Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
Controlled Release Formulations of Opioids
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. provisional application Serial No.
61/386,277,
filed September 24, 2010, and to U.S. application Serial No. 13/024,319, filed
February 9,
2011, the entirety of both which is incorporated herein by reference.
FIELD OF THE INVENTION
The invention is directed to pharmaceutical formulations comprising opioid
components that each has a release profile. The components may provide
immediate or
controlled release of the opioid. The invention is also directed to methods of
controlling
release of one or more opioid compounds and methods of treating pain.
BACKGROUND OF THE INVENTION
Opioids are a class of pain-relieving prescription medications frequently used
in the
treatment of a variety of acute and chronic, moderate to severe, pain.
However, opioids can
be rapidly absorbed and systemically excreted by the body through metabolic
inactivation. In
order to treat patients, especially those in severe pain, administration of
opioids often requires
careful dosing at frequent intervals to maintain effective steady state blood
levels of the
opioid, and thereby provide consistent analgesia. Otherwise, blood levels of
the opioid can
oscillate, resulting in poor and inconsistent pain relief
These difficulties associated with the administration of opioids suggests a
need to
develop an opioid therapy that can, following administration, maintain
consistent levels of
opioid in the blood and avoid oscillations in pain relief
SUMMARY OF THE INVENTION
The invention relates to pharmaceutical formulations for treating pain that
comprise
components containing opioid compounds and having different release profiles.
The
invention also relates to methods of controlling release of one or more opioid
compounds and
methods of treating pain.
The pharmaceutical formulations of the invention may comprise one or more
components having one or more release profiles, in which at least one of the
components
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comprise a compound having opioid receptor agonist activity. In embodiments
wherein there
is more than one component, the components may have the same release profile,
or the
components may have different release profiles.
In some embodiments, the compounds having opioid receptor agonist activity may
have agonist activity toward the mu ("pt.," morphine receptor), sigma ("cy,"
the phencyclidine
receptor), kappa ("K," the ketocyclazocine receptor) or delta ("6," the
endorphinlenkephalin
receptor) opioid receptors. Such compounds may include, among others,
morphine, codeine,
hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,
oxymorphone,
mixtures thereof, or salts thereof In certain embodiments, a component may
comprise two
opioid compounds in varying ratios. In particular embodiments, a component may
comprise
morphine and oxycodone, or salts thereof, in about a 3:2 ratio by weight.
In some embodiments, the components may have an immediate release profile or a
controlled release profile.
In certain embodiments, the formulation may comprise one or more additional
components, such as at least two, at least three, at least four, or at least
five components. In
some embodiments, the one or more additional components may comprise one or
more active
agents. In some embodiments, the one or more active agents may be compounds
having
opioid receptor agonist activity. In some embodiments, the one or more active
agents may be
one or more non-opioid analgesic compound(s), or a mixture of one or more non-
opioid
analgesic compound(s) and one or more compound(s) with opioid receptor agonist
activity,
or pharmaceutically acceptable salts, esters or prodrugs thereof In certain
embodiments, the
one or more active agents may be one or more hybrid opioid compound(s), or a
mixture of
one or more hybrid opioid compound(s) and one or more compound(s) with opioid
receptor
agonist activity, or pharmaceutically acceptable salts, esters or prodrugs
thereof
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components, wherein at least one of the opioid components is a
controlled
release opioid component that comprises an opioid. In certain embodiments, the
opioid is
selected from the group consisting of morphine, codeine, hydromorphone,
hydrocodone,
oxycodone, dihydrocodeine, dihydromorphine, oxymorphone, mixtures thereof, and
salts
thereof In particular embodiments, the opioid is oxycodone or a salt thereof
In certain embodiments, the pharmaceutical formulation provides a time to
maximum
opioid plasma concentration (Tmax) of about 4.5 to about 8 hours after
repeated
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administration. In particular embodiments, Tmax is about 5 to about 6 hours,
or about 6 hours,
after repeated administration.
In some embodiments, the controlled release component provides a time to
minimum
oxycodone plasma concentration (Tõõ.) of about 13 to about 16 hours after
repeated
administration. In particular embodiments, T. is about 14 hours after repeated
administration. In some embodiments, the repeated administration is through
steady-state
conditions.
In some embodiments, dissolution of the pharmaceutical formulation releases
about 0
to about 20 % of the opioid after two hours, or releases about 15 to about 60
% of the opioid
after four hours, or releases about 25 to about 80 % of the opioid after six
hours, or releases
about 35 to about 85 % of the opioid after eight hours, or releases about 45
to about 95 % of
the opioid after ten hours, or releases about 60 to about 100 % of the opioid
after twelve
hours, as measured in a USP type I apparatus at 37 C in water at 50 rpm.
In certain embodiments, when the pharmaceutical formulation comprises about 2
mg
of opioid, the pharmaceutical formulation may provide a mean maximum plasma
concentration (Cmax) of about 1 to about 3 ng/mL, or about 2 ng/mL, after
repeated
administration. In some embodiments, the repeated administration may be
through steady-
state conditions. In certain embodiments, the area-under-the-curve for between
about 0 and
about 24 hours (AUC24) may be about 14.7 ng=hr/mL to about 23.0 ng=hr/mL, or
about 15.8
ng=hr/mL to about 21.0 ng=hr/mL, or about 17.1 ng=hr/mL to about 19.7
ng=hr/mL, after single
administration.
In certain embodiments, when the pharmaceutical formulation comprises about 5
mg
of opioid, the pharmaceutical formulation may provide a mean Cmax of about 3
to about 7
ng/mL, or about 5 ng/mL, after repeated administration. In some embodiments,
the repeated
administration may be through steady-state conditions. In certain embodiments,
the AUC24
may be about 40.2 ng=hr/mL to about 62.8 ng=hr/mL, or about 43.2 ng=hr/mL to
about 57.2
ng=hr/mL, or about 46.7 ng=hr/mL to about 53.7 ng=hr/mL, after single
administration.
In certain embodiments, when the pharmaceutical formulation comprises about 10
mg
of opioid, the pharmaceutical formulation may provide a mean Cmax of about 5
to about 15
ng/mL, or about 10 ng/mL, after repeated administration. In some embodiments,
the repeated
administration may be through steady-state conditions. In certain embodiments,
the AUC24
may be about 80.5 ng=hr/mL to about 125.9 ng=hr/mL, or about 86.6 ng=hr/mL to
about 114.8
ng=hr/mL, or about 93.7 ng=hr/mL to about 107.7 ng=hr/mL, after single
administration.
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In certain embodiments, when the pharmaceutical formulation comprises about 20
mg
of opioid, the pharmaceutical formulation may provide a mean Cmax of about 10
to about 30
ng/mL, or about 20 ng/mL, after repeated administration. In some embodiments,
the repeated
administration may be through steady-state conditions. In certain embodiments,
the AUC24
may be about 166.0 ng=hr/mL to about 259.3 ng=hr/mL, or about 178.5 ng=hr/mL
to about
236.6 ng=hr/mL, or about 193.0 ng=hr/mL to about 222.0 ng=hr/mL, after single
administration.
In certain embodiments, when the pharmaceutical formulation comprises about 40
mg
of opioid, the pharmaceutical formulation may provide a mean Cmax of about 25
to about 55
ng/mL, or about 40 ng/mL, after repeated administration. In some embodiments,
the repeated
administration may be through steady-state conditions. In certain embodiments,
the AUC24
may be about 338.5 ng=hr/mL to about 528.9 ng=hr/mL, or about 363.9 ng=hr/mL
to about
482.3 ng=hr/mL, or about 393.5 ng=hr/mL to about 452.7 ng=hr/mL, after single
administration.
In certain embodiments, when the pharmaceutical formulation comprises about 80
mg
of opioid, the pharmaceutical formulation may provide a mean Cmax of about 50
to about 110
ng/mL, or about 80 ng/mL, after repeated administration. In some embodiments,
the repeated
administration may be through steady-state conditions. In certain embodiments,
the AUC24
may be about 868.4 ng=hr/mL to about 1356.9 ng=hr/mL, or about 933.5 ng=hr/mL
to about
1237.5 ng=hr/mL, or about 1009.5 ng=hr/mL to about 1161.5 ng=hr/mL, after
single
administration.
In some embodiments, the pharmaceutical formulation provides a mean minimum
oxycodone plasma concentration (C.) of about 0.5 to about 40 ng/mL, or about 4
to about
15 ng/mL, after repeated administration. In some embodiments, the repeated
administration
is through steady-state conditions.
In certain embodiments, the pharmaceutical formulation comprises a second
controlled release opioid component. In some embodiments, the second
controlled release
opioid component comprises an opioid selected from the group consisting of
morphine,
codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,
dihydromorphine,
oxymorphone, mixtures thereof, and salts thereof
In certain embodiments, the pharmaceutical formulation comprises an immediate-
release opioid component. In some embodiments, the immediate-release opioid
component
comprises an opioid selected from the group consisting of morphine, codeine,
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hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,
oxymorphone,
mixtures thereof, and salts thereof In further embodiments, the opioid in the
immediate-
release opioid component is morphine or a salt thereof In yet further
embodiments, the total
morphine, or salt thereof, and the total oxycodone, or salt thereof, in the
formulation are in a
ratio of about 3:2, morphine or salt thereof to oxycodone or salt thereof, by
weight.
In certain embodiments, the pharmaceutical formulation comprises a second
opioid
component and a third opioid component, wherein: (a) the second opioid
component is an
immediate-release opioid component and comprises an opioid having K agonist
activity; and
(b) the third opioid component is a controlled release opioid component and
comprises an
opioid having mu agonist activity. In some embodiments, the opioid having K
agonist
activity is oxycodone or a salt thereof, and the opioid having IA. agonist
activity is morphine or
a salt thereof
In certain embodiments, the controlled release opioid component comprises
morphine
or a salt thereof In some embodiments, the controlled release opioid component
comprises
morphine or salt thereof and oxycodone or salt thereof in an amount of about
3:2 by weight.
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof;
pharmaceutical formulation, when containing a total dose of oxycodone, or a
salt thereof, of
about 2 mg, provides a Tmax of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 14.7
ng=hr/mL to about
23.0 ng=hr/mL, or about 15.8 ng=hr/mL to about 21.0 ng=hr/mL, or about 17.1
ng=hr/mL to
about 19.7 ng=hr/mL, after single administration. The repeated administration
may be
through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 2 mg of
oxycodone, or a salt
thereof, and has an AUC24 that is proportional to the 2 mg AUC24. In some
embodiments, the
total dose AUC24 is linearly proportional to the 2 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 2 mg, provides a Cmax of about 1 to
about 3 ng/mL,
or about 2 mg, after repeated administration. In some embodiments, the
repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
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formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
from about 2 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 2
mg Cmax. In some embodiments, the total dose Cmax is linearly proportional to
the 2 mg Cmax.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of about 2 mg, provides a T. of about 13 to about 16 hours after repeated
administration. In
some embodiments, the repeated administration is through steady-state
conditions.
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof; the
pharmaceutical formulation, when containing a total dose of oxycodone, or a
salt thereof, of
about 5 mg, provides a Tmax of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 40.2
ng=hr/mL to about
62.8 ng=hr/mL, or about 43.2 ng=hr/mL to about 57.2 ng=hr/mL, or about 46.7
ng=hr/mL to
about 53.7 ng=hr/mL, after single administration. The repeated administration
may be
through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 5 mg of
oxycodone, or a salt
thereof, and has an AUC24 that is proportional to the 5 mg AUC24. In some
embodiments, the
total dose AUC24 is linearly proportional to the 5 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 5 mg, provides a Cmax of about 3 to
about 7 ng/mL,
or about 5 ng/mL, after repeated administration. In some embodiments, the
repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
from about 5 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 5
mg Cmax. In some embodiments, the total dose Cmax is linearly proportional to
the 5 mg Cmax.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 5 mg, provides a T. of about 13 to
about 16 hours
after repeated administration. In some embodiments, the repeated
administration is through
steady-state conditions.
