U.S. patent application number 15/683646 was filed with the patent office on 2017-12-07 for pharmaceutical compositions.
The applicant listed for this patent is LOCL PHARMA, INC.. Invention is credited to John AMELING, Paul BOSSE, Bernard SCHACHTEL, Ray TAKIGIKU.
Application Number | 20170348305 15/683646 |
Document ID | / |
Family ID | 40844760 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170348305 |
Kind Code |
A1 |
BOSSE; Paul ; et
al. |
December 7, 2017 |
PHARMACEUTICAL COMPOSITIONS
Abstract
Methods and compositions are provided which comprise effective
amounts of an analgesic to treat a subject, including reducing or
eliminating an adverse effect associated with the analgesic.
Inventors: |
BOSSE; Paul; (Jupiter,
FL) ; AMELING; John; (Jupiter, FL) ;
SCHACHTEL; Bernard; (Jupiter, FL) ; TAKIGIKU;
Ray; (Loveland, OH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LOCL PHARMA, INC. |
Las Vegas |
NV |
US |
|
|
Family ID: |
40844760 |
Appl. No.: |
15/683646 |
Filed: |
August 22, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14789883 |
Jul 1, 2015 |
9789104 |
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15683646 |
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|
14036946 |
Sep 25, 2013 |
9226901 |
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14789883 |
|
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|
|
13347552 |
Jan 10, 2012 |
9198867 |
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14036946 |
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12351704 |
Jan 9, 2009 |
8124126 |
|
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13347552 |
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61060758 |
Jun 11, 2008 |
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61043037 |
Apr 7, 2008 |
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61020139 |
Jan 9, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61P 1/08 20180101; A61P 25/08 20180101; A61K 31/485 20130101; A61K
31/404 20130101; A61K 31/454 20130101; A61K 9/0024 20130101; A61K
31/522 20130101; A61K 9/2027 20130101; A61K 9/2086 20130101; A61K
9/2054 20130101; A61K 31/4196 20130101; A61K 31/437 20130101; A61P
25/06 20180101; A61K 9/0056 20130101; A61K 31/5415 20130101; A61P
9/00 20180101; A61K 9/1694 20130101; A61K 31/165 20130101; A61P
39/00 20180101; A61K 47/36 20130101; A61K 9/209 20130101; A61K
31/24 20130101; A61K 9/5084 20130101; A61K 31/403 20130101; A61P
25/04 20180101; A61P 43/00 20180101; A61P 29/00 20180101; A61K
31/515 20130101; A61P 29/02 20180101; A61K 45/06 20130101; A61P
7/02 20180101; A61K 9/4808 20130101; A61K 31/167 20130101; A61K
31/422 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/20 20060101 A61K009/20; A61K 31/5415 20060101
A61K031/5415; A61K 31/522 20060101 A61K031/522; A61K 31/515
20060101 A61K031/515; A61K 31/454 20060101 A61K031/454; A61K 31/437
20060101 A61K031/437; A61K 31/422 20060101 A61K031/422; A61K
31/4196 20060101 A61K031/4196; A61K 31/404 20060101 A61K031/404;
A61K 31/403 20060101 A61K031/403; A61K 31/24 20060101 A61K031/24;
A61K 31/167 20060101 A61K031/167; A61K 31/165 20060101 A61K031/165;
A61K 9/48 20060101 A61K009/48; A61K 9/24 20060101 A61K009/24; A61K
45/06 20060101 A61K045/06 |
Claims
1. A solid oral pharmaceutical composition, comprising: a. a first
plurality of particulates, wherein each particulate of the first
plurality of particulates comprises an opioid analgesic, wherein
the opioid analgesic is hydromorphone or a pharmaceutically
acceptable salt thereof; and b. a second plurality of particulates,
wherein each particulate of the second plurality of particulates
comprises an antiemetic, wherein the second plurality of
particulates is formulated for immediate release, and wherein the
antiemetic reduces or eliminates an adverse effect of the opioid
analgesic.
2. The solid oral pharmaceutical composition of claim 1, wherein
the adverse effect of the opioid analgesic is nausea or
vomiting.
3. The solid oral pharmaceutical composition of claim 1, wherein
the hydromorphone or the pharmaceutically acceptable salt thereof
is present in an amount of 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg, 12
mg, 16 mg, or 32 mg.
4. The solid oral pharmaceutical composition of claim 1, wherein
the pharmaceutically acceptable salt of the hydromorphone is
hydromorphone hydrochloride.
5. The solid oral pharmaceutical composition of claim 1, wherein
the antiemetic is promethazine or a pharmaceutically acceptable
salt thereof, or ondansetron or a pharmaceutically acceptable salt
thereof.
6. The solid oral pharmaceutical composition of claim 5, wherein
the promethazine or the pharmaceutically acceptable salt thereof is
present in an amount of about 0.5 mg to about 60 mg.
7. The solid oral pharmaceutical composition of claim 5, wherein
the promethazine or the pharmaceutically acceptable salt thereof is
present in an amount of about 6.25, about 10 mg, about 12.5 mg, or
about 25 mg.
8. The solid oral pharmaceutical composition of claim 5, wherein
the promethazine is present in an amount of about 5.5 mg, about 11
mg, or about 22 mg.
9. The solid oral pharmaceutical composition of claim 5, wherein
the pharmaceutically acceptable salt of the promethazine is
promethazine hydrochloride.
10. The solid oral pharmaceutical composition of claim 5, wherein
the pharmaceutically acceptable salt of the ondansetron is
ondansetron hydrochloride.
11. The solid oral pharmaceutical composition of claim 1, wherein
the solid oral pharmaceutical composition only contains two active
agents.
12. The solid oral pharmaceutical composition of claim 1, wherein
the solid oral pharmaceutical composition comprises more than one
antiemetic.
13. The solid oral pharmaceutical composition of claim 1, wherein
the solid oral pharmaceutical composition comprises one or more
excipients.
14. The solid oral pharmaceutical composition of claim 13, wherein
the one or more excipients comprises: carnauba wax, crospovidone,
diacetylated monoglycerides, ethylcellulose, hydroxypropyl
methylcellulose, mannitol, sodium hydroxide, sodium stearyl
fumarate, talc, titanium dioxide, glyceryl monostearate 40-50,
methacrylic acid copolymer type C, polysorbate 80, sugar spheres,
triethyl citrate, microcrystalline cellulose, hypromellose,
croscarmellose sodium, magnesium stearate, stearic acid, sodium
starch glycolate, or yellow ferric oxide.
15. The solid oral pharmaceutical composition of claim 1, wherein
the solid oral pharmaceutical composition is in a capsule dosage
form.
16. A method for treatment of pain and reduction or prevention of
an adverse effect of an opioid analgesic, comprising administering
to a subject in need thereof the solid oral pharmaceutical
composition of claim 1.
17. The method of claim 16, wherein the solid oral pharmaceutical
composition is administered once, twice, or three times daily.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 14/789,883, filed Jul. 1, 2015, which is continuation of U.S.
application Ser. No. 14/036,946, filed on Sep. 25, 2013, now U.S.
Pat. No. 9,226,901, which is a continuation of U.S. application
Ser. No. 13/347,552, filed on Jan. 10, 2012, now U.S. Pat. No.
9,198,867, which is a continuation of U.S. application Ser. No.
12/351,704 filed on Jan. 9, 2009, now U.S. Pat. No. 8,124,126,
which claims the benefit of U.S. Provisional Application Nos.
