups. In order. to obtain a desirable dissolution profile, it may
be necessary to
incorporate two or more annnonio methacrylate copolymers having differing
physical
properties, such as different molar ratios of the quaternary ammonium groups
to the neutral
(meth)acrylic esters.
Certain methacrylic acid ester-type polymers are useful for preparing pH-
dependent
coatings which may be used in accordance with the present invention. For
example, there are
a family of copolymers synthesized from diethylaminoethyl methacrylate and
other neutral
methacrylic esters, also known as methacrylic acid copolymer or polymeric
methacrylates,
commercially available as Eudragit~ from Rohm GMBH and Co. Kg Darmstadt,
Germany.
There are several different types of Eudragit'~. For example, Eudragit E is an
example of a
methacrylic acid copolymer which swells and dissolves in acidic media.
Eudragit L is a
methacrylic acid copolymer which does not swell at about pH < 5.7 and is
soluble at about
pH > 6. Eudragit S does not swell at about pH < 6.5 and is soluble at about pH
> 7. Eudragit
RL and Eudragit RS are water swellable, and the amount of water absorbed by
these
polymers is pH-dependent; however, dosage forms- coated with Eudragit RL and
RS are pH-
independent.
In certain preferred embodiments, the acrylic coating comprises a mixture of
two
acrylic resin lacquers commercially available from Rohm under the Tradenames
Eudragit~
RL30D and Eudragit0 RS30D, respectively. Eudragit~ RL30D and Eudragit~ RS30D
are
copolymers of acrylic and methacrylic esters with a low content of quaternary
ammonium
34


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WO 03/013479 PCT/US02/24934
groups, the molar ratio of ammonium groups to the remaining neutral
(meth)acrylic esters
being 1:20 in Eudragit~ RL30D and 1:40 in EudragitOO RS30D. The mean molecular
weight
is about 150,000. The code designations RL (high permeability) and RS (low
permeability)
refer to the permeability properties of these agents. Eudragit~ RL/RS mixtures
are insoluble
in water and in digestive fluids. However, coatings formed from the same are
swellable and
permeable in aqueous solutions and digestive fluids.
The Eudragit0 RL/RS dispersions of the present invention may be mixed together
in
any desired ratio in order to ultimately obtain a sustained-release
formulation having a
desirable dissolution profile. Desirable sustained-release formulations may be
obtained, for
instance, from a retardant coating derived from 100% Eudragit~ RL, 50%
Eudragit~ RL and
50% Eudragit~ RS, and 10% Eudragit~ RL:Eudragit~ 90% RS. Of course, one
skilled in the
art will recognize that other acrylic polymers may also be used, such as, for
example,
Eudragit~ L. In embodiments of the present invention where the coating
comprises an
aqueous dispersion of a hydrophobic sustained release material, the inclusion
of an effective
amount of a plasticizes in the aqueous dispersion of hydrophobic material will
further
improve the physical properties of the sustained-release coating. For example,
because ethyl-
cellulose has a relatively high glass transition temperature and does not form
flexible films
under normal coating conditions, it is preferable to incorporate a plasticizes
into an
ethylcellulose coating containing sustained-release coating before using the
same as a coating
material. Generally, the amount of plasticizes included in a coating solution
is based on the
concentration of the film-former, e.g., most often from about 1 to about 50
percent by weight
of the film-former. Concentration of the plasticizes, however, can only be
properly
determined after careful experimentation with the particular coating solution
and method of
application.
Examples of suitable plasticizers for ethylcellulose include water insoluble
plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate,
tributyl citrate, and
triacetin, although it is possible that other water-insoluble plasticizers
(such as acetylated
monoglycerides, phthalate esters, castor oil, etc:) may be used. 'Triethyl
citrate is an especially
preferred plasticizes for the aqueous dispersions of ethyl cellulose of the
present invention.
Examples of suitable plasticizers for the acrylic polymers of the present
invention
include, but are not limited to citric acid esters such as triethyl citrate NF
XVI, tributyl
citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. Other
plasticizers which have
proved to be suitable for enhancing the elasticity of the films formed from
acrylic films such
as Eudragit~ RL/RS lacquer solutions include polyethylene glycol, propylene
glycol,


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an
especially preferred plasticizer
for the aqueous dispersions of ethyl cellulose of the present invention.
In certain embodiments, the uncoated/coated sustained release spheroids,
granules, or
matrix multiparticulates containing the opioid analgesic; opioid antagonist;
and one or more
aversive agents; are cured until an endpoint is reached at which the sustained
release
spheroids, granules, or matrix multiparticulates provide a stable dissolution
of the opioid. The
curing endpoint may be determined by comparing the dissolution profile (curve)
of the
dosage form immediately after curing to the dissolution profile (curve) of the
dosage form
after exposure to accelerated storage conditions of, e.g., at least one month
at a temperature
of 40°C and a relative humidity of 75%. Cured formulations are
described in detail in U.S.
Patent Nos. 5,273,760; 5,286,493; 5,500,227; 5,580,578; 5,639,476; 5,681,585;
and
6,024,982. Other examples of sustained-release formulations and coating: which
may be used
in accordance with the present invention include those described in U.S.
Patent Nos.
5,324,351; 5,356,467; and 5,472,712.
In addition to the above ingredients, the spheroids, granules, or matrix
multiparticulates may also contain suitable quantities of other materials,
e.g., diluents,
lubricants, binders, granulating aids, and glidants that are conventional in
the pharmaceutical
art in amounts up to about 50% by weight of the formulation if desired. The
quantities of
these additional materials will be sufficient to provide the desired effect to
the desired
formulation.
Specific examples of pharniaceutically acceptable carriers and excipients that
may be
used to formulate oral dosage forms are described in the Handbook of
Pharmaceutical
Excipients, American Pharmaceutical Association (1986), incorporated by
reference herein.
It has further been found that the addition of a small amount of talc to the
sustained
release coating reduces the tendency of the aqueous dispersion to stick during
processing, and
acts as a polishing agent.
OSMOTIC DOSAGE FORMS
Sustained release dosage forms according to the present invention may also be
prepared as osmotic dosage formulations. The osmotic dosage forms preferably
include a
bilayer core comprising a drug layer (containing the opioid analgesic and
optionally the
opioid antagonist and or one or more aversive agents) and a delivery c~ push
layer (which
36