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
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components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof; the
pharmaceutical formulation, when containing a total dose of oxycodone, or a
salt thereof, of
about 10 mg, provides a T. of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 80.5
ng=hr/mL to about
125.9 ng=hr/mL, or about 86.6 ng=hr/mL to about 114.8 ng=hr/mL, or about 93.7
ng=hr/mL to
about 107.7 ng=hr/mL, after single administration. The repeated administration
may be
through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 10 mg of
oxycodone, or a salt
thereof, and has an AUC24 that is proportional to the 10 mg AUC24. In some
embodiments,
the total dose AUC24 is linearly proportional to the 10 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 10 mg, provides a Cmax of about 5 to
about 15
ng/mL, or about 10 ng/mL, after repeated administration. In some embodiments,
the repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
from about 10 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 10
mg Cmax. In some embodiments, the total dose C. is linearly proportional to
the 10 mg
C.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 10 mg, provides a Tõõ. of about 13
to about 16 hours
after repeated administration. In some embodiments, the repeated
administration is through
steady-state conditions.
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof; the
pharmaceutical formulation, when containing a total dose of oxycodone, or a
salt thereof, of
about 20 mg, provides a T. of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 166.0
ng=hr/mL to about
259.3 ng=hr/mL, or about 178.5 ng=hr/mL to about 236.6 ng=hr/mL, or about
193.0 ng=hr/mL
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to about 222.0 ng=hr/mL, after single administration. The repeated
administration may be
through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 20 mg of
oxycodone, or a salt
thereof, and has an AUC24 that is proportional to the 20 mg AUC24. In some
embodiments,
the total dose AUC24 is linearly proportional to the 20 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 20 mg, provides a Cmax of about 10
to about 30
ng/mL, or about 20 ng/mL, after repeated administration. In some embodiments,
the repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
from about 20 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 20
mg Cmax. In some embodiments, the total dose Cmax is linearly proportional to
the 20 mg
Cmax=
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 20 mg, provides a Tnun of about 8
hours after
repeated administration. In some embodiments, the repeated administration is
through
steady-state conditions. In some embodiments, the pharmaceutical formulation
is formulated
for a total dose different from about 20 mg of oxycodone, or a salt thereof,
and having a Cmin
proportional to the 20 mg Cm,.. In some embodiments, the total dose C., is
linearly
proportional to the 20 mg C..
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof; the
pharmaceutical formulationõ when containing a total dose of oxycodone, or a
salt thereof, of
about 40 mg, provides a T. of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 338.5
ng=hr/mL to about
528.9 ng=hr/mL, or about 363.9 ng=hr/mL to about 482.3 ng=hr/mL, or about
393.5 ng=hr/mL
to about 452.7 ng=hr/mL, after single administration. The repeated
administration may be
through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 40 mg of
oxycodone, or a salt
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thereof, and has an AUC24 that is proportional to the 40 mg AUC24. In some
embodiments,
the total dose AUC24 is linearly proportional to the 40 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 40 mg, provides a Cmax of about 25
to about 55
ng/mL, or about 40 ng/mL, after repeated administration. In some embodiments,
the repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
from about 40 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 40
mg Cmax. In some embodiments, the total dose Cmax is linearly proportional to
the 40 mg
C.=
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 40 mg, provides a Tõõ. of about 13
to about 16 hours
after repeated administration. In some embodiments, the repeated
administration is through
steady-state conditions.
In embodiments of the invention, the pharmaceutical formulation may comprise
one
or more opioid components for humans in need thereof, such that the one or
more opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising oxycodone or a salt
thereof; the
pharmaceutical formulation, when containing a total dose of oxycodone, or a
salt thereof, of
about 80 mg, provides a Tmax of about 4.5 to about 7.5 hours, or about 5 to
about 6 hours, or
about 6 hours, after repeated administration, and an AUC24 of about 868.4
ng=hr/mL to about
1356.9 ng=hr/mL, or about 933.5 ng=hr/mL to about 1237.5 ng=hr/mL, or about
1009.5
ng=hr/mL to about 1161.5 ng=hr/mL, after single administration. The repeated
administration
may be through steady-state conditions.
In certain embodiments, the pharmaceutical formulation is formulated for a
total dose
of oxycodone, or a salt thereof, that is different from about 80 mg of
oxycodone, or a salt
thereof, and has an AUC24 that is proportional to the 80 mg AUC24. In some
embodiments,
the total dose AUC24 is linearly proportional to the 80 mg AUC24.
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 80 mg, provides a Cmax of about 50
to about 110
ng/mL, or about 80 ng/mL, after repeated administration. In some embodiments,
the repeated
administration is through steady-state conditions. In some embodiments, the
pharmaceutical
formulation is formulated for a total dose of oxycodone, or a salt thereof,
that is different
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from about 80 mg of oxycodone, or a salt thereof, and has a Cmax that is
proportional to the 80
mg Cmax. In some embodiments, the total dose Cmax is linearly proportional to
the 80 mg
Cmax=
In certain embodiments, the pharmaceutical formulation, when containing a
total dose
of oxycodone, or a salt thereof, of about 80 mg, provides a Tmm of about 13 to
about 16 hours
after repeated administration. In some embodiments, the repeated
administration is through
steady-state conditions.
The method for controlling release of one or more compounds having opioid
receptor
agonist activity for absorption in a human comprises administering a
pharmaceutical
formulation comprising one or more components, such that the one or more
opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising an opioid. In certain
embodiments, the
pharmaceutical formulation administered to the human is in accordance to the
pharmaceutical
formulations of the invention.
The method of treating pain in a human comprises administering a
pharmaceutical
formulation comprising one or more components, such that the one or more
opioid
components comprise one or more release profiles, and at least one of the
opioid components
is a controlled release opioid component comprising an opioid. In certain
embodiments, the
pharmaceutical formulation administered to the human is in accordance to the
pharmaceutical
formulations of the invention.
BRIEF DESCRIPTION OF DRAWINGS
FIG. la and lb provide schematic images of two embodiments of opioid
formulations
of the present invention.
FIG. 2 provides a target release profile for oxycodone coated pellets used in
the
opioid formulations of the present invention.
FIG. 3 provides a target release profile for morphine coated pellets used in
the opioid
formulations of the present invention.
FIG. 4 provides a target release profile for oxycodone granulation coated with
Eudragit L30D-55 used in the opioid formulations of the present invention.
FIG. 5 provides a target release profile for total oxycodone release in the
opioid
formulations of the present invention.
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FIG. 6 provides a target release profile for total oxycodone and morphine
release used
in the dual-opioid coated tablets of the present invention.
FIG. 7 provides a schematic demonstrating the methods used in producing the
oxycodone granules used in the present invention.
FIG. 8 provides a schematic demonstrating the methods used in producing the
oxycodone core pellets used in the present invention.
FIG. 9 provides a schematic demonstrating the methods used in producing the
morphine core pellets used in the present invention.
FIG. 10 provides a schematic demonstrating the methods used in coating the
either
morphine or oxycodone core pellets used in the present invention.
FIG. 11 provides a schematic demonstrating the methods used in producing the
dual
opioid coated tablets used in the present invention.
FIG. 12 provides a flow diagram for preparing extended release intermediate
oxycodone pellets used in the clinical study (Example 2).
FIG. 13 provides an oxycodone plasma concentration profile of two opioid
formulations of the present invention (Formulation A and Formulation B) and a
Reference
Formulation (MS Contin 30 mg (morphine CR) co-administered with OxyContin 20
mg
(oxycodone CR)) through 72 hours after treatment.
FIG. 14 provides an oxycodone plasma concentration profile of two opioid
formulations of the present invention (Formulation A and Formulation B) and a
Reference
Formulation (MS Contin 30 mg (morphine CR) co-administered with OxyContin 20
mg
(oxycodone CR)) through 24 hours after treatment.
FIG. 15 provides a projected oxycodone plasma profile from administration of
multiple doses at 12 hour intervals of an opioid formulation of the present
invention.
FIG. 16 provides a projected oxycodone plasma profile from administration of
multiple doses of an opioid formulation of the present invention having
different dosing
strengths.
FIG. 17 provides a projected oxycodone plasma profile from administration of
multiple doses at 12 hour intervals of an opioid composite formulation
(immediate release +
controlled release) of the present invention.
FIG. 18 provides a projected oxycodone plasma profile from administration of
multiple doses of an opioid composite formulation (immediate release +
controlled release) of
the present invention having different dosing strengths.
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FIG. 19 provides a release profile of morphine sulfate from coated beadlets
containing
morphine sulfate and oxycodone hydrochloride using Ammonio Methacrylate
Copolymer
Type B (RS) and Type A (RL) coating ratios of (a) RS/RL = 90/10 and (b)
RS/RL=80/20, at
various % coating levels.
FIG. 20 provides a release profile of oxycodone hydrochloride from coated
beadlets
containing morphine sulfate and oxycodone hydrochloride using Ammonio
Methacrylate
Copolymer Type B (RS) and Type A (RL) coating ratios of (a) RS/RL = 90/10 and
(b)
RS/RL=80/20, at various % coating levels.
FIG. 21 provides a release profile of morphine sulfate in enteric coated
tablets (using
50 % coated beadlets of Ammonio Methacrylate Copolymer Type B (RS) and Type A
(RL)
in a ratio of 90/10) at various % enteric coating levels.
FIG. 22 provides a release profile of oxycodone hydrochloride in enteric
coated
tablets (using 50 % coated beadlets of Ammonio Methacrylate Copolymer Type B
(RS) and
Type A (RL) in a ratio of 90/10) at various % enteric coating levels.
FIG. 23 provides a release profile for morphine sulfate in enteric coated
tablets (10 %
and 15 % coating level) at low, mid or high hardness levels.
FIG. 24 provides a release profile for oxycodone hydrochloride in enteric
coated
tablets (10 % and 15 % coating level) at low, mid or high hardness levels.
FIG. 25 provides a release profile of oxycodone hydrochloride from coated
beadlets
containing oxycodone hydrochloride using Ammonio Methacrylate Copolymer Type B
(RS)
and Type A (RL) coating ratios of RS/RL = 85/15 at various % coating levels.
FIG. 26 provides a release profile of oxycodone hydrochloride from coated
beadlets
containing oxycodone hydrochloride using Ammonio Methacrylate Copolymer Type B
(RS)
and Type A (RL) coating ratios of RS/RL = 80/20 at various % coating levels.
FIG. 27 provides a release profile of oxycodone hydrochloride from coated
beadlets
containing oxycodone hydrochloride using Ammonio Methacrylate Copolymer Type B
(RS)
and Type A (RL) coating ratios of RS/RL = 80/20 and RS/RL = 85/15 at various %
coating
levels.
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DETAILED DESCRIPTION OF THE INVENTION
The invention relates to pharmaceutical formulations and methods for the
alleviation
of acute or chronic pain by controlling the release of compounds having opioid
agonist
activity for absorption in humans. The pharmaceutical formulations and methods
of the
invention may provide effective analgesia to a patient while reducing or
eliminating
undesired side effects typically experienced with the administration of opioid
analgesic
compounds. Due to the controlled release of the compound (s), it is possible
to obtain a
substantially constant rate of release of the compound(s) over a specific
period of time,
corresponding to the dosage necessary for the treatment in question, so that
adherence to a
strict dosage regimen, e.g. requiring administration of a drug at set
intervals up to several
times a day, may be dispensed with.