61/020,139 filed Jan. 9, 2008, 61/043,037 filed Apr. 7, 2008, and
61/060,758 filed Jun. 11, 2008, each of which is incorporated by
reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] Available pain medications may have adverse effects, such as
nausea, vomiting, and skin rashes and sedation. As a result of such
adverse effects, many subjects are unable to tolerate recommended
dosages needed for effective pain relief because of adverse
effects. Accordingly, there remains a need for effective
therapeutics with reduced adverse effects.
BRIEF DESCRIPTION OF DRAWINGS
[0003] FIG. 1 illustrates a chromatograph for example of a standard
solution.
[0004] FIG. 2 illustrates one embodiment of a tablet of the
invention. A. Illustrates a top view of the tablet (numerals in
square brackets refer to measurements in millimeters and numerals
not in square brackets are in inches); B. illustrates a side view
of the tablet (numerals in square brackets refer to measurements in
millimeters and numerals not in square brackets are in inches).
[0005] FIG. 3 illustrates an example of chromatograph of a diluent
blank and standard solution.
[0006] FIG. 4 illustrates an example of a dissolution chromatograph
for a composition of the invention.
[0007] FIG. 5 illustrates an example of dissolution release profile
for a composition of the invention.
SUMMARY OF THE INVENTION
[0008] In one embodiment this invention provides compositions
comprising (1) an effective amount of: (a) an opioid analgesic; (b)
a stimulant; (c) an antiemetic; and (2) a pharmaceutically
acceptable carrier or vehicle.
[0009] In another embodiment this invention provides compositions
comprising (1) an effective amount (a) oxycodone or a
pharmaceutically acceptable salt thereof, (b) promethazine or a
pharmaceutically acceptable salt thereof, (c) modafinil or a
pharmaceutically acceptable salt thereof and (d) naltrexone or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0010] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) morphine or a
pharmaceutically acceptable salt thereof, (b) promethazine or a
pharmaceutically acceptable salt thereof, and (c) modafinil or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0011] In another embodiment this invention provides compositions
comprising an effective amount of butalbital or a pharmaceutically
acceptable salt thereof, acetaminophen and promethazine or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier or vehicle.
[0012] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) an opioid analgesic
agent; (b) an anti-emetic agent and (c) a beta blocker, serotonin
receptor agonist, vasoconstrictor, anti-platelet agent,
anti-convulsant, triptan, ergot, or calcitonin-gene-related peptide
receptor antagonist; and (2) a pharmaceutically acceptable carrier
or vehicle.
[0013] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) an opioid analgesic agent
and (b) sumatriptan or a pharmaceutically acceptable salt thereof;
and (2) a pharmaceutically acceptable carrier or vehicle.
[0014] In another embodiment this invention provides compositions
consisting of (1) an effective amount of (a) sumatriptan or a
pharmaceutically acceptable salt thereof and (b) promethazine or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0015] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) an opioid analgesic
agent, (b) a Cox-2 inhibitor agent, an anti-depressant agent, an
anti-convulsant agent, an anti-cholinergic agent, an NMDA receptor
antagonist agent, an anesthetic agent or an
.alpha..sub.2-adrenoreceptor agonist agent, (c) an opioid
antagonist agent, (d) an agent that reduces or eliminates an
adverse effect of the opioid agent; and (2) a pharmaceutically
acceptable carrier or vehicle.
[0016] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) an opioid analgesic
agent, (b) a non-opioid analgesic agent, (c) cyclazacine or
levallorphan; (d) an agent that reduces or eliminates an adverse
effect of the opioid analgesic agent; and (2) a pharmaceutically
acceptable carrier.
[0017] In another embodiment this invention provides a composition
comprising (1) an effective amount of (a) an opioid analgesic
agent, (b) a non-opioid analgesic agent, (c) an antiemetic; (d) an
abuse deterrent agent; and (2) a pharmaceutically acceptable
carrier. In one embodiment the abuse deterrent agent is niacin or a
pharmaceutically acceptable salt thereof; zinc sulfate; or sodium
lauryl sulfate.
[0018] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) an opioid analgesic
agent, (b) a non-opioid analgesic agent, (c) an opioid antagonist
agent, (d) aprepitant, perphenazine, acetylleucine
monoethanolamine, azasetron, benzquinamide, bietanautine,
bromopride, clebopride, diphenidol, methallatal, metopimazine,
oxyperndyl, pipamazine, sulpiride, thiethylperazine,
thioproperazine, or a pharmaceutically acceptable salt thereof; and
(2) a pharmaceutically acceptable carrier or vehicle.
[0019] In another embodiment this invention provides bi-layer
tablets comprising: (1) a controlled-release layer comprising from
about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically
acceptable salt thereof; and from about 290 to about 360 mg of
acetaminophen or a pharmaceutically salt; and (2) an
immediate-release layer comprising from about 11 mg to about 14 mg
of promethazine or a pharmaceutically salt thereof. In another
embodiment this invention provides bilayer tablets comprising (1)
an effective amount of (a) an opioid analgesic or a
pharmaceutically acceptable salt thereof and (b) one or more
antiemetic or a pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0020] In another embodiment this invention provides bilayer
tablets comprising: (1) a controlled release layer comprising (a)
from about 6.5 mg to about 8.5 mg of hydrocodone or a
pharmaceutically acceptable salt thereof, (b) from about 290 to
about 360 mg of acetaminophen or a pharmaceutically acceptable salt
thereof, (c) from about 135 mg to about 170 mg of silicified
microcrystalline cellulose, (d) from about 17 mg to about 23 mg of
hydroxy methyl propyl cellulose, (e) from about 1 mg to about 4 mg
of magnesium stearate, and (f) from about 1 mg to about 4 mg of
stearic acid; and (2) an immediate release layer comprising (a)
from about 11 mg to about 14 mg of promethazine or a
pharmaceutically acceptable salt thereof, (b) from about 100 mg to
about 140 mg of silicified microcrystalline cellulose, (c) from
about 12 mg to about 18 mg of croscarmellose sodium and (d) from
about 0.8 mg to about 1.5 mg of magnesium stearate.
[0021] In another embodiment this invention provides compositions
comprising (1) an effective amount of (a) hydrocodone or a
pharmaceutically acceptable salt thereof or oxycodone or a
pharmaceutically acceptable salt thereof; (b) acetaminophen or a
pharmaceutically acceptable salt thereof, (c) promethazine or a
pharmaceutically acceptable salt thereof and (d) about 0.75 mg of
naltrexone or a pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0022] In another embodiment this invention provides compositions
consisting of (1) an effective amount of (a) oxycodone or a
pharmaceutically acceptable salt thereof, (b) promethazine or a
pharmaceutically acceptable salt thereof and (c) naltrexone or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0023] In another embodiment this invention provides compositions
consisting of (1) an effective amount of (a) promethazine or a
pharmaceutically acceptable salt thereof, (b) propoxyphene or a
pharmaceutically acceptable salt thereof, (c) naproxen or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0024] In another embodiment this invention provides methods for
treating or preventing pain, comprising administering to a subject
in need thereof an effective amount of (a) an opioid analgesic
agent, (b) an antiemetic agent or an antihistamine, and (c) a
stimulant agent.
[0025] In another embodiment this invention provides methods for
treating or preventing a migraine headache comprising administering
to a subject in need thereof an effective amount of (a) an opioid
analgesic agent; (b) an antiemetic agent; and (c) a stimulant
agent.
[0026] In another embodiment this invention provides methods for
treating or preventing a headache comprising administering to a
subject in need thereof an effective amount of (a) an opioid
analgesic agent; and (b) an antiemetic agent. In one embodiment the
headache is a migraine headache, cluster headache or hemicrania
continua headache. In another embodiment the headache is a chronic
headache, tension headache or chronic tension headache.