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may contain the opioid antagonist and/or one or more aversive agents), wherein
the bilayer
core is surrounded by a semipermeable wall and optionally having at, least one
passageway
disposed therein.
The expression "passageway" as used for the purpose of this invention,
includes
aperture, orifice, bore, pore, porous element through which the opioid
analgesic (with or
without the antagonist) can be pumped, diffuse or migrate through a fiber,
capillary tube,
porous overlay, porous insert, microporous member, or porous composition. The
passageway
can also include a compound that erodes or is leached from the wall in the
fluid environment
of use to produce at least one passageway. Representative compounds for
forming a
passageway include erodible poly(glycolic) acid, or poly(lactic) acid in the
wall; a gelatinous
filament; a water-removable polyvinyl alcohol); leachable compounds such as
fluid-
removable pore-forming polysaccharides, acids, salts or oxides. A passageway
can be formed
by leaching a compound from the wall, such as sorbitol, sucrose, lactose,
maltose, or fructose,
to form a sustained-release dimensional pore-passageway. The passageway can
have any
shape, such as round, triangular, square and elliptical, for assisting in the
sustained metered
release of opioid analgesic from the dosage form. The dosage form can be
manufactured with
one or more passageways in spaced-apart relation on one or more surfaces of
the dosage
forni. A passageway and equipment for forming a passageway. are disclosed in
U.S. Patent
Nos. 3;845,770; 3,916,899; 4,063,064 and 4,088,864. Passageways comprising
sustained-
release dimensions sized, shaped and adapted as a releasing-pore formed by
aqueous leaching
to provide a releasing-pore of a sustained-release rate are disclosed in U.S.
Patent Nos.
4,200,098 and 4,285,987.
In certain embodiments, the bilayer core comprises a dnig layer with opioid
analgesic
and a displacement or push layer optionally containing the antagonist and/or
one or rriiore
aversive agents. The antagonist and/or one or more aversive agents may
optionally be
included in the drug layer instead of or in addition to being included in the
push layer. In
certain embodiments the drug layer may also comprise at least one polymer
hydrogel. The
polymer hydrogel may have an average molecular weight of between about 500 and
about
6,000,000. Examples of polymer hydrogels include but are not limited to a
maltodextrin
polymer comprising the formula (C6 H~2 OS)"~H20, wherein n is 3 to 7,500, and
the
maltodextrin polymer comprises a 500 to 1,250,000 number-average molecular
weight; a
poly(alkylene oxide) represented by, e.g., a polyethylene oxide) and a
polypropylene oxide)
having a 50,000 to 750,000 weight-average molecular weight, and more
specifically
represented by a polyethylene oxide) of at least one of 100,000, 200,000,
300,000 or 400,000
37


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weight-average molecular weights; an alkali carboxyalkylcellulose, wherein the
alkali is
sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to
175,000 weight-
average molecular weight; and a copolymer of ethylene-acrylic acid, in.~luding
methacrylic
and ethacrylic acid of 10,000 to 500,000 number-average molecular weight.
In certain embodiments of the present invention, the delivery or push layer
comprises
an osmopolymer. Examples of an osmopolymer include but are not limited to a
member
selected from the group consisting of a polyalkylene oxide and a
carboxyalkylcellulose. The
polyalkylene oxide possesses a 1,000,000 to 10,000,000 weight-average
molecular weight.
The polyalkylene oxide may be a member selected from the group consisting of
polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene
oxide having a
1,000,000 average molecular weight, polyethylene oxide comprising a 5,000,000
average
molecular weight, polyethylene oxide comprising a 7,000,000 average molecular
weight,
cross-linked polymethylene oxide possessing a 1,000,000 average molecular
weight, and
polypropylene oxide of 1,200,000 average molecular weight. Typical osmopolymer
carboxyalkylcellulose comprises a member selected from the group consisting of
alkali
carboxyalkylcellulose, sodium carboxymethylcellulose, potassium
carboxymethylcellulose,
sodium carboxyethylcellulose, lithium carboxymethylcellulose, sodium
carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,
carboxymethylhydroxyethyl
cellulose, carboxyethylhydroxyethylcellulose and
carboxymethylhydroxypropylcellulose.
The osmopolymers used for the displacement layer exhibit an osmotic pressure
gradient
across the semipermeable wall. The osmopolymers imbibe fluid into dosage form,
thereby
swelling and expanding as an osmotic hydrogel (also known as osmogel), whereby
they push
the contents of the drug layer from the osmotic dosage form.
The push layer may also include one or more osmotically effective compounds
also
known as osmagents and as osmotically effective solutes. They imbibe an
environmental
fluid, for example, from the gastrointestinal tract, into dosage form and
contribute to the
delivery kinetics of the displacement layer. Examples of osmotically active
compounds
comprise a member selected from the group consisting of osmotic salts and
osmotic
carbohydrates. Examples of specific osmagents include but are not limited to
sodium
chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium
chloride, sodium
phosphate, potassium sulfate, sodium sulfate, potassium phosphate, gl~~cose,
fructose and
maltose.
The push layer may optionally include a hydroxypropylalkylcellulose possessing
a
9,000 to 450,000 number-average molecular weight. The
hydroxypropylalkylcellulose is
38


CA 02456322 2004-02-03
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represented by a member selected from the group consisting of
hydroxypropylmethylcellulose, hydroxypropylethylcellulose,
hydroxy°propyl isopropyl
cellulose, hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.
The push layer may also optionally comprise an antioxidant to inhibit the
oxidation of
ingredients. Some examples of antioxidants include but are .not limited to a
member selected
from the group consisting of ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, a
mixture of ~ 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated
hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,
sodium
metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-.. hloro-2,6-
ditertiary
butylphenol, alphatocopherol, and propylgallate.
In certain alternative embodiments, the dosage form comprises a substantially
homogenous core comprising opioid analgesic, an opioid antagonist, one or more
aversive
agents, a pharmaceutically acceptable polymer (e.g., polyethylene oxide),
optionally a
disintegrant (e.g., polyvinylpyrrolidone), optionally an absorption enhancer
(e.g., a fatty acid,
a surfactant, a chelating agent, a bile salt, etc.). The substantially
homogenous core is
surrounded by a semipermeable wall having a passageway (as defined above) for
the release
of the opioid analgesic, the opioid antagonist, and the one or more aversive
agents.
In certain embodiments, the semipermeable wall comprises a member selected
from
the group consisting of a cellulose ester polymer, a cellulose ether polymer
and a cellulose
ester-ether polymer. Representative wall polymers comprise a member selected
from the
group consisting of cellulose acylate, cellulose diacylate, cellulose
triacylate; cellulose
acetate, cellulose diacetate, cellulose triacetate, mono-, di- and
tricellulose alkenylates, and
mono-, di- and tricellulose alkinylates. The poly(cellulose) used for t1."
present invention
comprises a number-average molecular weight of 20,000 to 7,500,000.
Additional semipermeable polymers for the purpose of. this invention comprise
acetaldehyde dimethycellulose acetate, cellulose acetate ethylcarbamate,
cellulose acetate
rnethylcarbamate, cellulose diacetate, propylcarbamate, cellulose acetate
diethylaminoacetate;
semipermeable polyamide; semipermeable polyurethane; semipermeable sulfonated
polystyrene; semipermeable cross-linked polymer formed by the coprecipitation
of a
polyanion and a polycation as disclosed in U.S. Patent Nos. 3,173,876;
3,276,586; 3,541,005;
3,541,006 and 3,546,876; semipermeable polymers as disclosed by Loeb and
Sourirajan in
U.S. Patent No. 3,133,132; semipenneable crosslinked polystyrenes;
semipermeable cross-
linked poly(sodium styrene sulfonate); semipermeable crosslinked
poly(vinylbenzyltrimethyl
ammonium chloride); and semipermeable polymers possessing a fluid permeability
of
39