One aspect of the invention relates to pharmaceutical formulations comprising
one or
more components having one or more release profiles, such that at least one of
the
components comprises a compound having opioid receptor agonist activity and
has a
controlled release profile. Another aspect of the invention relates to the
administration of the
pharmaceutical formulations of the invention to humans in need thereof
The formulations and methods described herein are used to treat different
types of
pain, including neuropathic pain and nociceptive pain, somatic pain and
visceral pain. In
various embodiments, formulations and methods described herein are used to
treat diabetic
neuropathy, trigeminal neuralgia, postherpetic zoster pain, and thalamic pain
syndrome (a
central pain). Neuropathic pain frequently coexists with nociceptive pain, and
the inventive
compounds and salts may be used to treat mixed pain states, i.e. a combination
of neuropathic
and nociceptive pain. For example, trauma that damages tissue and nerves,
burns (that burn
skin as well as nerve endings), and external nerve compression may cause both
neuropathic
and nociceptive pain. Examples of external nerve compression include tumor
nerve
compression and sciatica from herniated discs pressing on nerves. In other
embodiments, the
formulations and methods are used to treat low back pain, cancer pain,
osteoarthritis pain,
fibromyalgia pain and postoperative pain. In various other embodiments, the
formulations
and methods are used to treat pain associated with inflammation, bone pain,
and joint disease.
The formulations and methods of the invention may be used to treat pain caused
by a variety
of conditions, including, but not limited to, pain after surgery or trauma,
pain associated with
a medical illness and the like.
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The present invention encompasses formulations that can be administered to
provide
two opioids. An objective of the present invention is to activate certain
opioid receptors in
the brain by one opioid, and stage the arrival of a second opioid at some
timepoint after that
receptor is occupied by the first opioid. A dual-opioid extended-release
tablet is designed to
accomplish this. For example, in formulations that contain oxycodone and
morphine, there is
a need to delay the release of morphine until the oxycodone is at the receptor
by at least one-
half hour, and preferably more than one hour. There is also a need to re-
supply oxycodone
for uptake into the brain at roughly the same rate of elimination from the CNS
compartment.
It is anticipated that both the delay and the rate of release of oxycodone
should approximate
one another in the delayed, modified-release pellet components described
herein as well as
formulations that incorporate the pellets such as, but not limited to, tablets
and capsules.
Compounds Having Opioid Receptor Agonist Activity
The components of the pharmaceutical formulations may comprise a compound
having opioid receptor agonist activity. Such compounds may have agonist
activity toward
the -, K-, cy-, or 6-opioid receptors, including other classified receptor
subtypes. The
compounds having opioid receptor agonist activity may be naturally occurring,
semi-
synthetic or fully synthetic opiate compounds, derivatives or analogs thereof,
or
pharmaceutically acceptable salts, esters or prodrugs thereof Naturally
occurring opiates are
alkaloid compounds that are found in the resin of the opium poppy, and include
morphine,
codeine and thebaine. Semi-synthetic or fully synthetic opiates include, but
are not limited
to, dihydromorphine, heterocodeine, dihydrocodeine, dihydrornorphinone,
dihydrocodeinone,
3,6-diacetyl morphine, morphinone, 6-desoxymorphine, heroin, oxymorphone,
oxycodone, 6-
methylene-dihydromorphine, hydrocodone, etorphine, bupemorphine, naloxone or
naltrexone.
Compounds having u-opioid receptor agonist activity may include, but are not
limited
to, morphine (and structurally related analogs and derivatives), alvimopan,
buprenorphine,
codeine, 6-desomorphine, dihydromorphine, dihydromorphinone, dihydrocodeine,
dihydrocodeinone, 3,6-diacetylmorphine, 6-methylene-dihydromorphine,
diphenoxylate,
drotebanol, eseroline, etorphine, fentanyl, hydrocodone, levophenacylmorphan,
methadone,
oxymorphone, nicomorphine, pethidine, picenadol, tapentadole, thebaine, and
trimebutane.
Compounds having k-opioid receptor agonist activity may include, but are not
limited
to, asimadoline, butorphanol, bremazocine, cyclazocine, dextromethorphan,
dynorphin,
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enadoline, ketazocine, nalbuphine, nalfurafine, norbuprenorphine, oxycodone,
pentazocine,
salvinorin A, 2-methoxymethyl salvinorin B and its ethoxymethyl and
fluoroethoxymethyl
homologues, spiradoline, and tifluadom.
Compounds having 6-opioid receptor agonist activity may include, but are not
limited
to, deltorphin, ethoxymetopon, leu-enkephalin, met-enkephalin, mitragyna
speciosa (kratom),
mitragynine, mitragynine-pseudoindoxyl, N-phenethyl-14- norbuprenorphine,
norclozapine,
and 7-spiroindanyloxymorphone.
In certain embodiments, the compound is selected from morphine, codeine,
hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,
oxymorphone,
mixtures thereof, and pharmaceutically acceptable salts thereof
Salts include, but are not limited to, hydrochloride, sulfate, bisulfate,
tartrate, nitrate,
citrate, bitratrate, phosphate, malate, maleate, hydrobromide, hydroiodide,
fumarate,
succinate and the like.
The components of the pharmaceutical formulations may contain more than one
compound, such that the more than one compound is present in a ratio by
weight. For
example, the components may comprise two compounds, such that the compounds
are
present in a 2:1, 2:2, 2:3, 2:5, 3:1, or 3:4 weight ratio.
In particular embodiments, the compounds are morphine and oxycodone, or
pharmaceutical salts thereof, in ratio of about 3:2 by weight. Pharmaceutical
formulations
comprising compounds that contain morphine and oxycodone, or pharmaceutical
salts
thereof, in ratio of about 3:2 by weight, can administer up to a total amount
of 18 mg
morphine and 12 mg oxycodone per dosage. In some embodiments, pharmaceutical
formulations comprising compounds that contain morphine and oxycodone, or
pharmaceutical salts thereof, in ratio of about 3:2 by weight, can administer
up to an amount
of about 600 mg morphine, or pharmaceutical salts thereof, and about 400 mg
oxycodone, or
pharmaceutical salts thereof, per day.
Release Profiles and Characteristics of the Components
At least one of the components in the pharmaceutical formulations comprises a
compound having opioid receptor agonist activity and has a controlled release
profile.
The formulations may comprise additional components, wherein the additional
components may have an immediate release profile or a controlled release
profile for the
compound.
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The term "immediate release" as used herein refers to a release profile in
which there
is substantially no delay in the release of the compound for absorption.
The term "controlled release" as used herein refers to a release profile in
which there
is a modification in the release of the compound as compared to an immediate
release profile.
Types of controlled release profiles include delayed release, extended
release, and pulsatile
release profiles.
The term "delayed release" as used herein refers to a release profile in which
there is a
delay in the release of the compound for absorption.
The term "extended release" as used herein refers to a release profile in
which the
active compound is released at such a rate that blood levels are maintained
within the
therapeutic range, but below toxic levels, over a period of time of about 8
hours, or about 10
hours, or about 12 hours, or about 15 hours, or about 20 hours, or about 24
hours or about 30
hours, or about 35 hours, or even longer. The term "extended release"
differentiates release
profile in accordance with the invention from "immediate release" and "delayed
release"
release profiles. As used herein, "delayed-extended release" refers to release
profiles in
which release of the active compound is delayed, but is still extended greater
than
"immediate release" release profiles.
The term "pulsatile release" as used herein refers to a release profile in
which the
compound is released at intervals for absorption.
Immediate Release Component
The immediate release component may provide about 1 % to about 50 % of the
total
dosage of the compound(s) to be delivered by the pharmaceutical formulation.
For example,
the immediate release component may provide at least about 5 %, or about 10 %
to about 30
%, or about 45 % to about 50 % of the total dosage of the compound(s) to be
delivered by the
formulation. In alternate embodiments, the immediate release component
provides about 2,
4, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 % of the total dosage of the
compound(s) to be
delivered by the formulation.
The immediate release component may be a mixture of ingredients that breaks
down
quickly after administration to release the opioid compound. This can take the
form of, for
example, granules, particles, powders, liquids and pellets.
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Controlled Release Component
The controlled release component may provide about 30-95 % of the total dosage
of
the compound(s) to be delivered by the pharmaceutical formulation. For
example, the
immediate release component may provide about 70-90 %, or about 80 % of the
total dosage
of the compound(s) to be delivered by the pharmaceutical formulation. In
alternate
embodiments, the controlled release component provides about 30, 35, 40, 45,
50, 55, 60, 65,
70, 75, 80, 85, 90 or 95 % of the total dosage of the compound(s) to be
delivered by the
formulation.
A controlled release component may have a Tmax of about 1 to about 25 hours
following repeated or single administration, or about 20, 17, 15, 12, 11, 8,
6, 5, 4, 3, 2 or 1
hours following administration.
In certain embodiments, a controlled release component may have a T. of about
4.5
to about 8 hours after repeated administration, or about 5 to about 6 hours
after repeated
administration, or about 6 hours after repeated administration.
A controlled release component may have may have a Tflun about 10 to about 25
hours
after repeated administration, or about 12, 13, 14, 15, 16, 17, 18, 19 or 20
hours following
administration.
In certain embodiments, a controlled release component may have a Trnm of
about 13
to about 16 hours after repeated administration, or about 14 hours after
repeated
administration.
Dissolution of a controlled release component release about 0 to about 20 % of
the
compound or salt thereof after two hours, or releases about 15 to about 60 %
of the
compound or salt thereof after four hours, or releases about 25 to about 80 %
of the
compound or salt thereof after six hours, or releases about 35 to about 85 %
of the compound
or salt thereof after eight hours, or releases about 45 to about 95 % of the
compound or salt
thereof after ten hours, or releases about 60 to about 100 % of the compound
or salt thereof
after twelve hours, as measured in a USP type I apparatus at 37 C in water at
50 rpm.
A controlled release component may comprise about 2 mg to about 80 mg of the
compound. When controlled release component comprises about 2 mg, the
controlled release
component may provide a mean Cmax of about 1 to about 3 ng/mL, or about 2
ng/mL, after
repeated administration. The AUC24 may be about 14.7 ng=hr/mL to about 23.0
ng=hr/mL, or
about 15.8 ng=hr/mL to about 21.0 ng=hr/mL, or about 17.1 ng=hr/mL to about
19.7 ng=hr/mL,
after single administration.
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When a controlled release component comprises about 5 mg, the controlled
release
component may provide a mean Cmax of about 3 to about 7 ng/mL, or about 5
ng/mL, after
repeated administration. The AUC24 may be about 40.2 ng=hr/mL to about 62.8
ng=hr/mL, or
about 43.2 ng=hr/mL to about 57.2 ng=hr/mL, or about 46.7 ng=hr/mL to about
53.7 ng=hr/mL,
after single administration.
When a controlled release component comprises about 10 mg, the controlled
release
component may provide a mean Cmax of about 5 to about 15 ng/mL, or about 10
ng/mL, after
repeated administration. The AUC24 may be about 80.5 ng=hr/mL to about 125.9
ng=hr/mL,
or about 86.6 ng=hr/mL to about 114.8 ng=hr/mL, or about 93.7 ng=hr/mL to
about 107.7
ng=hr/mL, after single administration.