[0027] In another embodiment this invention provides methods for
treating pain, comprising administering to a subject in need
thereof an effective amount of (a) an opioid analgesic agent, (b)
an antiemetic agent; and (c) a non-opioid analgesic agent; wherein
the subject is about 65 years of age or older.
[0028] In another embodiment this invention provides methods for
treating or preventing photophobia comprising administering to a
subject in need thereof an effective amount of (a) an opioid
analgesic agent; and (b) an antiemetic agent. In one embodiment the
photophobia is associated with migraine headache.
[0029] In another embodiment this invention provides methods for
treating or preventing headache comprising: administering to a
subject in need thereof (1) an effective amount of (a) triptan or a
pharmaceutically acceptable salt thereof and (b) promethazine or a
pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle. In one embodiment
the triptan is sumatriptan. In another embodiment the headache is
migraine headache.
[0030] In another embodiment this invention provides methods for
treating or preventing pain comprising: administering to a subject
in need thereof (1) an effective amount of (a) an opioid analgesic
agent, (b) a Cox-2 inhibitor agent, an anti-depressant agent, an
anti-convulsant agent, an anti-cholinergic agent, an NMDA receptor
antagonist agent, an anesthetic agent or an
.alpha..sub.2-adrenoreceptor agonist agent, (c) an opioid
antagonist agent, (d) an agent that reduces or eliminates an
adverse effect of the opioid agent; and (2) a pharmaceutically
acceptable carrier or vehicle.
[0031] In another embodiment this invention provides methods for
treating or preventing pain comprising, administering to a subject
in need thereof a bi-layer tablet comprising: (1) a
controlled-release layer comprising from about 6.5 mg to about 8.5
mg of hydrocodone or a pharmaceutically acceptable salt thereof;
and from about 290 to about 360 mg of acetaminophen or a
pharmaceutically salt; and (2) an immediate-release layer
comprising from about 11 mg to about 14 mg of promethazine or a
pharmaceutically salt thereof.
[0032] In another embodiment this invention provides methods for
treating or preventing pain comprising, administering to a subject
in need thereof a bi-layer tablet comprising (1) an effective
amount of (a) oxycodone or a pharmaceutically acceptable salt
thereof and (b) promethazine or a pharmaceutically acceptable salt
thereof; and (2) a pharmaceutically acceptable carrier or
vehicle.
[0033] In another embodiment this invention provides methods for
treating or preventing pain comprising, administering to a subject
in need thereof a bi-layer tablet comprising: (1) a controlled
release layer comprising (a) from about 6.5 mg to about 8.5 mg of
hydrocodone or a pharmaceutically acceptable salt thereof, (b) from
about 290 to about 360 mg of acetaminophen or a pharmaceutically
acceptable salt thereof, (c) from about 135 mg to about 170 mg of
silicified microcrystalline cellulose, (d) from about 17 mg to
about 23 mg of hydroxy methyl propyl cellulose, (e) from about 1 mg
to about 4 mg of magnesium stearate, and (f) from about 1 mg to
about 4 mg of stearic acid; and (2) an immediate release layer
comprising (a) from about 11 mg to about 14 mg of promethazine or a
pharmaceutically acceptable salt thereof, (b) from about 100 mg to
about 140 mg of silicified microcrystalline cellulose, (c) from
about 12 mg to about 18 mg of croscarmellose sodium and (d) from
about 0.8 mg to about 1.5 mg of magnesium stearate.
[0034] In another embodiment this invention provides methods for
treating or preventing pain comprising, administering to a subject
in need thereof composition consisting of (1) an effective amount
of (a) promethazine or a pharmaceutically acceptable salt thereof,
(b) propoxyphene or a pharmaceutically acceptable salt thereof, (c)
naproxen or a pharmaceutically acceptable salt thereof; and (2) a
pharmaceutically acceptable carrier or vehicle.
[0035] In one embodiment of the invention, a composition is in the
form of a bilayer tablet, wherein the bilayer tablet comprises an
immediate-release layer and a controlled-release layer, wherein
each layer comprises one or more pharmaceutically active agents
disclosed herein.
[0036] In yet another embodiment of the invention a bilayer tablet
comprises an effective amount of an antiemetic and the antiemetic
is capable of achieving from about 70% to about 80% dissolution in
the stomach of a subject in about 5 to about 10 minutes following
oral administration.
[0037] In another embodiment of the invention a bilayer tablet
comprises an effective amount of an opioid analgesic, or a
non-opioid analgesic, and the opioid analgesic or the non-opioid
analgesic is capable of achieving from about 30% to about 60%
dissolution in the stomach of a subject in about 5 to about 10
minutes following oral administration.
DETAILED DESCRIPTION OF THE INVENTION
[0038] All patents and publications and referred to herein are
incorporated by reference in their entirety.
[0039] The invention is generally directed to compositions
comprising multiple pharmaceutically active agents that are useful
as therapeutics that alleviate, abate or eliminate one or more
conditions in a subject in need thereof, as further described
herein below.
[0040] An "effective amount" of when used in connection with
composition of the invention is an amount sufficient to produce a
therapeutic result in a subject in need thereof. For example a
therapeutic result can include, but is not limited to, treating or
preventing pain, nausea or vomiting by a subject.
[0041] An "effective amount" when used in connection with an opioid
analgesic agent alone or in combination is an amount that is
effective for treating or preventing pain, wherein the antagonist
agent is provided in combination with one or more pharmaceutically
active agents disclosed herein. In one embodiment, the one or more
pharmaceutically active agent is an antiemetic.
[0042] An "effective amount" when used in connection with an
antiemetic agent is an amount that is effective for preventing or
reducing or eliminating one or more adverse effects associated with
one or more pharmaceutically active agent disclosed herein. In
various embodiments, the one or more pharmaceutically active agent
includes but is not limited to an opioid analgesic and/or a
non-opioid analgesic.
[0043] In further embodiments, such adverse effects which are
reduced, prevented or eliminated include but are not limited to
incidence of nausea or vomiting. Furthermore, an "effective amount"
when used in connection with an antihistamine is an amount that is
effective for preventing or reducing the incidence of nausea or
vomiting, or preventing or reducing adverse effects associated with
an opioid analgesic (e.g., opioid-induced nausea and vomiting).
[0044] An "effective amount" when used in connection with a
stimulant agent is an amount that is effective to increase
alertness, or lessen soporific effects of an opioid agent, wherein
the stimulant agent is present in a dosage formulation alone or in
combination with one or more pharmaceutically active agent
disclosed herein. In various embodiments, the one or more
pharmaceutically active agent includes but is not limited to an
antiemetic agent, and a barbiturate.
[0045] An "effective amount" when used in connection with a
barbiturate agent is an amount that is effective for treating or
preventing pain, producing a sedative effect, anesthetic effect or
calming effect when provided alone or in combination with one or
more pharmaceutically active agent disclosed herein. In various
embodiments, the one or more pharmaceutically active agent includes
but is not limited to an opioid analgesic, a non-opioid analgesic,
antiemetic or combination thereof.
[0046] An "effective amount" when used in connection with a opioid
antagonist agent is an amount that is effective for preventing or
inhibiting abuse of a dosage form comprising an opioid analgesic
agent, wherein the antagonist agent is provided in combination with
one or more pharmaceutically active agent disclosed herein. In
various embodiments, the one or more pharmaceutically active agent
includes but is not limited to an opioid agent, a non-opioid
analgesic, a stimulant, a barbiturate, or a combination
thereof.