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2.5x10-$ to 2.5x10-2 (cmz /hnatm) expressed per atmosphere of hyc';.~static or
osmotic
pressure difference across the semiperneable wall. Other polymers useful in
the present
invention are known in the art in U.S. Patent Nos. 3,845,770; 3,916,899 and
4,160,020; and
in Handbook of Common Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press,
Cleveland,
Ohio.
In certain embodiments, preferably the semipermeable wall is nontoxic, inert,
and it
maintains its physical and chemical integrity during the dispensing life of
the drug. In certain
embodiments, the dosage form comprises a binder. An example of a binder
includes, but is
not limited to a therapeutically acceptable vinyl polymer having a 5,000 to
350,000 viscosity-
average molecular weight, represented by a member selected from the group
consisting of
poly-n-vinylamide, poly-n-vinylacetamide, polyvinyl pyrrolidone), also known
as poly-n-
vinylpyrrolidone, poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-
pyrrolidone, and poly-
n-vinyl-pynolidone copolymers with a member selected from the group consisting
of vinyl
acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl butyrate, vinyl
laureate, and vinyl
stearate. Other binders include for example, acacia, stai"h, gelatin, and
hydroxypropylalkylcellulose of 9,200 to 250,000 average molecular weight.
In certain embodiments, the dosage form comprises a lubricant, which may be
used
during the manufacture of the dosage form to prevent sticking to die wall or
punch faces.
Examples of lubricants include but are not limited to magnesium stearate,
sodium stearate,
stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium
oleate, caprylic acid,
sodium stearyl fumarate, and magnesium palmitate.
TRANSDERMAL DELIVERY SYSTEMS
The formulations of the present invention may be formulated as a transdermal
delivery system, such as transdermal patches. In certain embodiments of the
present
invention, a transdernial patch comprises an opioid agonist contained in a
reservoir or a
matrix, and an adhesive which allows the transdermal device to adhere to the
skin, allowing
the passage of the active agent from the transdermal device through the slc~n
of the patient,
with the inclusion of the aversive agents and opioid antagonists as disclosed
herein which are
not releasable when the dosage form is administered intact belt which are
releasable when the
dosage form is broken or tampered with in order to release the opioid from the
transdermal
system.


CA 02456322 2004-02-03
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Transdermal delivery system providing a controlled-release of an opioid
agonist is
known. For example, Duragesic~ patch (commercially available from Janssen
Pharmaceutical) contains an opioid agonist (fentanyl) and is said to provide
adequate
analgesia for up to 48 to 72 hours (2 to 3 days). This fornulation can be
reformulated with
an aversive agent and antagonist as disclosed herein.
There are several types of transdermal formulations of buprenorphine reported
in the
literaW re. See, for example, U.S. Patent No. 5,240,711 (Hille et al.), U.S.
Patent No.
5,225,199 (Hidaka et al.), U.S. Patent No. 5,069,909 (Sharma et al.), U.S.
Patent No.
4,806,341 (Chien et al.), and U.S. Patent No. 5,026,556 (Drust et al.), all of
which are hereby
incorporated by reference. These transdermal devices can also be reformulated
with the
aversive agents and antagonists as disclosed herein.
The transdermal delivery system used in the present invention may also be
prepared
in accordance with U.S. Patent No. 5,069,909 (Sharma et al.), hereby
incorporated by
reference. This patent describes a laminated composite for administering
buprenorphine
transdermally to treat pain. The transdermal delivery system used in the
present invention
may also be prepared in accordance with U.S. Patent No. 4,806,341 (Chien et
al.), hereby
incorporated by reference. This patent describes a transdermal morphinan
narcotic analgesic
or antagonist (including buprenorphine) pharmaceutical polymer matrix dosage
unit having a
backing layer which is substantially impervious to the buprenorphine, and a
polymer matrix
disc layer which is adhered to the backing layer and which has microdispersed
therein
effective dosage amounts of the buprenorphine.
The transdermal delivery system used in the present invention may also be that
described in U.S. Patent No. 5,026,556 (Drust et al.), hereby incorporated by
reference.
Therein, compositions for the transdermal delivery of buprenorphine comprise
buprenorphine
in a carrier of a polar solvent material selected from the group consisting of
C3-C4 diols, C3-
C6 triols, and mixtures thereof, and a polar lipid material selected from the
group consisting
of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein the
polar solvent
material and the lipid material are present in a weight ratio of solvent
material:lipid material
of from 60:40 to about 99:1. The transdernal delivery system used in the
present invention
may also be that described in U.S. Patent No. 4,588,580 (Gale, et. al.),
hereby incorporated
by reference. That system comprises a reservoir for the drug having a skin
proximal, material
releasing surface area in the range of about 5-100 cm2 and containing between
0.1 and 50%
by weight of a skin permeable form of the buprenorphine. The reservoir
contains an aqueous
41