When a controlled release component comprises about 20 mg, the controlled
release
component may provide a mean Cmax of about 10 to about 30 ng/mL, or about 20
ng/mL,
after repeated administration. The AUC24 may be about 166.0 ng=hr/mL to about
259.3
ng=hr/mL, or about 178.5 ng=hr/mL to about 236.6 ng=hr/mL, or about 193.0
ng=hr/mL to
about 222.0 ng=hr/mL, after single administration.
When a controlled release component comprises about 40 mg, the controlled
release
component may provide a mean Cmax of about 25 to about 55 ng/mL, or about 40
ng/mL,
after repeated administration. The AUC24 may be about 338.5 ng=hr/mL to about
528.9
ng=hr/mL, or about 363.9 ng=hr/mL to about 482.3 ng=hr/mL, or about 393.5
ng=hr/mL to
about 452.7 ng=hr/mL, after single administration.
When a controlled release component comprises about 80 mg, the controlled
release
component may provide a mean Cmax of about 50 to about 110 ng/mL, or about 80
ng/mL,
after repeated administration. The AUC24 may be about 868.4 ng=hr/mL to about
1356.9
ng=hr/mL, or about 933.5 ng=hr/mL to about 1237.5 ng=hr/mL, or about 1009.5
ng=hr/mL to
about 1161.5 ng=hr/mL, after single administration.
In some embodiments, a controlled release component provides a mean Cõõ. of
about
0.5 to about 40 ng/mL, or about 4 to about 15 ng/mL, after repeated
administration.
In certain embodiments, T., Timn, mean Cmax, and Cõõ. may be determined after
repeated administrations through steady state conditions. As used herein, the
term "steady
state" means that a plasma level for a given drug has been achieved and which
is maintained
with subsequent doses of the drug at a level which is at or above the minimum
effective
therapeutic level and is below the minimum toxic plasma level for compound.
For opioid
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analgesics such as oxycodone, the minimum effective therapeutic level will be
partially
determined by the amount of pain relief achieved in a given patient. It will
be well
understood by those skilled in the medical art that pain measurement is highly
subjective and
great individual variations may occur among patients. It is clear that after
the administration
of each dose the concentration passes through a maximum and then again drops
to a
minimum.
The steady state may be described as follows: at the time t = 0, the time the
first dose
is administered, the concentration C is also 0. The concentration then passes
through a first
maximum and then drops to a first minimum. Before the concentration drops to
0, another
dose is administered, so that the second increase in concentration does not
start at 0. Building
on this first concentration minimum, the curve passes through a second maximum
after the
second dose has been administered, which is above the first maximum, and drops
to a second
minimum, which is above the first minimum. Thus, the blood plasma curve
escalates due to
the repeated doses and the associated step-by-step accumulation of active
agent, until it levels
off to a point where absorption and elimination are in balance. This state, at
which
absorption and elimination are in equilibrium and the concentration oscillates
constantly
between a defined minimum and a defined maximum, is called steady state.
Active Agents of the Components
The one or more additional components may comprise one or more active agents.
For
example, the active agents may be any of the compounds having opioid receptor
agonist
activity as discussed herein.
The active agents may also comprise one or more non-opioid analgesic
compound(s),
or a mixture of one or more non-opioid analgesic compound(s) and one or more
compound(s)
with opioid receptor agonist activity, or pharmaceutically acceptable salts,
esters or prodrugs
thereof Non-opioid analgesic compounds may act to alleviate pain by other
mechanisms not
associated with binding to an opioid receptor. For example, the non-opioid
analgesic
compound may be a non-steroidal anti-inflammatory compound (NSAID), examples
of
which can include, but are not limited to, piroxicam, lomoxicam, tenoxicam,
salicylic acid
(aspirin) and other salicylates such as diflunisal; 2-arylpropionic acids such
as ibuprofen,
carprofen, fenbufen, fenoprofen, flubiprofen, ketoprofen, ketorolac,
loxoprofen, naproxen,
oxaprozin, tiaprofenic acid and suprofen; n-arylanthranilic acids such as
metenamic acid and
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meclofenamic acid; arylalkanoic acids such as diclofenac, aceclofenac,
acemetacin, etodolac,
idomethacin, sulindac and tolmetin and the like; or mixtures thereof
The non-opioid analgesic compound may also be a COX-1 or COX-2 inhibitor
compound including, but not limited to, celecoxib (Celebrex()), etoricoxib,
lumiracoxib,
parecoxib, rofecoxib, valdecoxib, or mixtures thereof The non-opioid analgesic
may also be
a calcium channel binding agent such as gabapentin or pregabalin, or a
derivative, analog or
prodrug thereof, or mixtures thereof
In certain embodiments, the non-analgesic compound is gabapentin enacarbil
(SolziraTm), which is a prodrug of gabapentin with the chemical name 1-M[142-
Methyl-I-
oxopropoxy)ethoxy]carbonyl]amino]methyl]cyclohexaneacetic acid. The structures
of
gabapentin, pregabalin and gabapentin enacarbil are shown below:
.c:OH
NH2
(¨)CO2H NH2
gabapentin pregabalin
0 0
N 0 0
H
OCCO2H
gabapentin enacarbil
The active agents may further be one or more hybrid opioid compound(s), or a
mixture of one or more hybrid opioid compound(s) and one or more compound(s)
with opioid
receptor agonist activity, or pharmaceutically acceptable salts, esters or
prodrugs thereof
Hybrid opioid compounds are compounds formed by covalently binding together
two or more
opioid compounds with a linker component. The linker component may be stable
or may
hydrolyze under physiological conditions to provide the parent opioid
compounds. Hybrid
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opioid compounds are described in U.S. Provisional Application Serial No.
61/153,537 to
Holaday et al., filed February 18, 2009. Hybrid opioid compounds are also
described in
International Patent Application Publication No. WO 2006/073396 to Portoghese
et al.
The hybrid opioid compound may comprise two or more compounds having opioid
receptor agonist activity, linked by a covalent linker component. The hybrid
opioid
compound may also comprise a compound having opioid receptor agonist activity
linked to a
non-opioid active agent including, but not limited to, a non-opioid analgesic
compound as
described above. In some embodiments, the non-opioid active agent is
gabapentin,
pregabalin, or gabapentin enacarbil.
The hybrid opioid compound may comprise two or more opiate compounds bonded
together by a covalent linker. The opiate compounds may include, but are not
limited to, the
opiate compounds described above.
The active compounds may be bonded to the linker components by various
chemical
bonds, preferably at a position on the active agent that does not impair the
biological activity
of the active agent. Typically, the active agents may be bonded to the linker
by a reactive
group on the active compound or at a position that may be activated to react
with a linker
component.
Preparing the Components
To obtain the components of the pharmaceutical compositions described herein,
a
combination of excipients is used at appropriate concentrations to provide
properties and
desired pharmacokinetics. Excipients used in the pharmaceutical compositions
described
herein are commercially-available, and listed in either the USP or NF.
Excipients are
selected that will contribute to the function and purpose of each of the
active intermediate
components and also to the final component. One of ordinary skill will
appreciate that the
concentrations of these excipients used may be increased or decreased as
desired to increase
or decrease specific properties in a final opioid formulation. Coating
materials used herein
are also commercially-available and listed in the USP or NF which are
incorporated herein by
reference.
The technology used to produce a compound-opioid extended-release tablet
described
herein is a combination of known pharmaceutical manufacturing processes. The
unit
processes for the manufacture of each active intermediate have been used in
several
commercially-available products, and therefore are scalable. Two important
aspects in
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producing the compound-opioid extended-release tablet are in the manufacture
and
performance of the different types of delayed, modified-release pellets. In
the example of a
dual opioid oxycodone/morphine compound product, the manufacture and
performance of the
delayed, modified-release oxycodone pellets and the delayed, modified-release
morphine
pellets is similarly important. These pellets should perform the same as free-
flowing,
untableted pellets as after tablet compaction. This important feature is best
accomplished by
adequately plasticizing the coating network to avoid cracking and brittle
fracture of the
coatings when under compression during tablet compaction.
The materials to be added to the compound(s) for the immediate release
component
can be, but are not limited to, microcrystalline cellulose, com starch,
pregelatinized starch,
potato starch, rice starch, sodium carboxymethyl starch,
hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose, ethyl-cellulose,
chitosan,
hydroxychitosan, hydroxymethylated chitosan, cross-linked chitosan, cross-
linked
hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose,
fructose,
glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid
derivatives (Carbopol,
Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs
(PEG2000-10000)
and high molecular weight PEGs (Polyox) with molecular weights above 20,000
daltons. It
may be useful to have these materials present in the range of 1.0 to 60%
(W/W).
In addition, it may be useful to have other ingredients in this system to aid
in the
dissolution of the drug, or the breakdown of the component after ingestion or
administration.
These ingredients can be surfactants, such as sodium lauryl sulfate, sodium
monoglycerate,
sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
glyceryl
mono stearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-
ionic surfactants
such as the Pluronic line of surfactants, or any other material with surface
active properties,
or any combination of the above. These materials may be present in the rate of
0.05-15%
(W/W).
The materials in controlled release components are the same as the materials
in the
immediate release component, but with additional polymers integrated into the
component, or
as coatings over the pellet or granule. The kind of materials useful for this
purpose can be,
but are not limited to, ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, methylcellulose,
nitrocellulose, Eudragit R,
and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in
excess of
8,000 daltons. These materials can be present in concentrations from 4-20%
(W/W).
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In certain embodiments, components may have pH-sensitive delayed release
profiles
or non-pH sensitive delayed release profiles. Materials in the pH-sensitive
delayed release
components may be the same as the materials in the immediate release
component, but with
additional polymers integrated into the component, or as coatings over the
pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to,
cellulose acetate
pthalate, Eudragit L, and other pthalate salts of cellulose derivatives. These
materials can be
present in concentrations from 4-20% (W/W).
Materials in the pH-sensitive delayed release components may be the same as
the
materials in the immediate release component, but with additional polymers
integrated into
the component, or as coatings over the pellet or granule. The kind of
materials useful for this
purpose can be, but are not limited to, polyethylene glycol (PEG) with
molecular weight
above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax,
paraffin,
acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
Typically these
materials can be present in the range of 0.5-25% (W/W) of this component.
Pharmaceutical Formulations
The pharmaceutical formulations may comprise one or more components having one
or more release profiles. Each of the components may comprise the same
compound(s), may
comprise different compound(s), or a mixture thereof (e.g., some components
have the same
compounds, other components have different compounds, within the same
formulation). In
addition, components may comprise active agents as described herein.
For example, the formulations may comprise at least one component, such that
the
one component has a controlled release profile.
The formulations may also comprise at least two components (a first and second
component), such that each components has a different release profile. For
example, the
second of the at least two components initiates release of the compound(s)
contained therein
at least one hour after the first component, with the initiation of the
release therefrom
generally occurring no more than six hours after initiation of release of
compound(s) from the
first component.
The formulations may also comprise at least three components (a first, second,
and
third component). The first component may be an immediate release component
whereby
initiation of release of the compound(s) therefrom is not substantially
delayed after
administration of the formulation. The second and third components are
controlled release
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components, whereby the release of the compound(s) may be delayed. The
controlled release
components may be a pH sensitive or a non-pH sensitive delayed component,
depending on
the type of formulation. The compound(s) released from the delayed release
components
may be delayed until after initiation of release of the compound(s) from the
immediate
release component. For example, the compound(s) release from the second
component may
achieve a Cmax at a time after the compound(s) released from the immediate
release
component may achieve a Cmax in the serum. The compound(s) released from the
third
component may achieve a Cmax in the serum after the Cmax of the compound(s)
released from
the second component.