[0047] An "effective amount" when in used in connection with one or
more of the agents disclosed herein is the total amount of one or
more of the agents that is useful for the treatment of pain.
[0048] The term "about" means the referenced numeric indication
plus or minus 10% of that referenced numeric indication.
[0049] Pharmaceutically active agents disclosed herein are capable
of use in a composition of the invention. A pharmaceutically active
agent, such as an opioid analgesic agent, non-opioid analgesic
agent, antitussive agent, antiemetic agent, antihistamine, a
stimulant, or a barbiturate, can be in the form of a
pharmaceutically acceptable salt thereof.
[0050] In some embodiments of the invention a composition comprises
an analgesic agent (e.g., one analgesic or two, three or more
analgesics) and agent (e.g., one, two or more of an antihistamine
or antiemetic) that reduces or eliminates an adverse effect of an
analgesic agent. In various embodiments, a composition of the
invention comprises one or more pharmaceutically active agents
provided in Table 1 or Table 2, or a pharmaceutically acceptable
salt thereof.
[0051] In one embodiment, a composition comprise, an effective
amount of an opioid analgesic agent, an effective amount of
non-opioid analgesic agent, and an effective amount of an agent
that reduces or eliminates an adverse effect of an analgesic
agent.
[0052] In another embodiment of the invention a composition
comprises an antiemetic and about 70 to about 80% of the antiemetic
dissolves in the stomach of a subject after about 5 to about 10
minutes following oral administration. In one embodiment, about
100% of the antiemetic dissolves in the stomach of a subject about
40, about 50 or about 60 minutes following oral administration. In
one embodiment, the antiemetic is promethazine or a
pharmaceutically acceptable salt thereof. In another embodiment,
the promethazine salt is promethazine HCl.
[0053] In another embodiment of the invention a composition
comprises an opioid analgesic and from about 30% to about 40% of
the opioid analgesic dissolves in the stomach of a subject after
about 5 to about 10 minutes following oral administration. In one
embodiment, about 100% of the opioid analgesic dissolves in the
stomach of a subject about 40, about 50 or about 60 minutes
following oral administration. In one embodiment, the opioid
analgesic is hydrocodone, oxycodone or a pharmaceutically
acceptable salt thereof. In another embodiment, the hydrocodone
salt is hydrocodone bitartrate; or the oxycodone salt is oxycodone
HCl.
[0054] In one embodiment, compositions of the invention are
administered to a subject at about every 4 to about 6 hours, about
every 12 hours, or about every 24 hours. In one embodiment, a
composition of the invention is administered once daily.
[0055] In one embodiment, the agent that reduces or eliminates an
adverse effect is an antiemetic agent or antihistamine. In further
embodiments, the adverse effect reduced or eliminated is associated
with an opioid analgesic. In an additional embodiment, the adverse
effect is associated with a non-opioid analgesic.
[0056] In various embodiments, an agent that reduces or eliminates
an adverse effect of an opioid analgesic agent or a non-opioid
analgesic agent includes but is not limited to promethazine,
dolasetron, granisetron, ondansetron, tropisetron, palonosetron,
domperidone, droperidol, haloperidol, chlorpromazine,
prochloperazine, metoclopramide, alizapride, cyclizine,
diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis,
dronabinol, nabilone, midazolam, lorazepam, hyoscine,
dexamethasone, trimethobenzamide, emetrol, and propofol or a
pharmaceutically acceptable salt thereof.
[0057] In one embodiment, a composition of the invention comprises
a non-opioid analgesic agent which is acetaminophen, ibuprofen,
naproxen or flurbiprofen, or a pharmaceutically acceptable salt
thereof. In one embodiment the agent is naproxen sodium or
magnesium.
[0058] In one embodiment, the opioid analgesic agent is hydrocodone
or oxycodone, or a pharmaceutically acceptable salt thereof
thiosemicarbazone, p-nitrophenylhydrazine, o-methyloxime,
semicarbazone, or bis (methylcarbamate) derivative, (each of the
foregoing being an opioid analgesic agent or derivative). In a
further embodiment, the opioid analgesic agent is hydrocodone
bitartrate or oxycodone hydrochloride.
[0059] In another embodiment the opioid analgesic agent is a
naturally occurring opiate, such as an alkaloid occurring in the
opium poppy. In one embodiment the naturally occurring opiate is
morphine, codeine, narcotine, papaverine, narceine, thebaine; or a
pharmaceutically acceptable salt thereof.
[0060] In one embodiment, a composition comprises an effective
amount of each of an opioid analgesic, a non-opioid analgesic and
an antiemetic or antihistamine, wherein the composition is capable
of providing an effective plasma concentration of the antihistamine
prior to an effective plasma concentrations of the opioid and the
non-opioid analgesic, post oral administration. For example, a
composition comprising an effective amount of each of an opioid
analgesic, non-opioid analgesic, and an antihistamine or
antiemetic--provides an effective plasma concentration of the
latter antihistamine or antiemetic in about 1 to about 20 minutes,
which is substantially earlier than effective plasma concentration
of an analgesic, which can be from about 20 minutes to about 12
hours. In one embodiment of the invention, a composition comprises
an effective amount of each of one or more pharmaceutically active
agents disclosed herein. In one embodiment, the composition is a
bilayer tablet comprising a controlled-release layer and an
immediate-release layer.
[0061] In one embodiment about 70% to about 80% of a
pharmaceutically active agent is capable of achieving dissolution
from the immediate-release layer at about 5 to about 10 minutes
following oral administration. In another embodiment about 70% to
about 80% of a pharmaceutically active agent is capable of
achieving dissolution from the immediate-release layer at about 5
to about 10 minutes following contact with a dissolution fluid,
such as the dissolution fluid described in Example 15.
[0062] In another embodiment about 100% of a pharmaceutically
active agent is capable of achieving dissolution from the
immediate-release layer at about 40 minutes following oral
administration. In another embodiment about 100% to of a
pharmaceutically active agent is capable of achieving dissolution
from the immediate-release layer at about 40 minutes following
contact with a dissolution fluid, such as the dissolution fluid
described in Example 15.
[0063] In another embodiment about 30% to about 40% of a
pharmaceutically active agent is capable of achieving dissolution
from the controlled-release layer at about 5 to about 10 minutes
following oral administration. In another embodiment about 30% to
about 40% of a pharmaceutically active agent is capable of
achieving dissolution from the controlled-release layer at about 5
to about 10 minutes following contact with a dissolution fluid,
such as the dissolution fluid described in Example 15.
[0064] In another embodiment about 90% of a pharmaceutically active
agent is capable of achieving dissolution from the
controlled-release layer at about 60 minutes following oral
administration. In another embodiment about 90% of a
pharmaceutically active agent is capable of achieving dissolution
from the controlled-release layer at about 60 minutes following
contact with a dissolution fluid, such as the dissolution fluid
described in Example 15.
[0065] In yet another embodiment, from about 90 to about 100% of a
pharmaceutically active agent is capable of achieving dissolution
from the immediate-release layer at about 40, about 50 or about 60
minutes following oral administration. In yet another embodiment,
from about 90 to about 100% of a pharmaceutically active agent is
capable of achieving dissolution from the immediate-release layer
at about 40, about 50 or about 60 minutes following contact with a
dissolution fluid, such as the dissolution fluid described in
Example 15.