CA 02456322 2004-02-03
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gel comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%
buprenorphine,
and release rate controlling means disposed in the flow path of the drug to
the skin which
limits the flux of the buprenorphine from the system through the skin.
The transdermal delivery system used in the present invention may also be that
described in PCT/USOl/04347 to Oshlack et al.
The present invention is contemplated to encompass all transdermal
formulations,
e.g., the technologies described above, with the inclusion of an aversive
agent and antagonist,
such that the dosage form deters abuse of the opioid therein.
The aversive agent and antagonist in non-releasable form when administered
intact
can be formulated in accordance with U.S. Patent No. 5,149,538 to Granger,
hereby
incorporated by reference. Alternatively, the aversive agent and the opioid
agonist can be
separated from the opioid by a layer which becomes disrupted when the dosage
forni is
tampered with, thereby mixing the aversive agent with the opioid agomst.
Alternatively, a
combination of both systems can be used.
SUPPOSITORIES
The controlled release formulations of the present invention may be formulated
as a
pharmaceutical suppository for rectal administration comprising an opioid
analgesic, opioid
antagonist, and at least one aversive agent in a controlled release mahix, and
a suppository
vehicle (base). Preparation of controlled release suppository fomnulations is
described in, e.g.,
U.S. Patent No. 5,215,758.
The suppository base chosen should be compatible with the agents) of the
present
invention. Further, the suppository base is preferably non-toxic and
nonirritating to mucous
membranes, melts or dissolves in rectal fluids, and is stable during storage.
In certain preferred embodiments of the present invention for both water-
soluble and
water-insoluble drugs, the suppository base comprises a fatty acid wax
selected from the
group consisting of mono-, di- and triglycerides of saturated, natural fatty
acids of the chain
length CIZ to C18.
In preparing the suppositories of the present invention other excipients may
be used.
For example, a wax may be used to form the proper shape for administration via
the rectal
route. This system can also be used without wax, but with the addition of
diluent filled in a
gelatin capsule for both rectal and oral administration.
Examples of suitable commercially available mono-, di- and triglycerides
include
saturated natural fatty acids of the 12-18 carbon atom chain sold under the
trade name Novata
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TM (types AB, AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by
Henkel, and
Witepsol TM (types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25,
W31,
W35, W45, 555, S58, E75, E76 and E85), manufactured by Dynamit Nobel.
Other pharmaceutically acceptable suppository bases may be substituted in
whole or
in part for the above-mentioned mono-, di- and triglycerides, The amount of
base in the
suppository is determined by the size (i.e. actual weight) of the dosage form,
the amount of
base (e.g., alginate) and drug used. Generally, the amount of suppository base
is from about
20 percent to about 90 percent by weight of the total weight of the
suppository. Preferably,
the amount of base in the suppository is fiom about 65 percent to about 80
percent, by weight
of the total weight of the suppository.
In certain embodiments of the dosage forms of the present invention may also
include
a surfactant. Surfactants useful in accordance with the present invention,
include for
example, ionic and nonionic surfactants or wetting agents commonly used in the
formulation
of pharmaceuticals, including but not limited to castor oil derivatives,
cholesterol,
polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid
esters, poloxamers,
polysorbates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
compounds,
monoglycerides or ethoxylated derivatives thereof, diglycerides or
polyoxyethylene
derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or
derivatives thereof,
ethoxylated alcohols,, ethoxylated esters, ethoxylated amides,
polyoxypropylene compounds,
propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated
esters,
alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,
ethylene glycol esters,
diethylene glycol esters, propylene glycol esters, glycerol esters,
polyglycerol fatty acid
esters, SPAN's (e.g., sorbitan esters), TWEEN's (i.e., sucrose esters),
glucose (dextrose)
esters, alkali metal sulfates, quaternary ammonium compounds, amidoamines, and
aminimides, simethicone, lecithins, alcohols, phospholipids, and mixtures
thereof.
Mixed surfactant/wetting agents useful in accordance with the present
invention
include, for example, sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and
sodium
lauryl sulfate/PEG 60001stearic acid, etc.
In certain embodiments of the present invention, the dosage' form may also
include an
emulsifying agent. Emulsifying agents useful in accordance with the present
invention
include, for example, monoglycerides, sucrose/fatty acid esters,
polyglycerol/fatty acid.esters,
sorbitanfatty acid esters, lecithins, potassium and sodium salts of rosin
acids and higher fatty
acids, as well as sulfates and sulfonates of these acids, amine salts of
hydroxylamines of
long-chain fatty acid esters, quaternary ammonium salts such as stearyl-
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CA 02456322 2004-02-03
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dimethylberizylammonium chloride and tridecylbenzenehydroxyethylirnidazole
chloride,
phosphoric esters of higher alcohols such as capryl and octyl alcohol, and
monoesters of oleic
acid and pentaerytluitol such as sorbitan monooleates, and mixtures thereof.
The oral dosage form and methods for use of the present invention may further
include, in addition to an opioid analgesic and opioid antagonist, one or more
drugs that may
or may not act synergistically with the opioid analgesic. Thus, in certain
embodiments, a
combination of two opioid analgesics may be included in the dosage form. For
example, the
dosage form may include two opioid analgesics having different properties,
such as half life,
solubility, pbtency, and a combination of any of the foregoing.
In yet further embodiments, one or ~ more opioid analgesic is included and a
further
non-opioid drug is also included. Such non-opioid drugs woul.~i preferably
provide additional
analgesia, and include, for example, aspirin, acetaminophen; non-steroidal
anti-inflammatory
drugs ("NSAIDS"), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate
(NMDA) receptor
antagonists, e.g., a morphinan such as dextromethorphan or dextrorphan, or
ketamine;
cyclooxygenase-II inhibitors ("COX-II inhibitors"); and/or glycine receptor
antagonists.
In certain preferred embodiments of the present invention, the invention
allows for the
use of lower doses of the opioid analgesic by virtue of the inclusion of an
additional non-
opioid analgesic, such as an NSAID or a COX-2 inhibitor. By using lower
amounts of either
or both drugs, the side effects associated with effective pain management in
humans are
reduced.
Suitable non-steroidal anti-inflammatory agents, including ibuprofen,
diclofenac,
naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,
indoprofen, piro-
profen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,
aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,
sulindac, tolmetin,
zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clida~-~ac, oxpinac,
mefenamic acid,
meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,
diflurisal, flufenisal,
piroxicam, sudoxicam or isoxicam, and the like. Useful dosages of these drugs
are well
known to those skilled in the art.
N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art,
and
encompass, for example, morphinans such as dextromethorphan or dextrorphan,
ketamine, or
pharmaceutically acceptable salts thereof. For purposes of the present
invention, the term
"NMDA antagonist" is also deemed to encompass drugs that block a major
intracellular
consequence of NMDA-receptor activation, e.g. a ganglioside such as GM1 or
GT~b a
phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6-

44


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aminohexyl)-5-chloro-1-naphthalenesulfonamide. These drugs are stated' to
inhibit the
development of tolerance to and/or dependence on addictive drugs, e.g..,
narcotic analgesics
such as morphine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838
(both to Mayer, et
al.), and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.),
all of which are
hereby incorporated by reference. The NMDA antagonist may be included alone,
or in
combination with a local anesthetic such as lidocaine, as described in these
Mayer, et.al.
patents.
The treahnent of chronic pain via the use of glycine receptor antagonists and
the
identification of such drugs is described in U.S. Pat. No. 5,514,680 (Weber,
et al.).
COX-2 inhibitors have been reported in the art and many chemical structures
are
known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are
described, for
example, in U.S. Patent Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142;
5,536,752;
5,521,213; 5,474,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265;
5,409,944;
and 5,130,311, all of which are hereby incorporated by reference. Certain
preferred COX-2
inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238),
meloxicam, 6-
methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as ~~ ioxx),
nabumetone
(prodrug for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or
combinations
thereof. Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg
to about 140
mg per kilogram of body weight per day are therapeutically effective in
combination with an
opioid analgesic. Alternatively, about 0.25 mg to about 7 g per patient per
day of a COX-2
inhibitor is administered in combination with an opioid analgesic.
In yet further embodiments, a non-opioid drug can be included- which provides
a
desired effect other than analgesia, e.g., antitussive, expectorant,
decongestant, antihistamine
drugs, local anesthetics, and the like.
The invention disclosed herein is meant to encompass the use pf any
pharmaceutically
acceptable salts thereof of the disclosed opioid analgesics. The
pharmaceutically acceptable
salts include, but are not limited to, metal salts such as sodium salt,
potassium salt, secium
salt and the like; alkaline earth metals such as calcium salt, magnesium salt
arid the like;
organic amine salts such as triethylamine salt, pyridine salt, picoline salt,
ethanolamine salt,
triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamme salt
and the like;
inorganic -acid salts such as hydrochloride, hydrobromide, sulfate, phosphate
and the like;
organic acid salts such as formate, acetate, trifluoroacetate, maleate,
tartrate and the like;
sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and
the like;
amino acid salts such as arginate, asparginate, glutamate and the like.


CA 02456322 2004-02-03
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Some of the opioid analgesics disclosed herein may contain one or more
asymmetric
centers and may thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms.
The present invention is also meant to encompass the use of any of such
possible forms as
well as. their racemic and resolved fours and mixtures thereof. When the
compounds
described herein contain olefmic double bonds or other centers of geometric
asymmetry, and
unless specified otherwise, it is intended to include both E and Z geometric
isomers. The use
of all tautomers are intended to be encompassed by the present invention as
well.
The oral dosage forms of the present invention may be in the form of tablets,
troches,
lozenges, powders or granules, hard or soft capsules, microparticles (e.g.,
microcapsules,
microspheres and the like), buccal tablets, etc.
In certain embodiments, the present invention provides for a method of
preventing
abuse of an oral controlled release dosage form of an opioid analgesic
comprising preparing
the dosage forms as described above.
In certain embodiments, the present invention provides for a m~;thod of
preventing
diversion of an oral controlled release dosage form of, an opioid analgesic
comprising
preparing the dosage forms as described above.
In certain embodiments, the present invention provides for a method of
treating pain
by administering to a human patient the dosage forms described above.
The following examples illustrate various aspects of the present invention.
They are
not to be construed to limit the claims in any manner whatsoever.
EXAMPLE 1
A 20 mg oxycodone formulation is prepared containing naloxone as the
antagonist and xanthan gum as the aversive agent
In this example, a small amount of xanthan gum is added to the oxycodone
formulation during the granulation process. Other gelling agents such as
curdlan,
carrageenan, alginates, pectin, gelatin, furcelleran, agar, guar gum, locust
bean gum, tara
gum, tragacanth, acacia, glucomannans, karaya, starch and starch derivatives,
egg white
powder, facto albumin, soy protein, Jargel, gellan gum, welan gum, rhamsan
gum, and the
like, could also be used as gelling agents. Other semi-synthetic materials
such as chitosan,
pullulan, polylaevulan, hydroxypropyl cellulose, methylcellulose,
hydroxypropylmethyl
cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose, all ether
derivatives of
46