In certain embodiments, the immediate release component may produce a Cmax for
the
compound(s) released therefrom within from about 0.5 to about 2 hours, with
the second
component producing a Cmax for the compound(s) released therefrom in no more
than about
four hours. In general, the Cmax for such a second component may be achieved
no earlier than
two hours after administration of the formulation; however, it is possible to
achieve Cmax in a
shorter period of time by adjusting the concentration of excipients and/or
coatings described
herein to achieve a formulation with a desired pharmacokinetic profile.
In certain embodiments, release of compound(s) from the third component may be
started after initiation of release of compound(s) from both the first and
second components.
In some embodiments, Cmax for compound(s) released from the third component
may be
achieved within eight hours.
The formulations may also comprise at least four components (a first, second,
third,
and fourth component), with each of the at least four components having
different release
profiles. For example, the compound(s) released from each of the at least four
different
components may achieve a Cmax at a different time.
The formulations may also comprise at least five components (a first, second,
third,
fourth, and fifth component). The first component may be an immediate release
component
of a first compound or a first set of compounds, while the second and third
components may
be controlled release components of the first compound or a first set of
compounds. The
fourth and fifth components may be controlled release components of a second
compound or
a second set of compounds. As an example, in certain embodiments, the first
compound may
be oxycodone and the second compound may be morphine.
In certain embodiments, the formulation may be in the form of a capsule,
comprising
components that are in the form of separate tablets or pellets. Thus, for
example, an
24
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immediate release component may be in the form of a tablet or pellet, and
controlled release
components may be in the form of other tablets or pellets, each of which
provides for a
delayed release of the compound(s) contained therein, whereby the Cmax of the
compound(s)
released from each of the pellets, or tablets containing the pellets, is
reached at different
times, with the C. of the formulation being achieved in less than twelve
hours.
In certain embodiments, the pharmaceutical formulation itself will comprise a
controlled release profile. For example, Cmax for all of the compound(s)
released from the
formulation may be achieved in about 20, 17, 15, 12, 11, 8, 6, 5, 4, 3, 2 or 1
hours following
administration of the formulation. In some embodiments, Cmax may be achieved
in less than
2, 1 or 0.5 hours following administration of the formulations. In other
embodiments, Cmax
may be achieved in greater than 4.5, 5, 6, 7, 8, 9, or 10 hours following
administration of the
component.
The formulation may have a Tmax of about 1 to about 25 hours following
repeated or
single administration, or about 20, 17, 15, 12, 11, 8, 6, 5, 4, 3, 2 or 1
hours following
administration.
In certain embodiments, Tmax may be about 4.5 to about 8 hours, or about 5 to
about 6
hours, or about 6 hours, after repeated administration. In some embodiments,
the repeated
administration is under steady state conditions.
The formulation may comprise about 1 mg to about 100 mg of the compounds(s),
or
may comprise about 2 mg to about 80 mg of the compound(s). When the
formulation
comprises about 2 mg, the controlled release component may provide a mean Cmax
of about 1
to about 3 ng/mL, or about 2 ng/mL, after repeated administration. The AUC24
may be about
14.7 ng=hr/mL to about 23.0 ng=hr/mL, or about 15.8 ng=hr/mL to about 21.0
ng=hr/mL, or
about 17.1 ng=hr/mL to about 19.7 ng=hr/mL, after single administration.
When the formulation comprises about 5 mg, the controlled release component
may
provide a mean Cmax of about 3 to about 7 ng/mL, or about 5 ng/mL, after
repeated
administration. The AUC24 may be about 40.2 ng=hr/mL to about 62.8 ng=hr/mL,
or about
43.2 ng=hr/mL to about 57.2 ng=hr/mL, or about 46.7 ng=hr/mL to about 53.7
ng=hr/mL, after
single administration.
When the formulation comprises about 10 mg, the controlled release component
may
provide a mean Cmax of about 5 to about 15 ng/mL, or about 10 ng/mL, after
repeated
administration. The AUC24 may be about 80.5 ng=hr/mL to about 125.9 ng=hr/mL,
or about
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86.6 ng=hr/mL to about 114.8 ng=hr/mL, or about 93.7 ng=hr/mL to about 107.7
ng=hr/mL,
after single administration.
When the formulation comprises about 20 mg, the controlled release component
may
provide a mean Cmax of about 10 to about 30 ng/mL, or about 20 ng/mL, after
repeated
administration. The AUC24 may be about 166.0 ng=hr/mL to about 259.3 ng=hr/mL,
or about
178.5 ng=hr/mL to about 236.6 ng=hr/mL, or about 193.0 ng=hr/mL to about 222.0
ng=hr/mL,
after single administration.
When the formulation comprises about 40 mg, the controlled release component
may
provide a mean Cmax of about 25 to about 55 ng/mL, or about 40 ng/mL, after
repeated
administration. The AUC24 may be about 338.5 ng=hr/mL to about 528.9 ng=hr/mL,
or about
363.9 ng=hr/mL to about 482.3 ng=hr/mL, or about 393.5 ng=hr/mL to about 452.7
ng=hr/mL,
after single administration.
When the formulation comprises about 80 mg, the controlled release component
may
provide a mean Cmax of about 50 to about 110 ng/mL, or about 80 ng/mL, after
repeated
administration. The AUC24 may be about 868.4 ng=hr/mL to about 1356.9
ng=hr/mL, or about
933.5 ng=hr/mL to about 1237.5 ng=hr/mL, or about 1009.5 ng=hr/mL to about
1161.5
ng=hr/mL, after single administration.
In certain embodiments, Cõ,õ may occur within about 12 to about 18 hours
following
administration of the component during steady-state conditions. In some
embodiments, Cnun
may occur at about 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours following
administration of the
formulation. In some embodiments, Cnun may occur less than about 10, 9, 8, 7,
6, 5, or 4
hours following administration of the formulation. In some embodiments, Cmin
may occur at
greater than about 14, 15, 16, 17, 18, 19, or 20 hours following
administration of the
formulation. In particular embodiments, the Cõ,õ that occurs more than about
12 hours after
administration, may occur up to about 1, 2, 3, or 4 hours after the
administration of a
formulation that has not yet been absorbed into the bloodstream.
The certain embodiments, the formulation may have a Tmin about 10 to about 25
hours
after repeated administration, or about 12, 13, 14, 15, 16, 17, 18, 19 or 20
hours following
administration.
In certain embodiments, the formulation may have a Tnun of about 13 to about
16
hours after repeated administration, or about 14 hours after repeated
administration.
In some embodiments, the formulation may provide a mean Cnun of about 0.5 to
about
ng/mL, or about 4 to about 15 ng/mL, after repeated administration.
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Dissolution of the formulation releases about 0 to about 20 % of the
compound(s) or
salt thereof after two hours, or releases about 15 to about 60 % of the
compound(s) or salt
thereof after four hours, or releases about 25 to about 80 % of the
compound(s) or salt thereof
after six hours, or releases about 35 to about 85 % of the compound(s) or salt
thereof after
eight hours, or releases about 45 to about 95 % of the compound(s) or salt
thereof after ten
hours, or releases about 60 to about 100 % of the compound(s) or salt thereof
after twelve
hours, as measured in a USP type I apparatus at 37 C in water at 50 rpm.
It is to be understood that when it is disclosed herein that a formulation
initiates
release after another component, such terminology means that the formulation
is designed
and is intended to produce such later initiated release. It is known in the
art, however,
notwithstanding such design and intent, some "leakage" of compound(s) may
occur. Such
"leakage" is not "release" as used herein.
In particular embodiments, the pharmaceutical formulation may comprise one or
more
components that contain two opioid compounds in a 2:1, 2:2, 2:3, 2:5, 3:1, or
3:4 weight
ratio. In certain embodiments, the components may comprise morphine and
oxycodone in
about a 3:2 weight ratio.
As an example, the pharmaceutical formulation may comprise a controlled
release
component comprising a mixture of morphine and oxycodone, and an immediate
release
component comprising oxycodone. In some embodiments, the Tmax of oxycodone in
the
immediate release component may be from about 10 minutes to about one hour
after
ingestion. In other embodiments, the Tmax will be from about 10 minutes to
about 30 minutes
or 45 minutes. The controlled release component may be released at a slower
rate and over a
longer period of time. For example, in some embodiments, the controlled
release component
may release effective amounts of the mixture of morphine and oxycodone over 12
hours. In
other embodiments, the controlled release component may release effective
amounts of
morphine and oxycodone over 4 hours or over 8 hours. In still other
embodiments, the
controlled release component t may release effective amounts of morphine and
oxycodone
over 15, 18, 24 or 30 hours.
In some embodiments, the later released active agents may be released from the
pharmaceutical formulation in pulses so that pulses of the compounds are
released at intervals
after ingestion of the formulation. For example, in certain embodiments,
controlled release
component may release a first pulse of the later released active agents about
0.5 - 1 hour after
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ingestion, followed by a second pulse after about of 4 hours after ingestion
and a third pulse
of drug after about 8 hours after ingestion.
Preparing Formulations
In one aspect, the pharmaceutical compositions are tablets and capsules for
oral
administration. These tablets or capsules may contain conventional excipients
such as
binding agents, fillers, lubricants, disintegrants, or wetting agents. In one
aspect the tablets or
capsules are coated according to methods well known in the art.
The granulation that will best serve this purpose will be highly deformable
during
compaction, thereby minimizing as much as possible any leakage from the coated
pellets
before the designated time of release. In one embodiment, it may be desirable
to have a brief
lag, or delay in the initial burst, or release of oxycodone in the immediate
release bolus
portion of the formulation. In some embodiments, the tablet is less than about
500 mg, about
450 mg, about 400 mg, about 350 mg, about 300 mg, about 250mg, about 200 mg,
about 150
mg, about 100 mg, about 50 mg, about 25 mg, or about 10 mg weight, and the
drug load is
about 20%, about 15% , about 10%, about 5% (w/w) or less of the formulation.
In one
embodiment, the goal would be to have as efficient a tablet size as possible,
while affording
good uniformity and integrity of the pellets in the tablet.
The disintegrant used in the tablet of the present invention is not
particularly limited,
as far as it is a disintegrant used for pharmaceutical preparations. Examples
can include
crospovidone, crystalline cellulose, hydroxypropylcellulose with a low degree
of substitution,
croscarmellose sodium, carmellose calcium, carboxystarch sodium, carboxymethyl
starch
sodium, potato starch, wheat starch, com starch, rice starch, partly
pregelatinized starch, and
hydroxypropyl starch. One or two or more of these can be used. Crospovidone is
particularly preferable. The sort of disintegrant used for coating granules
according to the
present invention may be identical to or different from that used inside the
granules.
Examples of pharmaceutically acceptable additives used in the tablet of the
present
invention can include excipients, lubricants, pH adjusters, taste-masking
agents, sweeteners,
acidifiers, refrigerants, foaming agents, preservatives, fluidizers,
antioxidants, colorants,
stabilizers, surfactants, buffering agents, flavors, binders and drug
solubilizers. A person
skilled in the art may immediately list specific examples of these additives.
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These additives can be appropriately formulated in the inside of a granule, in
the
outside of a granule coated with a disintegrant, in the coating of a
disintegrant and in all
these, as far as they do not damage the advantages of the present invention.
Any lubricant used for pharmaceutical preparation can be used without
limitation.