[0066] In yet another embodiment, from about 90 to about 100% of a
pharmaceutically active agent is capable of achieving dissolution
from the controlled-release layer at about 40, about 50 or about 60
minutes following oral administration. In yet another embodiment,
from about 90 to about 100% of a pharmaceutically active agent is
capable of achieving dissolution from the controlled-release layer
at about 40, about 50 or about 60 minutes following contact with a
dissolution fluid, such as the dissolution fluid described in
Example 15. An illustrative dissolution profile for a composition
of the invention is depicted in FIG. 5.
[0067] In various embodiments, the composition is in the form of
any oral dosage form disclosed herein, including but not limited to
a pill, tablet, or capsule. In one embodiment, the composition is
in the form of a bilayer tablet having an immediate-release layer
and a controlled-release layer, wherein one or more
pharmaceutically active agents are present in the immediate-release
layer and one or more pharmaceutically active agents are present in
the controlled release layer. In another embodiment, the
immediate-release layer comprises one or more antiemetic, and the
controlled-release layer comprises one or more pharmaceutically
active agents disclosed herein, but which are not an antiemetic or
antihistamine. In a further embodiment, an antiemetic or
antihistamine is present in both the immediate-release and
controlled-release layer. In another embodiment, the immediate
release layer comprises promethazine or a pharmaceutically
acceptable salt thereof. In another embodiment, the promethazine
salt is promethazine HCl. In another embodiment, the
controlled-release layer comprises an opioid analgesic. In a
further embodiment, the opioid analgesic is hydrocodone or
oxycodone, or a pharmaceutically acceptable salt thereof. In one
embodiment the hydrocodone salt is hydrocodone bitartrate. In
another embodiment, the oxycodone salt is oxycodone HCl. In a
further embodiment, the controlled-release layer further comprises
one or more non-opioid analgesic. In one embodiment, the non-opioid
analgesic is acetaminophen or a pharmaceutically acceptable salt
thereof. In one embodiment, the composition is in a form that
achieves a hardness of from about 5 to about 15 kiloponds and has a
thickness of about 5, about 5.5, about 6, about 6.5, about 7, about
7.5, about 8, about 8.5, about 9, about 9.5 or 10 mm. In one
embodiment, the tablet has a hardness of about 9.5 kiloponds. In
another embodiment, the tablet has a hardness of about 12.5
kiloponds. It will be understood that as to the kilopond and
thickness measurements, increments of 0.1 decimal points are within
the scope of the invention.
[0068] In one embodiment, the composition is capable of providing
an effective plasma concentration of an antiemetic in about 1
minute to about 20 minutes after administration to a subject. In
another embodiment, the antiemetic is promethazine or a
pharmaceutically acceptable salt thereof. In a further embodiment
the salt is promethazine HCl.
[0069] In various embodiments, a composition comprises from about
1% to about 20% by weight of an antihistamine; from about 10% to
about 80% by weight a non-opioid analgesic; and from about 1% to
about 20% by weight of an opioid analgesic. In some embodiments,
the antihistamine is promethazine, dolasetron, granisetron,
ondansetron, tropisetron, palonosetron, domperidone, droperidol,
haloperidol, chlorpromazine, prochloperazine, metoclopramide,
alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine,
hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam,
hyoscine, dexamethasone, trimethobenzamide, emetrol, or propofol,
or pharmaceutically acceptable salt thereof.
[0070] In one embodiment, the composition is capable providing an
effective plasma concentration of promethazine or a
pharmaceutically acceptable salt thereof in about 1 minute to about
20 minutes after administration to a subject.
[0071] In one embodiment, a method is provided for reducing or
eliminating an adverse effect of an analgesic agent, comprising
administering to a subject in need thereof a composition comprising
an effective amount of each of an opioid analgesic agent, a
non-opioid analgesic agent and an agent which reduces or eliminates
a adverse effect of the analgesic agents.
[0072] In one embodiment, a method is provided for treating or
preventing pain, comprising administering to a subject in need
thereof an effective amount of a composition comprising an
effective amount of each of an opioid analgesic, or a
pharmaceutically acceptable salt thereof, a non-opioid analgesic,
or a pharmaceutically acceptable salt thereof, and an agent which
reduces a adverse effect associated with the opioid or non-opioid
analgesic agent. In one embodiment, the agent that reduces an
adverse effect is an antiemetic or an antihistamine.
[0073] In another embodiment the pain is associated with cancer,
chronic or acute pain, a headache, chronic headache, a migraine
headache, a surgical procedure, acute or chronic physical injury,
bone fracture or a crush injury, spinal cord injury, an
inflammatory disease (e.g., pancreatitis), a non-inflammatory
neuropathic or dysfunctional pain condition, or a combination
thereof. In one embodiment the subject is a mammal, e.g., a human,
mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human
primate, such as a monkey, chimpanzee or baboon. In one embodiment,
the subject is a human. In one embodiment a stimulant that has
anti-sedative properties, which can bring pain relief to the
subject with reduced sedative effects common to some opioid
analgesic formulations.
[0074] In some embodiments, the agent useful for reducing or
eliminating an adverse effect associated with administration of an
opioid or non-opioid analgesic agent, is promethazine, dolasetron,
granisetron, ondansetron, tropisetron, palonosetron, domperidone,
droperidol, haloperidol, chlorpromazine, prochloperazine,
metoclopramide, alizapride, cyclizine, diphenhydramine,
dimenhydrinate, meclizine, hydroxyzine, cannabis, dronabinol,
nabilone, midazolam, lorazepam, hyoscine, dexamethasone,
trimethobenzamide, emetrol, or propofol, or pharmaceutically
acceptable salt thereof.
[0075] A composition can be in any form disclosed herein, such as a
multi-layer tablet (e.g., a bi-layer tablet). In one embodiment,
the multi-layer tablet is a bi-layer tablet that comprises: (a) an
immediate-release layer that comprises an effective amount of an
agent which reduces or eliminates an adverse effect of an opioid
analgesic; and (b) a controlled-release layer that comprises an
effective amount of each of an opioid analgesic agent and a
non-opioid analgesic agent.
[0076] In one embodiment, the agent that reduces or eliminates an
adverse effect associated with administration of an opioid or
non-opioid analgesic agent is released in a subject at a
substantially faster rate than an opioid or non-opioid analgesic in
a composition of the invention. For example, in one embodiment, a
plasma concentration of the agent that reduces or eliminates an
adverse effect of an opioid analgesic is achieved in about 1 minute
to about 20 minutes following oral administration, as compared with
a plasma concentration of an analgesic agent, which can be achieved
in about 30 minutes to about 8 hours following oral administration.
In various embodiments, the compositions of the invention comprise
an agent that reduces or eliminates an adverse effect associated
with administration of an opioid analgesic or non-opioid analgesic,
where the agent provides an effective plasma concentration in about
1 minute to about 20 minutes following oral administration.
[0077] In one embodiment, the agent that reduces or eliminates an
adverse effect associated with an opioid or a non-opioid analgesic
is an antihistamine or antiemetic. In various embodiments, As
indicated above, compositions can comprise an antiemetic agent
including, for example, aprepitant, dronabinol, perphenazine,
palonosetron, trimethobenzamide, metoclopramide, domperidone,
prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acetylleucine
monoethanolamine, alizapride, azasetron, benzquinamide,
bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,
metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine,
tropisetron, droperidol, haloperidol, prochloperazine,
metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam,
hyoscine, dexamethasone, emetrol, propofol and a pharmaceutically
acceptable salt or mixtures thereof.