CA 02456322 2004-02-03
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cellulose, and the like, could also be used as alternate gelling materials.
The formulation of
Example 1 is listed in Table 1 below.
TABLE 1
In redients Amt/Unit m Amount/I3atch m


Oxycodone HCl 20.0 2n9.6*


Spray Dried Lactose 59.25 592.5


Povidone 5.0 50.0


Eudragit RS30D (solids)10.0 100


Triacetin 2.0 . 20.0


Naloxone HCl 0.61 6.12**


Xanthan gum 9.0 90.0


Stearyl Alcohol 25.0 250.0


Talc 2.5 25.0


Magnesium Stearate 1.25 12.5


Opadry Pink Y-S-14518A5.0 50.0


*adjusted for 99.G% assay and 4.2~/o residual moisture.
**adjusted for 99.23% assay and 0.5% residual moisture.
Process
1. Dispersion: Dissolve naloxone HCl in water and the solution is added to the
Eudragit/Triacetin dispersion.
2. Granulation: Spray the Eudragit/Triacetin dispersion onto the oxycodone
HCI, Spray
Dried Lactose, xanthan gum and Povidone using a fluid bed granulator.
3. Milling: Discharge the granulation and pass through a mill ,
4. Waxing: Melt the stearyl alcohol and add to the milled granulation using a
mixer. Allow
to cool.
5. Milling: Pass the cooled granulation through a mill.
6. Lubrication: Lubricate the granulation with talc and magnesium stearate
using a mixer.
7. Compression: Compress the granulation into tablets using a tablet press.
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EXAMPLE 2
A 40 mg oxycodone formulation was prepared containing naloxone as the
antagonist
and xanthan gum as the aversive agent
To determine the effect of varying amount of xanthan gum on the gelling
property and
dissolution rate of an oXycodone tablet, three levels of xanthan gum were
added to 40 mg
oxycodone granulation and compressed into tablets. Oxycodone recovery from
water
extraction of the tablet and the drug release rate were determined. The
oxycodone
granulation formulation of Example 2 is listed in Table 2 below.
TABLE 2
In redients Amt/Unit (m )


Oxycodone HCl 40.0


Spray Dried Lactose 39.25


Povidone ' S.0


Eudra it RS30D (solids)10.0


Triacetin 2.0


Naloxone HCL 0.9


Stearyl Alcohol 25.0


Talc 2.5


Magnesium Stearate 1.25.


Total ~ 125.9


Examples 2A to 2C were prepared adding different amounts (3mg, Smg, and 9mg)
of
xanthan gum to a 125.9 mg oxycodone granulation of Example 2.
EXAMPLE 2A
In redients Amt/LTnit m


Oxycodone granulation 125.9


Xanthan gum 3


Total ~ 128.9


EXAMPLE 2B
In redients Amt/Unit m )


Oxycodone granulation 125.9


Xanthan gum 5


Total 130.9


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EXAMPLE 2C
In redients Amt/Unit m


Oxycodone granulation125.9


Xanthan gum 9


Total 134.9


Process
1. Dispersion: Dissolve naloxone HCl in water and the solution is added to the
Eudragit/Triacetin 'dispersion.
2. Granulation: Spray the Eudragit/Triacetin dispersion onto the Oxycodone
HCI, Spray
Dried Lactose and Povidone using a fluid bed granulator.
3. Milling: Discharge the granulation and pass through a mill.
4. Waxing: Melt the stearyl alcohol and add to the milled granulation using a
mixer. ,Allow
to cool.
S. Milling: Pass the cooled granulation through a mill.
6. Lubrication: Lubricate the granulation with talc and magnesium stearate
using a mixer.
7. Add xanthan gum (3 levels) to the granulation and mix well.
8. Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 3
The granulation of Example 2 was compressed into tablets using a tablet press
without the addition of xanthan gum, and Examples 2, 2A-C were tested under
the following
dissolution conditions and gave the results listed in Table 3 below.
1. Apparatus: USP Type II (paddle), 150 rpm.
2. Medium: 700 ml SGF for first hour, thereafter made 900 ml with phosphate
buffer to pH
7.5.
3. Sampling time: 1,2,4,8,12,18 and 24 hours.
4. Analytical: High Performance Liquid Chromatography.
TABLE 3
Dissolution Results
Time (hrs)% Dissolved


Ex.2A Ex.2B Ex.2C Ex.2 Spec
(3 mg (5 mg (9 mg (no
xanthan)xanthan)xanthan)xanthan
added)


1 48 43 46 45 28-58


4 86 73 79 75 5~-88


12 101 98 99 93 >80


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The dissolution results show that all the tablets prepared have similar
dissolution
profiles. The inclusion of xanthan gum does not appear to substantially
c=:tinge the
oxycodone dissolution rate.
When 1 mL of water was added to the tablets containing xanthan gum on a tea
spoon,
the solution was not viscous. However, when the samples were heated and
allowed to cool,
the samples became very viscous. It was very difficult to withdraw this gel-
like solution into
a syringe for injection.
EXAMPLE 4
A 20 mg oxycodone formulation containing naloxone as the antagonist and a
tittering
agent as the aversive agent is prepared
In this example, a small amount of denatonium benzoate is added to an
oxycodone
formulation during the granulation process. The bitter taste would reduce the
abuse of
oxycodone by oral or intranasal route. The oxycodone formulation of Example 4
is listed in
Table 4 below.
TABLE 4
In redients Amt/Unit m AmountlBatch m


Oxycodone HCl 20.0 209.6*


Spray Dried Lactose 59.25 592.5


Povidone 5.0 50.0


Eudragit RS30D (solids)' 10.0 100


Triacetin 2.0 20.0


Naloxone HCl 0.61 6.12**


Denatonium benzoate 0.07 0.68


Stearyl Alcohol 25.0 250.0


Talc 2.5 25.0


Magnesium Stearate 1.25 12.5


Opadry Pink Y-S-14518A5.0 50.0


*adjusted for 99.6% assay and 4.2% residual moisture.
**adjusted for 99.23% assay and 0.5% residual moisture.
Process
1. Dispersion: Dissolve naloxone HCL and denatonium benzoate in water and the
solution is
added to the Eudragit/Triacetin dispersion.
2. Granulation: Spray the EudragitlTriacetin dispersion onto the Oxycodone
HCl, Spray
Dried Lactose and Povidone using a fluid bed granulator.
3. Milling: Discharge the granulation and pass through a mill.