Examples of the lubricant used in the tablet of the present invention can
include light
anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate,
aluminum stearate,
aluminum monostearate, sucrose fatty acid esters, polyethylene glycol, sodium
stearyl
fumarate, stearyl alcohol, talc, titanium oxide, hydrous silicon dioxide,
magnesium silicate,
synthetic aluminum silicate, calcium hydrogen phosphate, hardened castor oil,
hardened
rapeseed oil, Carnauba Wax, bees wax, microcrystalline wax and sodium lauryl
sulfate. One
or two or more kinds of these lubricants can be used. Among these, it is
preferable to use one
or more selected from light anhydrous silicic acid and magnesium stearate.
Particularly, a
combination of silicic anhydride contained in the inside of a granule and
magnesium stearate
contained in the outside of the granule is preferable.
When the formulations are in the form of a tablet, the shape of the tablet is
not
particularly limited, as far as it can be produced without difficulty using an
ordinary
manufacturing apparatus or a manufacturing apparatus with some modifications.
A disc
shape that is a general concept for tablets can be mentioned as a typical
example. The whole
size is not particularly limited. For example, the shorter diameter (diameter
for a disc tablet)
is appropriately in the range of 6 to 20 mm, preferably 8 to 12 mm. The
thickness is neither
particularly limited, but appropriately 1 to 10 mm, preferably 2 to 8 mm.
In some embodiments, it may be desirable to have the initial short delay
accomplished
by adding a delayed-release coating to the tablet which would also serve as a
taste-masking
agent. This coating may be white, or colored or clear or opaque if desired. An
identifying
NDC code (in the United States) or similar identifying code may also be
printed on the tablet
if desired.
The compound used in the tablet of the present invention may be coated with a
filmcoating agent, an excipient, a binder, a lubricant, or the like depending
on its properties
and a plasticizer may be added.
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Anti-Abuse Properties
In another aspect of the invention, the pharmaceutical compositions described
herein
possess properties that are useful in deterring their use to create
compositions that are likely
to be used for nonmedical purposes, or as a drug of abuse.
Intentional or inadvertent tampering from extended release formulations will
rapidly
deliver a massive dose (as a result of converting the sustained release
product into an
immediate release form) and produce profound a variety of serious and life
threatening side
effects, including respiratory depression and failure, sedation,
cardiovascular collapse, coma
and death.
Addicts and recreational drug users commonly use extended release opioids by a
variety of routes of administration. Commonly used methods include (a)
parenteral (e.g.,
intravenous injection), (b) intranasal (e.g., snorting), and (c) episodic or
repeated oral
ingestion of intact or crushed tablets or capsules.
One mode of abuse involves the extraction of the opioid from the component by
first
mixing the table or capsule with a suitable solvent (e.g., water or alcohol),
and then filtering
and/or extracting the opioid component from the mixture for intravenous
injection. Another
mode of abuse of extended release opioids involves dissolving the drug in
water, alcohol or
another "recreational solvent" to hasten its release and to ingest the
contents orally, in order
to provide high peak concentrations and maximum euphoriant effects.
The term "tampering" means any manipulation by mechanical, thermal and/or
chemical means which changes the physical properties of the component, e.g.,
to liberate the
opioid 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,
mechanical extraction,
solvent extraction, solvent immersion, combustion, heating or any combination
thereof
The term "abuse," "opioid agonist abuse" or "opioid abuse" in the context of
the
present invention, when it refers to the effects of opioid agonists in causing
such, includes
intermittent use, recreational use and chronic use of opioid agonists alone or
in conjunction
with other drugs: (i) in quantities or by methods and routes of administration
that do not
conform to standard medical practice; (ii) outside the scope of specific
instructions for use
provided by a qualified medical professional; (iii) outside the supervision of
a qualified
medical professional; (iv) outside the approved instructions on proper use
provided by the
drug's legal manufacturer; (v) which is not in specifically approved
components for medical
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use as pharmaceutical agents; (vi) where there is an intense desire for and
efforts to procure
same; (vii) with evidence of compulsive use; (viii) through acquisition by
manipulation of the
medical system, including falsification of medical history, symptom intensity,
disease
severity, patient identity, doctor shopping, prescription forgeries; (ix)
where there is impaired
control over use; (x) despite harm; (xi) by procurement from non-medical
sources; (xii) by
others through sale or diversion by the individual into the non-medical supply
chain; (xiii) for
medically unapproved or unintended mood altering purposes.
The term "abuse resistant," "abuse deterrent" and "deter abuse" are used
interchangeably in the context of the present invention and include
pharmaceutical
compositions and methods that (i) resist, deter, discourage, diminish, delay
and/or frustrate
the intentional, unintentional or accidental physical manipulation or
tampering of the
component (e.g., crushing, shearing, grinding, chewing, dissolving, melting,
needle
aspiration, inhalation, insufflation, extraction by mechanical, thermal and
chemical means,
and/or filtration); (ii) resist, deter, discourage, diminish, delay and/or
frustrate the intentional,
unintentional or accidental use or misuse of the component outside the scope
of specific
instructions for use provided by a qualified medical professional, outside the
supervision of a
qualified medical professional and outside the approved instructions on proper
use provided
by the drug's legal manufacturer (e.g., intravenous use, intranasal use,
inhalational use and
oral ingestion to provide high peak concentrations); (iii) resist, deter,
discourage, diminish,
delay and/or frustrate the intentional, unintentional or accidental conversion
of an extended
release component of the invention into a more immediate release form; (iv)
resist, deter,
discourage, diminish, delay and/or frustrate the intentional and iatrogenic
increase in physical
and psychic effects sought by recreational drug users, addicts, and patients
with pain who
have an addiction disorder; (v) resist, deter, discourage, diminish, delay
and/or frustrate the
attempts at surreptitious administration of the component to a third party
(e.g., in a beverage);
(vi) resist, deter, discourage, diminish, delay and/or frustrate attempts to
procure the
component by manipulation of the medical system and from non-medical sources;
(vii) resist,
deter, discourage, diminish, delay and/or frustrate the sale or diversion of
the component into
the non-medical supply chain and for medically unapproved or unintended mood
altering
purposes; (viii) resist, deter, discourage, diminish, delay and/or frustrate
intentional,
unintentional or accidental attempts at otherwise changing the physical,
pharmaceutical,
pharmacological and/or medical properties of the component from what was
intended by the
manufacturer.
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When the component of the pharmaceutical formulation is tampered, the
pharmaceutical formulation reduces the amount of opioid agonist released in
immediate
release form, which in turn reduces the euphoric, pleasurable, reinforcing,
rewarding, mood
altering and toxic effects of the opioid agonist of the component.
In specific embodiments, the use of certain excipients such as Povidone
(Kollidon 30)
or Polyoxyl 35 Castor Oil (Cremophor ELTM) or Sodium Lauryl Sulfate create an
unusable
gelatinous mass if tampered with. The addition of aqueous or hydroalcoholic
solvents would
render the pulverized excipient and drug mixture to a gelatinous mass that
would be
problematic for easy extraction of the opioid. The Cremophor, in admixture
with the
methacrylic acid polymers and cellulosic polymers are examples of prime
ingredients that
cause this feature of the invention.
Other methods of creating abuse-resistant opioid compositions are provided in
U.S.
published patent application US 20090082466, the teachings of which are
incorporated herein
by reference in their entirety.
Administration of the Formulation
An aspect of the present invention is a method for treating pain comprising
administering a formulation as described herein.
The formulations may be administered, for example, by any of the following
routes of
administration: sublingual, buccal, transmucosal, transdermal, parenteral,
oral etc. In certain
embodiments, the formulations may be prepared in a manner suitable for oral
administration.
Thus, for example, for oral administration, each of the components may be used
as a pellet,
granule, powder, liquid or a particle, which are then formed into a unitary
pharmaceutical
product, for example, in a capsule, or embedded in a tablet, or suspended in a
liquid for oral
administration. The term "formulation" as used herein also refers to a unitary
pharmaceutical
product containing at least one component.
In certain embodiments, the formulations are for oral administration and may
be in the
form of a tablet or a capsule or in the form of a multiple unit component. The
formulations
may be adapted for oral administration 1-6 times a day, normally 1-4 times
daily such as 1-3
times, twice daily, or once daily. In the present context the term "once
daily" is intended to
mean that it is only necessary to administer the pharmaceutical composition
once a day in
order to obtain an effective therapeutic amount of the compound to provide a
suitable
therapeutic response.
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The final dose of the compound(s) provided by administration of the
formulation may
be about, by weight, 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80
mg, about 75
mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45
mg, about
40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about
12 mg,
about 10 mg, about 8 mg, about 5 mg, about 4, mg, about 3 mg, about 2 mg, or
about 1 mg.
The dosage of the opioid compound depends on the particular substance, the
age,
weight condition, etc., of the human or animal that will be treated with the
composition, etc.
All such factors are well known to a person skilled in the art.
EXAMPLES
The present invention will be understood more readily by reference to the
following
examples, which are provided by way of illustration and are not intended to be
limiting of the
invention.
Example 1: Opioid Components
Components for use in pharmaceutical formulations were developed, as shown in
Tables 1-8.
Table 1: Target Component 1 (oxycodone):
Pellet Core!:
Oxycodone hydrochloride USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 75%
Povidone
(Kollidon 30) USP Binding Agent 2-4%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
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Table 2: Target Component 1 (morphine):
Pellet Core:
Morphine Sulfate USP Drug Substance 20%
Microcrystalline Cellulose
NF Diluent 75%
(Avicel PH-101)
Povidone
(Kollidon 30) USP Binding Agent 2-4%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L3 OD-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
Table 3: Target Component 2 (oxycodone):
Pellet Core.
Oxycodone hydrochloride USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 70-75%
Methocel K50 USP Binding Agent 4-9%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L3 OD-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
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Table 4: Target Component 2 (morphine):
Pellet Core:
Morphine Sulfate USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 70-75%
Methocel K50 USP Binding Agent 4-9%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
Table 5: Target Component 3 (oxycodone):
Pellet Core:
Oxycodone hydrochloride USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 65-75%
Methocel EIS USP Binding Agent 4-14%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
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Table 6: Target Component 3 (morphine):
Pellet Core:
Morphine sulfate USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 65-75%
Methocel EIS USP Binding Agent 4-14%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
Table 7: Target Component 4 (oxycodone):
Pellet Core:
Oxycodone hydrochloride USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 65-75%
Povidone
(Kollidon 25) USP Binding Agent 4-14%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
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Table 8: Target Component 4 (morphine):
Pellet Core:
Morphine sulfate USP Drug Substance 20%
Microcrystalline Cellulose
(Avicel PH-101) NF Diluent 65-75%
Povidone
(Kollidon 25) USP Binding Agent 4-14%
Polyoxyl 35 Castor Oil
NF Wetting Agent 0.5-1.5%
(Cremophor EL)
Coating:
Methacrylic Acid Copolymer Dispersion
(Eudragit L30D-55)1 NF Functional Film Sub-Coat 12%
Hypromellose Acetate Succinate
(AQOAT AS-HF) NF Functional Film Over-Coat 48%
Talc USP Antitacking Agent 30%
Triethyl Citrate NF Plasticizer 9.5%
Sodium Lauryl Sulfate NF Wetting Agent 0.5%
Purified Water2 USP Processing Agent N/A
lAmount per tablet based on the solids content of the dispersion
2Removed during processing
Example 2: Pharmacokinetic Profile of Opioid Formulations
A. An oxycodone formulation is provided that has the following
pharmacokinetic
profile. The pharmacokinetic profile is achieved by adjusting the
concentration of excipients
using the methods described in the charts shown in FIGS. 7-11. This 8mg
oxycodone
formulation has a Cmax of 8 hours and a Cmm of 14 hours.