[0078] In one embodiment, a composition comprises an effective
amount of an opioid analgesic agent, a non-opioid analgesic agent,
and an agent that reduces or eliminates an adverse effect
associated with administration of the opioid or non-opioid
analgesic. An adverse effect of opioid or non-opioid analgesic
agents includes but is not limited to nausea, vomiting, other
gastric upset, skin rash, an allergic reaction such as swelling,
difficulty breathing, closing of throat, abdominal pain, unusual
bleeding or bruising, sedation, CNS depression, or respiratory
depression. In one embodiment, the adverse effect that is reduced
or eliminated is nausea, vomiting, constipation, or a combination
thereof.
[0079] In a further embodiment, the opioid analgesic agent is, for
example, hydrocodone, oxycodone propoxyphene, or fentanyl, or a
pharmaceutically acceptable salt thereof; the non-opioid analgesic
agent is, for example, acetaminophen, ibuprofen, ketoprofen,
naproxen, or aspirin or a pharmaceutically acceptable salt thereof;
and the agent useful for preventing and/or suppressing an adverse
effect is, for example, an antihistamine such as promethazine or a
pharmaceutically acceptable salt thereof. In one embodiment of the
invention, the pharmaceutically acceptable salt of naproxen is
naproxen sodium.
[0080] In one embodiment an opioid analgesic agent, a non-opioid
analgesic agent and an agent that reduces or eliminates an adverse
effect are formulated in a bi-layer tablet.
[0081] In one embodiment the bi-layer tablet comprises an
immediate-release layer and a controlled-release layer. In another
embodiment, the immediate-release layer comprises one or more
pharmaceutically active agent disclosed in Table 1 or Table 2 and
the control release layer comprise one or more pharmaceutically
active agents disclosed in Table for Table 2. In a further
embodiment, the immediate-release layer comprises an antiemetic or
antihistamine and the controlled-release layer comprises an opioid
analgesic, a barbiturate, a stimulant, a triptan or a combination
thereof. An illustrative bilayer tablet is depicted in FIG. 2. In
one embodiment, a bilayer tablet of the invention has the
dimensions as depicted in FIG. 2.
[0082] In another embodiment the compositions comprise an effective
amount of each of an analgesic agent, an antitussive agent, and an
agent that reduces or eliminates an adverse effect of the analgesic
agent or the antitussive agent. Under some embodiments the
antitussive is also an analgesic.
[0083] In some embodiments the compositions comprise acetaminophen,
hydrocodone or oxycodone, or a pharmaceutically acceptable salt
thereof; and an antitussive agent such as dolasetron, domperidone,
meclizine, dronabinol, a benzodiazepine, an anticholinergic,
hydrocodone or oxycodone, or a pharmaceutically acceptable salt
thereof.
[0084] In a further embodiment of this invention, the opioid
analgesic agent is, for example, hydrocodone, or oxycodone or a
pharmaceutically acceptable salt thereof; the non-opioid analgesic
agent is, for example, acetaminophen, ibuprofen, ketoprofen,
naproxen, lidocaine, or aspirin or a pharmaceutically acceptable
salt thereof; the antiemetic agent is, for example 5-HT.sub.3
receptor antagonist, a dopamine antagonist, an antihistamine, a
cannabinoid, benzodiazepines, an anticholinergic, wherein all or
less than all of the total amount of the antiemetic agent is
formulated for immediate-release.
[0085] Another embodiment of this invention is directed to methods
for the treatment of pain, comprising administering an effective
amount of each of an opioid analgesic agent, a non-opioid analgesic
agent and an agent that reduces or eliminates an adverse effect of
the opioid analgesic agent to a subject in need thereof.
[0086] The methods allow for use of analgesics in populations at
risk of adverse effect such as nausea, vomiting, other gastric
upsets, skin rashes, allergic reactions such as swelling,
difficulty breathing, closing of throat, abdominal pain, unusual
bleeding or bruising, skin rashes, sedation, CNS depression, or
respiratory depression.
[0087] In one embodiment, the compositions comprise an effective
amount of each of an opioid analgesic, an antiemetic, and an opioid
antagonist, the composition is capable of providing protection from
a metabolic consequence of vomiting, particularly severe vomiting,
in a subject particularly prone to adverse effects associated with
an opioid analgesic. An example of metabolic consequence of
vomiting is dehydration. In a further embodiment, the subject
administered a composition of the invention is about 55 years of
age or older, about 60 years of age or older, about 65 years of age
or older, or about 70 years of age or older. In one embodiment, the
composition administered to such a subject comprises an opioid
analgesic and one or more antiemetic agent. In one embodiment, the
composition comprises oxycodone, promethazine, and naltrexone, or a
pharmaceutically acceptable salt thereof.
[0088] In various embodiments, a dosage form of the invention
provides an effective plasma concentration of an antiemetic or
antihistamine at from about 1 minute to about 20 minutes after
administration, such as about 1 min, 2 min, 3 min, 4 min, 5 min, 6
min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min,
15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23
min, 24 min, 25 min. In some embodiments, the release rate occurs
at substantially faster as compared with release rates for the
analgesic agents. Therefore, in one embodiment, after
administration to a subject, the antihistamine (e.g., promethazine
dolasetron, granisetron, ondansetron, tropisetron, palonosetron,
domperidone, droperidol, haloperidol, chlorpromazine,
prochloperazine, metoclopramide, alizapride, cyclizine,
diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis,
dronabinol, nabilone, midazolam, lorazepam, hyoscine,
dexamethasone, trimethobenzamide, emetrol or propofol, or a
pharmaceutically acceptable salt thereof) is released or an
effective plasma concentration of an antihistamine or antiemetic is
achieved before release of the opioid or non-opioid analgesic.
[0089] In some embodiments, a dosage form of the invention provides
an effective plasma concentration of said opioid analgesic or said
non-opioid analgesic at from about 20 minutes to about 24 hours
after administration, such as about 20 minutes, 30 minutes, 40
minutes, 50 minutes, 1 hr, 1.2 hrs, 1.4 hrs, 1.6 hrs, 1.8 hrs, 2
hrs, 2.2 hrs, 2.4 hrs, 2.6 hrs, 2.8 hrs, 3 hrs, 3.2 hrs, 3.4 hrs,
3.6 hrs, 3.8 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs,
11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19
hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, or 24 hrs following
administration.
[0090] In further embodiments, the opioid or non-opioid analgesic
is present in an effective plasma concentration in a subject from
about 1 hour to 24 hour or 1 day to 30 days, including but not
limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days. In
addition, administration of dosage compositions can be effected
through patch delivery systems which are known in the art.
[0091] In one embodiment compositions comprise an effective amount
of each of an opioid analgesics, a non-opioid analgesic agent, an
antihistamine, anti-psychotic, anti-anxiety agent, or other CNS
depressant is administered a reduced dosage of one or lessen and
adverse effect (e.g. CNS depression). In another embodiment the
dosage of one or more of pharmaceutically active agents is adjusted
according to the severity of the pain and the response of the
subject.
[0092] In subjects having a terminal disease or chronic condition,
pain management can be of a primary concern to the subject's
quality of life.
[0093] In some of these subjects tolerance to opioid analgesics can
develop with continued use. In one embodiment, adjustments are made
to the amounts or time-release characteristics of the component of
a composition, such as a composition comprising an effective amount
of each of an opioid analgesic, a non-opioid analgesic and an
antihistamine. In this embodiment the adjustments can provide pain
relief to a subject with tolerance to opioid analgesics. In one
embodiment the amount of the opioid analgesic may be increased in
the composition. In another embodiment the time release
characteristics of the opioid analgesic may be adjusted so as to
change the ratio of immediate-release opioid analgesic to
controlled-release opioid analgesic.