CA 02456322 2004-02-03
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4. Waxing: Melt the stearyl alcohol and add to the milled granulation using a
mixer. Allow
to cool.
5. Milling: Pass the cooled granulation through a mill.
6. Lubrication: Lubricate the granulation with talc and magnesium stearate
using a mixer.
7. Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 5
In Example 5, a substantially non-releasable form of a bittering agent
(denatonium
benzoate) is prepared by coating denatonium benzoate particles with a coating
that renders
the denatonium benzoate substantially non-releasable. The formulation of
Example 5 is
listed in Table 5 below.
TABLE 5
htgredie~ats , ' a:Antt~ufaat ~ i
~~-,;'' , .. ~~(tii ) ~ ~~'


LOADING , .,; ; .;
,. .


denatonium benzoate 0.07


Sugar Spheres (30!35 50.0
mesh) ~


Opadry White Y-5-7068 2.5


Purified Water 42.5*


OVERCOATING


Opadry White Y-5-7068 3.02


Purified Water 17.11*


NON RELEASE COATING
(FOR RENDERING ~ ~ '
BITTERING AGENT
SUBSTANTIALLYNON
RELEASABLE) ,


Eudragit RS30D (dry 12.10
wt.)


Triethyl Citrate 2.42


Talc 4.84


Purified Water 49.21 * .


OVERCOATING


Opadry White Y-5-7068 4.12


Purified Water 23.35* .


Total 79.07


Remains in product as residual moisture only
PROCESS:
1. Solution Preparation Dissolve the denatonium benzoate in Purified Water.
Once
dissolved, add the Opadry White and continue mixing until a
homogeneous dispersion is yielded.
2. Loading Apply the above dispersion onto the Sugar Spheres using a
fluid bed coating machine.
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3. Overcoating Prepare an overcoating solution by dispersing Opadry White in
Purified Water. Apply this dispersion over the sugar spheres
loaded with denatonium benzoate using a fluid bed coating
machine.
4. Retardant Coating Prepare the non-release coating solution by mixing the
Eudragit
RS30D, Triethyl Citrate, Talc, and Purified Water. Apply this
dispersion over the loaded and overcoated sugar spheres using
a fluid bed coating machine.
S. Overcoating Prepare a second overcoating solution by dispersing Opadry
White in
Purified Water. Apply this dispersion over the non-release
coated denatonium benzoate spheres using a fluid bed coating
machine
6. Curing Cure the spheres at 45°C for approximately 48 hours.
EXAMPLE 6
In Example 6, a substantially non-releasable foam of a bittering agent
(denatonium
benzoate) is prepared as denatonium benzoate containing granulates. The
;ranulates are
comprised of denatonium benzoate dispersed in a matrix that renders the
denatonium
benzoate substantially non-releasable. The formulation of Example 6 is listed
in Table 6
below.
TABLE 6
Izzgredient ' ~. Ai~z t%uizzt
'


.
~, ~jzz


Denatonium benzoate0.07


Dicalcium Phosphate53.0


Poly (DI-Lactide-Co-12.0


Glycolide) polymer


(PLGA)


MW~ 100,000


Ethyl Acetate


Total 65.07


* Used as a vehicle for application of PLGA polymer.
PROCESS:
1. Solution Preparation Dissolve PLGA in Ethyl Acetate by mixing.
2. Granulation Place the denatonium benzoate, and Dicalcium Phosphate in a
fluid
bed coating machine and granulate by spraying the above solution.
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EXAMPLE 7
In Example 7, a substantially non-releasable form of a bittering agent
(denatonium benzoate)
is prepared as denatonium benzoate extruded pellets. The formulation of
Example 7 is listed
in Table 7 below.
TABLE 7
,,
Izzgl edzent . ;;~, v ~hlztluiiit
~llz
Denatonium benzoate 0.07
Eudragit RSPO 180.0
Stearyl Alcohol 55.0
Total 235.07
PROCESS:
1.Milling Pass stearyl alcohol flakes through an impact
mill.


2.Blending Mix Denatonium benzoate, Eudragit, and milled
Stearyl Alcohol in a


twin shell blender.


3.Extrusion Continuously feed the blended material into
a twin screw extruder and


collect the resultant strands on a conveyor.


4.Cooling Allow the strands to cool on the conveyor.


5.PelletizingCut the cooled strands into pellets using a
Pelletizer.


6.Screening Screen the pellets and collect desired sieve
portion.


EXAMPLE 8
Naltrexone HCl beads
In Example 8, Naltrexone HCl beads for incorporation into capsules were
prepared
having the following formulation in Table 8 below.
TABLE 8
Ingredients Amt/unit
(mg)


Step 1. Drug layeringNaltrexone HCl ~ 2.1


Non-pared beads (30/35 39.98
mesh)


Opadry Clear 0.4
(Hydroxypropymethyl
cellulose)


Sodium ascorbate 0.027


Ascorbic acid 0.05


Step 2. Anionic Eudragit L30D (dry) 2.164
polymer
coat


Triethyl Citrate ~ 0.433


Cabosil 0.108


53


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Step 3. SustainedEudragit RS30D (dry) 17.475
release
coat


Triethyl citrate 3.495


Cabosil 0.874


Step 4. Seal coatOpadry Clear 1.899
(Hydroxypropylmethyl
cellulose)


Cabosil 0.271


Total (on dry 69.287
basis)


PROCESS:
1. Dissolve naltrexone HCI, ascorbic acid, sodium ascorbate and Opadry Clear
in water.
Spray the drug solution onto non-pared beads in a fluid bed coater with
Wurster insert.
2. Disperse Eudragit L30D, Triethyl citrate, and Cabosil in water. Spray the
dispersion onto
the drug-loaded beads in the fluid bed coater.
3. Disperse Eudragit RS30D, triethyl citrate, and Cabosil in water. Spray the
dispersion
onto the beads in the fluid bed coater.
4. Dissolve Opadry Clear in water. Spray the solution onto the beads in the
fluid bed coater.
5. Cure the beads at 60°C for 24 hours.
Naltrexone multiparticulates
EXAMPLE 9
A naltrexone melt extruded multiparticulate formulation was prepared. The melt
extnided multiparticulate formulation is listed in Table 9 below.
TABLE 9
Ingredients Amt/Unit
(mg)


Naltrexone HCl 2.0


Eudragit RSPO 88.0


Stearyl alcohol 15.0


Stearic acid 15.0


BHT 1.0


Total 121.0


PROCESS:
1. Blend milled Stearic acid, stearyl alcohol, Naltrexone HCI, BHT, and
Eudragit RSPO
using a V-blender.
2. Extnide the mixture using a Powder Feeder, Melt Extruder(equipped with the
6 x 1
mm die head), Conveyor, Lasermike, and Pelletizer.
Powder feed rate-4.2 kg/hr; vacuum-980 mBar
Conveyor-such that diameter of extrudate is lmm
Pelletizer-such that pellets are cut to lmm in length
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3. Screen pellets using #16 mesh and #20 mesh screens. Collect material that
passes
through the #16 mesh screen and is retained on the #20 mesh screen.
4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT 114 mg and
NMT 126
mg.
EXAMPLE 10
Naltrexone CR.Beads
A naltrexone sustained release bead formulation was prepared which can be
incorporated into an opioid controlled release granulation and compressed into
tablets. The
naltrexone controlled release bead formulation is listed in Table 10 below.
TABLE 10
Ingredients Amt/unit*
(mg)