B. An oxycodone formulation is provided that has the following
pharmacokinetic
profile. The pharmacokinetic profile is achieved by adjusting the
concentration of opioid
compound and excipients using the methods described in the charts shown in
FIGS. 7-11.
This 8mg oxycodone formulation has a Cmax of 6 hours and a Cm., of 16 hours.
C. A dual opioid oxycodone/morphine formulation is provided that has the
following pharmacokinetic profile. The pharmacokinetic profile is achieved by
adjusting the
concentration of opioid compound and excipients using the methods described in
the charts
shown in FIGS. 7-11. This 8mg oxycodone/4 mg morphine formulation has a Cmax
of 6-20
hours for both opioids, and a Cmm of 15-26 hours for both opioids.
D. A dual opioid oxycodone/morphine formulation is provided that has the
following pharmacokinetic profile. The pharmacokinetic profile is achieved by
adjusting the
concentration of opioid compound and excipients using the methods described in
the charts
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shown in FIGS. 7-11. This 18mg morphine/12 mg oxycodone formulation has a Cmax
of 6
hours, and a Caan of 16 hours.
Example 3: Preparation of Extended Release Intermediate Pellets Formulations
Extended release intermediate pellet formulations A and B were prepared having
the
compositions as shown in Tables 9 and 10.
Table 9: Formulation A:
=Component :: Quality* ::
:Functionmg/dose 'i' IiT":':': 1
Pellet Core
Oxycodone hydrochloride USP Drug Substance 20.00 15.19
Microcrystalline Cellulose USP Filter/Diluent 75.00 56.96
Povidone (Kollidon 30) USP Filter/Diluent 4.00 3.04
Polyoxyl 35 Castor Oil NF Lubricant 1.00 0.76
Purified Water USP Process Aid - -
Pellet Barrier Film Coat
Ammonio Methacrylate
NF Film Forming Agent 1.55 1.17
Copolymer, Type A (RL)
Ammonio Methacrylate
NF Film Forming Agent 6.18 4.70
Copolymer, Type B (RS)
Triethyl Citrate NF Plasticizer 0.77 0.59
Magnesium Stearate NF Antitacking Agent 1.50 1.14
Isopropyl Alcohol USP Process Aid - -
Purified Water USP Process Aid - -
Pellet Enteric Film Coat
Methacrylic Acid
NF Film Forming Agent 12.75 9.68
Copolymer Disp., Type C
Triethyl Citrate NF Plasticizer 1.28 0.97
Talc NF Antitacking Agent 6.38 4.84
Isopropyl Alcohol USP Process Aid - -
Purified Water USP Process Aid - -
Dusting Powder
Colloidal Silicon Dioxide NF Lubricant 1.26 0.96
Total 131.66 100.00
* USP = United States Pharmacopeia; NF = National Formulary
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Table 10: Formulation B:
I
Component ::: Quality" :::: Function:::
;TIOIOSe Yk'1,T.F
Pellet Core
Oxycodone hydrochloride USP Drug Substance 20.00 13.92
Microcrystalline Cellulose USP Filter/Diluent 75.00 52.22
Povidone (Kollidon 30) USP Filter/Diluent 4.00 2.79
Polyoxyl 35 Castor Oil NF Lubricant 1.00 0.70
Purified Water USP Process Aid
Pellet Barrier Film Coat
Ammonio Methacrylate
NF Film Forming Agent 3.09 2.15
Copolymer, Type A (RL)
Ammonio Methacrylate
NF Film Forming Agent 12.36 8.61
Copolymer, Type B (RS)
Triethyl Citrate NF Plasticizer 1.55 1.08
Magnesium Stearate NF Antitacking Agent 3.00 2.09
Isopropyl Alcohol USP Process Aid
Purified Water USP Process Aid
Pellet Enteric Film Coat
Methacrylic Acid
NF Film Forming Agent 13.91 9.68
Copolymer Disp., Type C
Triethyl Citrate NF Plasticizer 1.39 0.97
Talc NF Antitacking Agent 6.95 4.84
Isopropyl Alcohol USP Process Aid
Purified Water USP Process Aid
Dusting Powder
Colloidal Silicon Dioxide NF Lubricant 1.38 0.96
Total 143.63 100.00
* USP = United States Pharmacopeia; NF = National Formulary
The manufacturing process of mixing the formulations is illustrated in the
flow
diagram of FIG. 12. To prepare the formulations, oxycodone hydrochloride,
microcrystalline
cellulose, and Povidone (Kollidon 30) were individually, manually screened
through a # 20
mesh screen into a collecting container. The screened mix was transferred to a
granulation
bowl of a high shear granulator and dry mixed for three minutes.
A granulating solution comprising purified water mixed with Polyoxyl 35 Castor
Oil
was sprayed at a constant rate into the granulation bowl, mixing at low-speed-
impeller or
low-speed-chopper setting. The resulting granulation mixture was visually
assessed
continuously, and additional purified water was sprayed onto the mass as
required.
The granulation mixture then underwent an extrusion-spheronization process
using an
extruder and plate spheronizer. The wet mass was uniformly extruded through a
0.8 mm
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screen into the marmurizing bowl where the extrudate was formed into
appropriate sized
pellets.
The pellets were dried using a Fluid Bed Dryer Granulator to a Loss on Drying
(LOD)
test target of < 3%. To obtain the preferred fraction, the dried pellets were
sieved through a #
20 and # 40 mesh size stainless steel screen into a double polyethylene-lined
fiber drum for
storage pending pellet spray coating.
The pellets then underwent spray coating using a Fluid Bed Dryer. In a
stainless steel
vessel, the coating components were mixed into an isopropyl alcohol/water
solution using a
pneumatic propeller mixer for at least one hour until a clear solution
resulted. In a separate
stainless steel vessel, the enteric coating solution was prepared by mixing
the enteric coating
components with a pneumatic mixer for at least one hour until a clear solution
resulted. .
The polymer coating solutions were sprayed onto the pellets while continuously
monitoring
the spray conditions. The completed pellets were discharged into a double
polyethylene-
lined fiber drum for work-in-process storage pending lubrication.
The lubricated pellets were sieved through a # 18 and #40 mesh size stainless
steel
screen to obtain the preferred fraction, and discharged into a double
polyethylene-lined fiber
drum for storage pending tablet blending.
Example 4: Pharmacokinetic Testing of Formulations A and B
Methods
A single-dose, three-period, three-sequence, three-treatment crossover study
was
conducted to compare the oxycodone pharmacokinetic profile human subjects
orally
administered Formulation A or B as described in Example 3, or with a Reference
Formulation (MS Contin 30 mg (morphine CR) co-administered with OxyContin 20
mg
(oxycodone CR)).
Each subject participated in a series of three periods, wherein each period
was
comprised of (i) pre-administration screening and check-in, (ii)
administration of the
formulation, and (iii) post-administration sample collection and follow-up.
The subjects
received a different formulation in each period, and were divided randomly to
determine in
which order the formulations were administered.
The pre-administration screening and check-in involved a physical examination
and
recordation of the subject's vital signs. Naltrexone (50 mg), an opioid
antagonist, was
administered 0.5 hours prior to administration. Blood samples were collected
at 10 minutes
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and after 0.5, 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 18, 21, 24, 48,
and 72 hours post-dose
of the formulation.
Morphine and oxycodone in the plasma of the blood samples were measured by
liquid
chromatography with tandem mass spectrometry (LC/MS/MS) methods that were
validated
across the following ranges:
Morphine 0.25 - 100 ng/mL
Oxycodone 50 - 50,000 pg/mL
Results
The mean plasma concentration of oxycodone at the sample collection timepoints
is
shown in FIG. 13 (through 72 hours) and FIG. 14 (the first 24 hours). As
compared to the
Reference Formulation, Formulation A resulted in higher plasma levels of
oxycodone
between 5 and 16 hours after treatment, although the plasma levels were
generally lower
thereafter. On other hand, Formulation B produced about the same or greater
plasma levels
of oxycodone as compared to the Reference Formulation at 6 hours after
treatment and
continuing through 48 hours. During this period, the plasma levels of
oxycodone provided by
Formulation B were, on average, 30 % greater than the plasma levels provided
by the
Reference Formulation.
These data were used to project oxycodone plasma profiles that would result
from
administering multiple doses of Formulation B, as shown in FIGS. 15 and 16.
FIG. 15
presents the oxycodone plasma profile through administration of 4 doses of
Formulation B
and indicates that, under this dosing regimen, oxycodone plasma levels can be
maintained
between about 7 and about 20 ng/mL.
FIG. 16 shows the oxycodone plasma profile that may result from different
dosing
strengths, and focuses on a single dose with the multiple dose regimen after
the plasma levels
achieve a steady-state; steady state is characterized by consistent peaks and
troughs in the
multiple dose plasma profile. FIG. 16 indicates that, at steady state, Cmax
will reflect the
strength of the administered dose.
FIGS. 17 and 18 present projections of the oxycodone plasma profile for
multiple
doses of a formulation comprising a composite of an immediate release
formulation (10 %)
and Formulation B (90%). FIG. 17 demonstrates the oxycodone plasma profile
through
administration of 4 doses of the composite formulation and indicates that,
under this dosing
regimen, oxycodone plasma levels can be maintained between about 10 and about
19 ng/mL.
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FIG. 18 shows the oxycodone plasma profile that may result following
administration
of the composite formulation at different dosing strengths. FIG. 18 focuses on
a single dose
with the multiple dose regimen after the plasma levels achieve a steady-state,
which is
characterized by consistent peaks and troughs in the multiple dose plasma
profile. The
projection indicates that, at steady state, Cmax will be less than the
administered dose.
Comparisons of the oxycodone plasma profile of Formulation A to the Reference
Formulation and the oxycodone plasma profile of Formulation B to the Reference
Formulation are shown in Tables 11 and 12.
Table 11: Comparing Formulation A and the Reference Formulation
Formulation* Reference Formulation
AUCt [pg=hr/mLi 167077.87 + 18761.51 194706.30 41996.62
Cmax [pg/mL] 24410.50 4864.72 20525.70 4520.50
Tmax IhI 5.00 (2.00 ¨ 6.00) 3.00 (2.00 ¨ 5.00)
Table 12: Comparing Formulation A and the Reference Formulation
Formulation IV Reference Formulationr
AUCt [pg=hr/mLi 180846.58 + 22868.36 194706.30 41996.62
Cmax [pg/mL] 16471.00 3543.53 20525.70 4520.50
Tmax IhI 5.75 (5.00 ¨ 12.0) 3.00 (2.00 ¨5.00)
While AUCt of Formulations A and B were less than AUCt of the Reference
Formulation,
AUCt of Formulations A and B were within 14 % and 7 %, respectively. Also, T.
of both
Formulations A and B were greater than Tmax of the Reference Formulation,
which was not
expected..
Example 5: Immediate-Release Composition of Oxycodone with Controlled Release
Mixture of Oxycodone-Morphine.
An oral solid oral component tablet, comprising a core of 5.0 mg oxycodone
hydrochloride and 5.0 mg morphine sulfate as active ingredients together with
ammonio
methacrylate copolymer, hypromellose, lactose, magnesium stereate,
polyethylene glycol
400, povidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium
dioxide and
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triacetin, is prepared according to standard methods known in the art for
preparation of
tablets. The outside of the tablet is coated with a controlled release
formulation comprising
mg of oxycodone hydrochloride and gelatin, hypromellose, maize starch,
polyethylene
glycol, polysorbate 80, red iron oxide, silicon dioxide, dodium laurel
sulfate, sucrose,
5 titanium dioxide and yellow iron oxide. The resulting tablet is
administered to patients for
the alleviation of pain and results in effective analgesia with no incidence
of morphine-
induced respiratory depression.