[0094] In one embodiment, the compositions comprise: hydrocodone,
oxycodone, or a pharmaceutically acceptable salt thereof, in a
dosage range of from about 1.0 mg to about 200 mg; acetaminophen or
a pharmaceutically acceptable salt thereof in a dosage range of
from about 200 mg to about 1000 mg; and, promethazine or a
pharmaceutically acceptable salt thereof in a dosage range of from
about 0.5 mg to about 100 mg.
[0095] In another embodiment, a compositions comprises: oxycodone
or a pharmaceutically acceptable salt thereof in a dosage range of
from about 10 mg to about 80 mg; Naltrexone or a pharmaceutically
acceptable salt thereof in a dosage range of from about 0.5 mg to
about 0.75 mg; and, promethazine or a pharmaceutically acceptable
salt thereof in a dosage range of from about 12.5 mg to about 50
mg.
[0096] In yet another embodiment, the compositions comprises:
oxycodone or a pharmaceutically acceptable salt thereof in a dosage
range of from about 10 mg to about 80 mg; and promethazine or a
pharmaceutically acceptable salt thereof in a dosage range of from
about 12.5 mg to about 50 mg. These compositions can be formulated
using conventional technologies to provide for an extended time
release over a desired dosage interval, such as 4 hours, 6 hours, 9
hours, 12 hours, or 24 hours. In another embodiment, the
compositions comprise about 7.5 mg of hydrocodone, about 325 mg of
acetaminophen or a pharmaceutically acceptable salt thereof, and
about 12.5 mg of promethazine or a pharmaceutically acceptable salt
thereof.
[0097] In another embodiment, the compositions comprise about 7.5
mg of oxycodone or a pharmaceutically acceptable salt thereof,
about 325 mg of acetaminophen or a pharmaceutically acceptable salt
thereof, and about 12.5 mg of promethazine or a pharmaceutically
acceptable salt thereof.
[0098] In another embodiment compositions comprise an effective
amount of hydrocodone or oxycodone, or a pharmaceutically
acceptable salt thereof; an effective amount of acetaminophen or a
pharmaceutically acceptable salt thereof; and an effective amount
of promethazine or a pharmaceutically acceptable salt thereof,
combined in a single, oral pill, tablet or lollipop, form having
dosage levels that can be safely doubled for combating severe
pain.
[0099] In a further embodiment all or less than the entire total
amount of the promethazine or a pharmaceutically acceptable salt
thereof is formulated for immediate-release into the subject's
blood stream.
[0100] In a further embodiment all or less than the entire amount
of the hydrocodone or oxycodone, or a pharmaceutically acceptable
salt thereof is formulated for controlled-release into the
subject's body.
[0101] In various embodiments, the agents are formulated as a
dosage form (e.g., tablet, capsule, gel, lollipop), parenteral,
intraspinal infusion, inhalation, nasal spray, transdermal patch,
iontophoresis transport, absorbing gel, liquid, liquid tannate,
suppositories, injection, I.V. drip, other formulation, or a
combination thereof to treat subjects.
[0102] In another embodiment, the agents are formulated as single
oral dosage form such as a tablet, capsule, cachet, soft gelatin
capsule, hard gelatin capsule, extended release capsule, tannate
tablet, oral disintegrating tablet, multi-layer tablet,
effervescent tablet, bead, liquid, oral suspension, chewable
lozenge, oral solution, lozenge, lollipop, oral syrup, sterile
packaged powder including pharmaceutically-acceptable excipients,
other oral dosage forms, or a combination thereof.
[0103] In another embodiment a composition of the invention
comprises an agent in immediate-release, quick release,
controlled-release, extended release, other release formulations or
patterns, or a combination thereof.
[0104] In one embodiment, a composition of the invention comprises
three active agents, such as a decongestant, an antitussive, an
expectorant, a mucus-thinning drug, an analgesic or an
antihistamine. For example, in one embodiment one of the agents is
an antitussive such as, e.g., codeine, dihydrocodeine, hydrocodone,
dextromethorphan, dextrorphan, or a pharmaceutically acceptable
salt thereof; the other agent is a decongestant such as, e.g.,
phenylephrine, pseudoephedrine, or a pharmaceutically acceptable
salt thereof; and the other agent is an expectorant. One will
recognize that an active agent may fit into more than one category
(e.g., hydrocodone is an antitussive and opioid analgesic).
[0105] In any of the embodiments disclosed herein, a composition of
the invention can be administered using one or more different
dosage forms which are further described herein. For example, a
composition comprising multiple active agents can be administered
in solid, semi-solid, micro-emulsion, gel, patch or liquid form.
Such dosage forms are further described herein. Examples of such
dosage forms are known, such as tablet forms disclosed in U.S. Pat.
Nos. 3,048,526, 3,108,046, 4,786,505, 4,919,939, 4,950,484; gel
forms disclosed in U.S. Pat. Nos. 4,904,479, 6,482,435, 6,572,871,
5,013,726; patches for delivery of pharmaceutical compositions such
as those disclosed in U.S. Pat. Nos. 5,741,510, 4,624,665,
4,626,539, 4,834,978, 6,469,227, 5,919,479, 6,261,595, 6,303,142,
6,341,387, 6,465,006, 6,613,350, 6,780,426, 7,094,228, 6,756,053;
capsule forms disclosed in U.S. Pat. Nos. 4,800,083, 4,532,126,
4,935,243, 6,258,380; liquid forms disclosed in U.S. Pat. Nos.
4,625,494, 4,478,822, 5,610,184; or I.V. forms disclosed in U.S.
Pat. Nos. 4,871,353, 4,925,444, 5,484,406; each of which is
incorporated herein by reference in its entirety.
[0106] Immediate-release refers to the release of an active agent
substantially immediately upon administration. In one embodiment,
immediate-release results in dissolution of an agent within 1-20
minutes after entering the stomach. Dissolution can be of all or
less than the entire amount of the active agent. For example,
dissolution of 100% of an agent (antihistamine or antiemetic) can
occur in the prescribed time. Alternatively, dissolution of less
than all of the agent can occur in about 1 minute to about 20
minutes (e.g., dissolution of about 70%, about 75%, about 80%,
about 85%, about 90%, about 91%, about 92%, about 93%, about 94%,
about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%
or 99.9% of an agent).
[0107] In one embodiment, the compositions comprise an antiemetic
in an amount capable of achieving a serum level Cmax of from about
0.2 ng/mL to about 1 ng/mL at a Tmax of from about 1 to about 6
hours following oral administration. In one embodiment the
antiemetic is promethazine or a pharmaceutically acceptable salt
thereof. In another embodiment, the pharmaceutically acceptable
salt is promethazine HCl. In a further embodiment, the composition
is a bilayer tablet that has an immediate release layer and a
controlled-release layer. In yet a further embodiment, the
controlled release layer comprises an opioid analgesic agent or a
non-opioid analgesic agent. In a further embodiment the
immediate-release layer comprises promethazine or a
pharmaceutically acceptable salt thereof.