Steel. Drug layeringNaltrexone HCl . 0.609


Non-pared beads (30/35 67.264
mesh)


Opadry Clear 0.54


Step 2. Seal coatEudragit L 2.545


Triethyl citrate 0.636


Glyceryl monostearate 0.239 _


Step 3. SustainedEudragit RS30D (dry) 43.789
release
coat


Triethyl citrate - 8.758


Cabosil 2.189


Step 4. Seal coatOpadry Clear 2.053
(Hydroxypropylmethyl
cellulose)


Cabosil . 1.368


Total 130


PROCESS:
1. Dissolve naltrexone HCl and Opadry (HPMC) in water. Spray the drug solution
onto
non-pared beads in a fluid bed coater with Wurster insert.
2. Disperse Eudragit L, Triethyl citrate, and glyceryl monostearate in water.
Spray the
dispersion onto the drug-loaded beads in the fluid bed coater.
3. Disperse Eudragit RS, triethyl citrate, and Cabosil in water. Spray the
dispersion onto the
beads in the' fluid bed coater.
4. Dissolve Opadry in water. Spray the solution onto the beads in the fluid
bed coater.
5. Cure the beads at 60°C for 24 hours.


CA 02456322 2004-02-03
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EXAMPLE 11
Controlle.dRel'ease.Oxyco,done
In Example 11, a sustained release 20. mg controlled release oxycodone
formulation
was prepared having the formulation listed in Table 11 below.
TABLE 11
Ingredients Amt/Unit (mg)


Oxycodone HCl 20.0


Spray Dried Lactose59.25


Povidone 5.0


Eudragit RS30D (solids)10.0


Triacetin 2.0


Stearyl Alcohol 25.0


Talc 2.5


Magnesium Stearate 1.25


Opadry Pink Y-S-14518A4.0


Total 129.0


PROCESS:
1. Granulation: Spray the Eudragit/Triacetin dispersion onto the Oxycodone
HCI, Spray
Dried Lactose and Povidone using a fluid bed granulator.
2. Milling: Discharge the granulation and pass through a mill.
3. Waxing: Melt the stearyl alcohol and add to the milled granulation using a
mixer. Allow
to cool.
4. Milling: Pass the cooled granulation through a mill.
5. Lubrication: Lubricate the granulation with talc and magnesium stearate
using a mixer.
6. Compression: Compress the granulation into tablets using a tablet pre..-.s.
7. Fihn coating: Apply an aqueous film coat to the tablets.
EXAMPLE 12
In Example 12, naltrexone beads prepared in accordance with Example 16 are .
incorporated into the sustained release 20 mg oxycodone tablets prepared in
accordance with
Example 11 and having the formula listed in Table 12 below.
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TABLE 12
Ingredients Amt/unit*
(mg)


Step 1. GranulationOxycodone HCl 20.0


Spray Dried Lactose 59.25


Povidone 5.0


Eudragit RS30D (dry) 10.0


Triacetin - 2.0


Stearyl alcohol 25.0


Talc 2.5


Magnesium 1.25


Step 2. CombinationOxyContin granulation 125
tablet (Example


Naltrexone CR beads 140
(Formula 2)


PROCESS:
1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCI, spray dried
lactose and
povidone using a fluid bed granulator.
2. Discharge the granulation and pass through a mill.
3. Melt the stearyl alcohol and add to the milled granulation using a mill.
Allow to cool.
4. Pass the cooled granulation through a mill.
5. Lubricate the granulation with talc and magnesium stearate. Using a mixer.
6. Mix naltrexone beads with the above granulation and compress into tablets.
ALTERNATE PROCESS:
1. Spray the Eudragit/triacetin dispersion onto the Oxycodone HCI, spray dried
lactose and
povidone using a fluid bed granulator.
2. Discharge the granulation and pass through a mill.
3. Mix naltrexone beads (example 2) with the above granulation in a Hobar
mixer.
4. Melt the stearyl alcohol and add to the above mixture. Allow to cool.
5. Pass the cooled granulation through a mill.
6. Lubricate the granulation with talc and magnesium stearate using a mixer.
7. Compress into tablets.
Releasable naltrexone can be a) overcoated onto the pellets by e.g., including
it in an
Opadry solution, b) modifying the sequestered component to release the desired
naltrexone,
c) including the naltrexone with the opioid agonist; or included in any
otl::,r method known in
the art. The amount of naltrexone should be in an amount to have a desired
pharmacological
effect as disclosed herein and can be immediate or sustained release.
One or more aversive agents as described herein can be incorporated into the
oxycodone tablets by one skilled in the art. The one or more aversive agents
may be in
releasable, non-releasable, or substantially non-releasable form or a
combination thereof
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EXAMPLE 13
Controlled Release Hydrocodone
A sustained release hydrocodone formulation was prepared having the formula in
Table 13 below.
TABLE 13
Ingredients Amt/Unit Amt/Batch
(mg) (g)


Hydrocodone Bitartrate15.0 320.0


Eudragit RSPO 76.0 1520.0


Eudragit RLPO 4.0 80.0


Stearyl Alcohol 25.0 500.0


Total 120.0 2400.0


PROCESS:
1. Blend milled Stearyl Alcohol, Eudragit RLPO, Hydrocodone Bitartrate, and
Eudragit
RSPO using a Hobart Mixer.
2. Extrude the granulation using a Powder Feeder, Melt Extruder(equipped with
the 6 x 1
mm die head), Conveyor, Lasermike, and Pelletizer.
Powder feed rate-40g/min; vacuum-980 mBar
Conveyor-such that diameter of extrudate is lmm
Pelletizer-such that pellets are cut to lmm in length
3. Screen pellets using #16 mesh and #20 mesh screens. Collect material that
passes
through the #16 mesh screen and is retained on the #20 mesh screen.
4. . Fill size #2 clear gelatin capsules with the pellets. Range: NLT (not
less than) 114 mg
and NMT (not more than) 126 mg.
The sequestered naltrexone formulation of Example 9 can be incorporated in a
capsule with the hydrocodone pellets. Preferably, the sequestered naltrexone
pellets are
indistinguishable from the hydrocodone pellets.
Releasable naltrexone can be a) overcoated onto the pellets by e.g., including
it in an
Opadry solution, b) modifying the sequestered component to release the desired
naltrexone,
c) including the naltrexone with the opioid agonist; or included in any other
method known in
the art. The amount of naltrexone should be in an amount to have a desired
pharmacological
effect as disclosed herein and can be immediate or sustained release.
One or more aversive agents as described herein can be incorporated into a
capsule
with the hydrocodone pellets, into the hydrocodone pellets, or on the
hydrocodone pellets by
one skilled in the art. The one or more aversive agents may be in releasable,
non-releasable,
58


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or substantially non-releasable form or a combination thereof. Preferably,
when pellets
comprising the aversive agents) are incorporated into the capsule they are
indistinguishable
from the hydrocodone pellets.
EXAMPLE 14
Oxycodone HCI beads
A sustained release oxycodone HCl bead fornmlation was prepared having the
formula in Table 14 below.
TABLE 14
Ingredients Amt/unit*
(mg)


Step 1. Drug layeringOxycodone HCl 10.5


Non-pareil beads (30/35 45.39
mesh)