Example 6: General Procedure for Preparation of Controlled Release
Formulations
10 The following manufacturing description is provided by way of example
for the
preparation of an controlled release, compressed tablet containing morphine
sulfate and
oxycodone hydrochloride.
Preparation of Pellet Cores
The active drug substances (morphine sulfate and oxycodone hydrochloride),
microcrystalline cellulose, USP and Povidone K30, NF were individually
manually screened
through a # 20 mesh screen into a collecting container. The screened mix was
transferred to
the granulation bowl of a high shear granulator such as the PMA-25 or PMA-65
and dry
mixed for 3 minutes.
A granulating solution consisting of a previously mixed solution of Purified
Water,
USP and Polyoxyl 35 Castor Oil, NF was sprayed at a constant rate into the
granulation bowl
and mixed at low speed impeller/low speed chopper setting. Granulation outcome
was
visually assessed on a continuous basis and additional Purified Water, USP was
sprayed onto
the mass if required. At the end of the granulation period, a sample was
removed for an in-
process test for water content.
After sampling was completed, the granulation was discharged to the extrusion-
spheronization process using a Luwa extruder and plate spheronizer or
equivalent. The wet
mass was uniformly extruded through a 0.8 mm screen into the marmurizing bowl
where the
extrudate was formed into appropriate sized pellets.
Fluid bed drying of the pellets was conducted using suitable process
parameters with
a GPCG-3, GPCG-5 or equivalent to a Loss on Drying (LOD) test target of < 5%.
The dried
pellets were sieved to obtain the preferred fraction through a # 20 and # 40
mesh size
stainless steel screen into a double PE-lined fiber drum for work-in-process
storage pending
pellet spray coating.
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Preparation of Modified Release Coated Beadlets
The ammonio methacrylate copolymers and triethyl citrate were mixed using a
pneumatic propeller mixer into an isopropyl alcohol/water solution contained
in a stainless
steel vessel for at least one hour until a clear solution was obtained. Talc
was then added to
the vessel with continuous stirring. Fluid bed spray coating of the core
pellets was conducted
using suitable process parameters with a GPCG-5 Wurster fitted with a 1.0 mm
spray nozzle.
Preparation of Enteric Coated Beadlets
In a separate container, the enteric coating solution was prepared by mixing
methacrylic acid copolymer and triethyl citrate with a pneumatic mixer in a
stainless steel
vessel for at least one hour. Talc was then added to the vessel with
continuous stirring. The
polymer coating solutions were successively sprayed at a constant rate to
completion onto the
beadlets while the spray conditions were continuously monitored. The enteric
coated
beadlets were discharged into a double polyethylene-lined fiber drum for work-
in-process
storage pending lubrication.
Example 7. Dissolution Testing Method for Controlled Release Formulations
The dissolution test method was designed to be used with an automated
dissolution
sampling station (e.g., Varian VK 8000). If such an instrument is not
available, appropriate
adjustments can be made in order to pull samples manually.
Apparatus: USP <711> Apparatus 2 (Paddles)
Automated Dissolution Sampling Station
Vessel Size/Type: About 1000 mL / clear glass, round-bottom vessel
Rotation Speed: About 50 rpm throughout
Media and Volume: Stage 1 (Acid Stage) from 0-2 hours: 750 mL of acidic
Dissolution
Medium A at 37.0 0.5 C for 2 hours
Stage 2 (Buffer Stage) from 2-11 hours: 1000 mL at 37.0 0.5 C,
created by adding 250 mL of Dissolution Medium B and 20
mL Dissolution Medium A to the remnants of the media in the
vessel from Stage 1. The Stage 2 media should have a pH of
about 6.8
Test Temperature: About 37.0 0.5 C
Sinker: Basket Sinker (0.46" x 0.80") 40 Mesh, 316-SS wire cloth
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Pull Volume: About 10 mL
Profile Time-points: About 1, 2, 3, 4, 6, 9 and 11 hours
Media Replacement: No
Sampling: Automated
Filter Type/Size: In-line 10-um polyethylene full flow filter
Example 8: Controlled Release Opioid Formulation Compositions
Following the procedure of Example 6, the following formulations were
prepared:
Table 13: Modified Release Beadlets Formulations Using Ammonio Methacrylate
Copolymer Having RS/RL Ratio of 90/10.
m p o neat :Quantity per Uoit: 70::::Pg:C:P0k(04
Morphine Sulfate + Oxycodone HC1 40 62.5
Core Pellets
Ammonio Methacrylate copolymer 16.3 25.5
Type B (RS PO)
Ammonio Methacrylate copolymer 1.8 2.8
Type A (RL PO)
Triethyl Citrate NF/EP 2.3 3.5
Talc (197 Grade) USP/EP/JP 3.6 5.6
Water purified Removed by evaporation during the coating
process
Various formulations were prepared having different % coating levels (e.g., 25
%, 35
%, 45 %, 50 % and 55 %) of the ammonio methacrylate RS/RL polymers. FIGS.
19(a) and
20(a) provide representative dissolution profiles for morphine sulfate and
oxycodone
hydrochloride, respectively.
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Table 14. Tablet Formulations Using Morphine / Oxycodone Enteric Coated /
Modified
Release Beadlets.
:=====
Component :Q.uantity per Unit Unit ON*:
.==
.== .==
=
= (mg),:
=.==
Morphine Sulfate + Oxycodone HC1 20 20
Modified Release Beadlets (RS/RL=
90:10 + Enteric Coating)
Microcrystalline Cellulose PH101 73.1 73.1
Granulated
Povidone K30 6.4 6.4
Magnesium Stearate 5712 0.5 0.5
8% w/w Povidone solution Water removed by evaporation post process.
(used for granulation)
Various tablet formulations were prepared having different % enteric coating
levels
(e.g., 10 %, 15 %, 20 %, 25 %, 30 % and 40 %). FIGS. 21 and 22 provide
representative
dissolution profiles for morphine sulfate and oxycodone hydrochloride,
respectively.
Example 9. Dissolution Testing of Various % Modified Release Coating Levels
and
Enteric Coating Levels.
Two lots (-3 kg) of morphine sulfate / oxycodone (3:2 by weight ratio) core
pellets
were coated using RS/RL polymer ratios of 90/10 (Lot 1, see Table 13) and
80/20 (Lot 2).
Each lot was coated with different coating levels (25%, 35%, 45%, 50% and 55%)
and
samples were collected during the coating process. Dissolution testing (FIGS.
19 and 20)
was performed on Lots 1 and 2 at the different coating levels.
In addition, coated pellets obtained from Lot 1 (at a 50 % RS/RL coating
level) were
subjected to enteric coating at different % coating levels (10%, 15 %, 25 %,
30 % and 40 %)
to produce enteric coated tablets and dissolution testing was performed (FIGS.
21 and 22).
Enteric coated tablet lots (using 10 % and 15 % enteric coat) were also
analyzed for
dissolution as a function of tablet hardness (low, medium or high) to
determine the resistance
of the tablets to various compression levels (FIGS. 23 and 24).
A summary of the dissolution testing is provided in Table 15.
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Table 15. Dissolution Testing Experiments.
:Test Perforrnvd Eatcli.:# Stage Coating
Levc1%::
.....
Dissolution 2925-069 Modified Release 25
(RS/RL 80/20) Coated Beads
45
55
Dissolution 2925-076 Modified Release 25
(RS/RL 90/10) Coated Beads
45
55
Dissolution 2925-115 Enteric Coated Tablets 10
(RS/RL 90/10) (50 % Modified Release
Coated Beads)
30
:Test Performed,: Batch # Stage Tablet
Hardness
Dissolution 2925-161 Tablet Compression Low Hardness
(RS/RL 90/10) (10% Enteric Coated Tablets)
Mid Hardness
High Hardness
Dissolution 2925-161 Tablet Compression Low Hardness
(RS/RL 90/10) (15% Enteric Coated Tablets)
Mid Hardness
High Hardness
FIGS. 19 and 20 show the versatility of modified release core beadlets at
various %
coating levels in obtaining the dissolution profile of interest. A full
spectrum of dissolution
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profiles allows for the targeting of specific in vivo pharmacokinetic plasma
levels and the
determination of in vitro to in vivo correlations.
FIGS. 21 and 22 also show the versatility of enteric coated, modified release
core
beadlets at various % enteric coating levels in obtaining the dissolution
profile of interest.
Once again, a full spectrum of dissolution profiles allows for the targeting
of specific in vivo
pharmacokinetic plasma levels and the determination of in vitro to in vivo
correlations.
FIGS. 23 and 24 show the effect of compression forces on tablets that contain
enteric
coated beadlets comprising a modified release coated pellet of morphine
sulfate and
oxycodone hydrochloride. It is generally known that a high compression force
can
significantly reduce the dissolution of tablets, especially when coating
polymers are
employed that are known to be brittle, such as with ammonio methacrylate
copolymer Type
A and B. FIGS. 23 and 24 demonstrate that a low or high compression force does
not affect
the dissolution of tablets. This result is unexpected and demonstrates the
resilience of the
formulation / coatings to compression forces.
Example 10. Controlled Release Opioid Formulation Compositions
Following the procedure of Example 6, the following formulations were
prepared:
Table 16: Tablet Formulations of Modified Release Beadlets (RS/RL)
with/without
Enteric Coating (Eudragit L100-55 Type C).
:Component Modified: Modified Release:
Release :RS/RL 80/20
RS/RL 85/15
Modified Release Coating Level (%
10 % 15 'Yo 10 % 20 'Yo 10 20 (Y4::
Oxycodone Hydrochloride 18.18 17.39 18.09 16.58 15.19 13.92
Cellulose Microcrystalline 68.18 65.22 63.32 58.04 56.96 52.22
Povidone K30 3.64 3.48 3.04 2.79
Hypromellose 8.14 7.46
(Methocel EIS Premium LV)
Polyoxyl 35 Castor Oil 0.91 0.87 0.90 0.83 0.76
0.70
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Ammonio Methacrylate 4.68 6.71 5.59 10.25 4.70
8.61
Copolymer Type B (RS PO)
Ammonio Methacrylate 0.83 1.18 1.40 2.56 1.17
2.15
Copolymer Type A (RL PO)
Triethyl Citrate NF/EP 0.86 1.24 0.70 1.28 0.59
1.08
Magnesium Stearate 5712 2.73 3.91 1.36 2.49 1.14
2.09
!!tkIclragit::&100,5tiga
Triethyl Citrate NF/EP 0.97 0.97
Talc (197 Grade) USP/EP/JP 0.5 0.5 4.84 4.84
Silicon Dioxide Colloidal 0.96 0.96
Total 100 100
100 100 100 100
FIGS. 25-27 provide representative dissolution profiles for morphine sulfate
and
oxycodone hydrochloride, respectively, for the formulations provided in Table
16. These
figures show the versatility of modified release core beadlets at various %
coating levels in
obtaining the dissolution profile of interest. Enteric coated beadlet
formulations are also
provided that allow for a full spectrum of dissolution profiles to be
achieved.
* * * *
It should be understood, of course, that the foregoing relates only to certain
disclosed
embodiments of the present invention and that numerous modifications or
alterations may be
made therein without departing from the spirit and scope of the invention as
set forth in the
appended claims.
49