Opadry Clear 2.5


Step 2. SustainedEudragit RS30D (dry) 7.206
release
coat


Eudragit RL30D (dry) 0.379


Triethyl citrate 1.517


Cabosil 0.379


Step 3. Seal coatOpadry Clear 1.899
(Hydrox ropylmethyl cellulose)


Cabosil 0.271


Total ' 70.0


PROCESS:
1. Dissolve oxycodone HCl and Opadry (HPMCj in water. Spray the drug solution
onto
non-pared beads in a fluid bed coater with Wurster insert.
2. Disperse Eudragit RS, Eudragit RL, triethyl citrate, and Cabosil in water.
Spray the'
dispersion onto the beads in the fluid bed coater.
3. Dissolve Opadry in water. Spray the solution onto the beads in the fluid
bed coater.
4. Cure the beads at 60°C for 24 hours.
The sequestered naltrexone formulation of Example 8 can be incorporated in a
capsule with the oxycodone beads. Preferably, the sequestered naltrexone beads
are
indistinguishable from the oxycodone beads.
Releasable naltrexone can be a) overcoated onto the pellets by e.g., including
it in an
Opadry solution, b) modifying the sequestered component to release the desired
naltrexone,
c) including the naltrexone with the opioid agonist; or included in any other
method known in
the art. The amount of naltrexone should be in an amount to have a desire.-.-3
pharmacological
effect as disclosed herein and can be immediate or sustained release.
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One or more aversive agents as described herein can be incorporated into a
capsule
with the oxycodone beads, into the oxycodone beads, or on the oxycodone beads
by one
skilled in the art. The one or more aversive agents may be in releasable, non-
releasable, or
substantially non-releasable form or a combination thereof. Preferably, when
beads
comprising the aversive agents) are incorporated into the capsule they are
indistinguishable
from the oxycodone beads.
Controlled Release,Hydromorphone
EXAMPLE 15
A sustained release hydromorphone HCl formulation was prepared having the
formula in Table 15 below:
TABLE 15
Ingredients Amt/Unit
(mg)


Hydromorphone 12.0
HCl


Eudragit RSPO ' 76.5


Ethocel 4.5


Stearic acid 27.0


Total -. I 120.0


PROCESS:
1. Blend milled Stearic acid, ethocel, Hydrocodone Bitartrate, and Eudragit
RSPO using
a V-blender.
2. Extrude the mixture using a Powder Feeder, Melt Extruder(equipped with the
6 x 1
mm die head), Conveyor, Lasermike, and Pelletizer.
Powder feed rate-4.2 kg/hr; vacuum-980 mBar
Conveyor-such that diameter of extrudate is lmm
Pelletizer-such that pellets are cut to lmm in length
3. Screen pellets using #16 mesh and #20 mesh screens. Collect material that
passes
through the #16 mesh screen and is retained on the #20 mesh screen.
4. Fill size #2 clear gelatin capsules with the pellets. Range: NLT 114 mg and
NMT 126
mg.
The sequestered naltrexone fornmlation of Example 15 can be incorporated in a
capsule with the hydromorphone pellets. Preferably, the sequestered naltrexone
pellets are
indistinguishable from the hydrocodone pellets.
Releasable naltrexone can be a) overcoated onto the pellets by e.g., including
it in an


CA 02456322 2004-02-03
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Opadry solution, b) modifying the sequestered component to release the desired
naltrexone,
c) including the naltrexone with the opioid agonist; or included in any oth
:.r method known in
the art. The amount of naltrexone should be in an amount to have a desired
pharmacological
effect as disclosed herein and can be immediate or sustained release.
One or more aversive agents as described herein can be incorporated into a
capsule
with the hydromorphone pellets, into the hydromoiphone pellets, or on the
hydromorphone
pellets by one skilled in the art. The one or more aversive agents may be in
releasable, non-
releasable, or substantially non-releasable form or a combination thereof.
Preferably, when
pellets comprising the aversive agents) are incorporated into the capsule
t'~ey are
indistinguishable from the hydromorphone pellets.
EXAMPLE 16
A 20 mg oxycodone dosage form containing naloxone as the antagonist and
multiple
deterring agents is prepared
Various deterring agents used in the previous examples are combined in one
product
to produce a tablet which could provide tampering resistance to multiple types
of abuse by
the addicts. A small amount of naloxone hydrochloride, denatonium benzoate,
and xanthan
gum are added to an oxycodone formulation during the granulation process. The
oxycodone
granulation formulation of Example 16 is listed in Table 16 below.
TABLE 16
In redients Amt/Unit m AmountBatcli m


Oxycodone HCl 20.0 209.6*


Spray Dried Lactose59.25 592.5


Povidone 5.0 50.0


Eiidragit RS30D 10.0 100
(solids)


Triacetin 2.0 20.0


Naloxone HCl 0.61 6.12**


Denatonium benzoate0.07 0.68 .


Xanthan gum 9.0 90.0


Stearyl Alcohol 25.0 250.0


Talc 2.5 25.0


Ma esium Stearate 1,25 12.5
.


Opadry Pink Y-S-14518A~ ~ 5.0 50.0


*adjusted for 99.6% assay and 4.2% residual moisture.
**adjusted for 99.23% assay and 0.5% residual moisture.
61


CA 02456322 2004-02-03
WO 03/013479 PCT/US02/24934
Process
Dispersion: Dissolve naloxone HCl and denatonium benzoate in water and the
solution is
added to the Eudragit/Tracetin dispersion.
Granulation: Spray the Eudragit/Triacetin dispersion onto the Oxycodone HCl,
Spray Dried
Lactose, xanthan gum and Povidone using a fluid bed granulator.
Milling: Discharge the granulation and pass through a mill.
Waxing: Melt the stearyl alcohol and add to the milled granulation using a
mixer. Allow to
cool.
Milling: Pass the cooled granulation through a mill.
Lubrication: Lubricate the granulation with talc and magnesium stearate using
a mixer.
Compression: Compress the granulation into tablets using a tablet press.
EXAMPLE 17-20
Examples 4-7 can be repeated utilizing a sufficient amount of capsaicin in
place of,
or in addition to the aversive agents disclosed therein.
While the invention has been described and illustrated with reference to
certain
preferred embodiments thereof, those skilled in the art will appreciate that
obvious
modifications can be made herein without departing from the spirit and scope
of the
invention. Such variations are contemplated to be within the scope of the
appended claims.
62

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Admin Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2002-08-06
(87) PCT Publication Date 2003-02-20
(85) National Entry 2004-02-03
Examination Requested 2004-02-03
Dead Application 2007-08-06

Abandonment History

Abandonment Date Reason Reinstatement Date
2006-08-07 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $800.00 2004-02-03
Filing $400.00 2004-02-03
Registration of Documents $100.00 2004-07-09
Registration of Documents $100.00 2004-07-09
Maintenance Fee - Application - New Act 2 2004-08-06 $100.00 2004-07-28
Maintenance Fee - Application - New Act 3 2005-08-08 $100.00 2005-04-27
Current owners on record shown in alphabetical order.
Current Owners on Record
EURO-CELTIQUE, S.A.
Past owners on record shown in alphabetical order.
Past Owners on Record
BREDER, CHRISTOPHER
COLUCCI, ROBERT
OSHLACK, BENJAMIN
SACKLER, RICHARD
WRIGHT, CURTIS
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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