[0108] In another embodiment, the compositions comprise
promethazine or a pharmaceutically acceptable salt thereof in an
amount capable of achieving a serum level Cmax of about 0.46 ng/mL
at a Tmax of about 2 to about 3 hours following oral
administration. In one embodiment, the promethazine or a
pharmaceutically acceptable salt is at a dose by weight in the
composition of about 10 mg to about 15 mg. In another embodiment,
the promethazine or pharmaceutically acceptable salt is at a dose
(by weight in the composition) of about 12.5 mg. In a further
embodiment, the composition is in the form of a bilayer tablet that
has an immediate release layer and a controlled-release layer. In
yet another embodiment, the promethazine or a pharmaceutically
acceptable salt is the only pharmaceutically active agent in the
immediate release layer of a bilayer tablet of the invention. In
one embodiment, the promethazine is promethazine HCl. In yet a
further embodiment, the controlled release layer comprises an
opioid analgesic agent or a non-opioid analgesic agent. In a
further embodiment, the opioid analgesic is the only
pharmaceutically active agent in the controlled-release layer of a
bilayer tablet, non-opioid analgesic is the only pharmaceutically
active agent in the controlled-release layer of a bilayer tablet or
both the opioid analgesic and non-opioid analgesic are the only
pharmaceutically active agents of the composition.
[0109] In another embodiment, immediate-release occurs when there
is dissolution of an agent within 1-20 minutes after oral
administration. In another embodiment, immediate-release results in
substantially complete dissolution within about 1 hour following
oral administration. In one embodiment, a composition of the
invention is capable of providing about 80% dissolution of an
antiemetic in about 5 minutes (e.g., FIG. 5).
[0110] In various embodiments, immediate-release occurs when there
is dissolution of an agent within 1-20 minutes after
administration. Dissolution can occur in a subject's stomach and/or
intestine. In another embodiment, immediate-release results in
complete or less than complete dissolution within about 1 hour
following administration to a subject. In another embodiment,
immediate-release results in complete or less than complete
dissolution within about 1 hour following rectal administration.
When used in association with the dissolution profiles discussed
herein, the term "immediate-release" refers to wherein all or less
than the entire amount of a dosage form is dissolved.
[0111] In some embodiments, immediate-release is through
inhalation, such that dissolution occurs in a subject's lungs, as
further described herein. Dissolution of less than all of an active
includes but is not limited to dissolution of about 50%, 60%, 70%,
80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.1%, 99.2%, 99.35, 99.4%,
99.5%, 99.6%, 99.7%, 99.8% or 99.99% of the active agent. Methods
for measuring dissolution profiles are known (e.g., Example 15,
infra).
[0112] In terms of a composition of the invention,
"controlled-release" refers to the release of at least one
pharmaceutically active agent from a dosage form at a particular
desired point in time after the dosage form has is administered to
a subject. Generally, controlled-release includes sustained but
otherwise complete release. A sudden and total release in the
stomach at a desired and appointed time or a release in the
intestines such as through the use of an enteric coating, are both
considered controlled-release. Controlled-release can occur at a
predetermined time or in a predetermined place within the digestive
tract. It is not meant to be a passive, uncontrolled process as in
swallowing a normal tablet. Examples include, but are not limited
to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;
5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,556; 5,871,776;
5,902,632; and 5,837,284 each of which is incorporated herein by
reference in its entirety.
[0113] A control release dosage form begins its release and
continues that release over an extended period of time. Release can
occur beginning almost immediately or can be sustained. Release can
be constant, can increase or decrease over time, can be pulsed, can
be continuous or intermittent, and the like. Generally, however,
the release of at least one pharmaceutically active agent from a
controlled-release dosage form will exceed the amount of time of
release of the drug taken as a normal, passive release tablet.
Thus, for example, while all of at least one pharmaceutically
active agent of an uncoated aspirin tablet should be released
within, for example, four hours, a controlled-release dosage form
could release a smaller amount of aspirin over a period of six
hours, 12 hours, or even longer. Controlled-release in accordance
with the compositions and methods described herein generally means
that the release occurs for a period of six hours or more, such as
12 hours or more.
[0114] Extended-release, or sustained-release, refers to the
release of an agent, from a composition or dosage form in which the
agent is released according to a desired profile over an extended
period of time. In one embodiment, controlled-release results in
dissolution of an agent within 20-720 minutes after entering the
stomach. In another embodiment, controlled-release occurs when
there is dissolution of an agent within 20-720 minutes after being
swallowed. In another embodiment, controlled-release occurs when
there is dissolution of an agent within 20-720 minutes after
entering the intestine. In another embodiment, controlled-release
results in substantially complete dissolution after at least 1 hour
following administration. In another embodiment, controlled-release
results in substantially complete dissolution after at least 1 hour
following oral administration. In another embodiment,
controlled-release results in substantially complete dissolution
after at least 1 hour following rectal administration. For example,
controlled-release compositions allow delivery of an agent to a
subject over an extended period of time according to a
predetermined profile. Such release rates can provide
therapeutically effective levels of agent for an extended period of
time and thereby provide a longer period of pharmacologic or
diagnostic response as compared with conventional rapid release
dosage forms. Such longer periods of response provide for many
inherent benefits that are not achieved with immediate-release
dosages. In using analgesics for treatments of chronic pain,
controlled-release formulations can be used instead of conventional
short-acting formulations. When used in connection with the
dissolution profiles discussed herein, the term
"controlled-release" refers to wherein all or less than all of the
total amount of a dosage form, made according to methods and
compositions described herein, delivers an active agent over a
period of time greater than 1 hour.
[0115] In one embodiment, controlled-release refers to delayed
release of an agent, from a composition or dosage form in which the
agent is released according to a desired profile in which the
release occurs after a period of time.
[0116] When present in a controlled-release oral dosage form, the
compositions described herein can be administered at a
substantially lower daily dosage level than immediate-release
forms. At comparable daily dosage levels, the controlled-release
oral solid dosage forms can provide greater in pain relief than
immediate-release forms.
[0117] Bilayer Tablet
[0118] In one embodiment of the invention, the invention relates to
multi-layer tablets, such as bi-layer tablets. In one embodiment,
the bi-layer tablet comprises: (a) an immediate-release layer; and
(b) a controlled-release layer. In various embodiments, the
immediate-release layer or the controlled-released layer comprises
one or more pharmaceutically active agents. In one embodiment, a
bilayer tablet of the invention has a hardness of about 7, 7.5, 8,
8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 or 15
kiloponds (kp). In one embodiment, the bilayer tablet has a
hardness of about 9.5 kp. In a further embodiment, a bilayer tablet
of the invention has a thickness of about 5, 5.5, 6, 6.5, 7, 7.5,
8, 8.5, 9, 9.5 or 10 mm. It will be understood that as to the
kilopond and thickness measurements, increments of 0.1 decimal
points are within the scope of the invention. A nonlimiting example
of a bilayer tablet of the invention is depicted in FIG. 2. In
various embodiments, the tablet can be rectangular, tubular, oblong
(e.g., FIG. 2), circular, oval or in a capsule form.
[0119] In various embodiments, a bilayer tablet of the invention
provides an effective amount of one or more pharmaceutically active
agents for about 4 to about 6 hours following oral administration,
about 12 hours following oral administration, about 24 hours
following oral administration, or 48 hours following
administration. In various embodiments, the one or more
pharmaceutically active agents provided in 4-6 hour, 12 hour, 24
hour or 48 hour dosing intervals. Therefore, a bilayer tablet of
the invention is capable of providing any of the one or more
pharmaceutically active agents disclosed herein in the foregoing
dosing intervals.
[0120] In one embodiment, a composition comprises promethazine or a
pharmaceutically acceptable salt thereof and about 70 to about 80%
of the promethazine or pharmaceutically acceptable salt thereof
dissolves in the stomach of a subject after about 5 to about 10
minutes following oral administration. In one embodiment, the
promethazine is promethazine HCl.
[0121] In one embodiment, a composition comprises hydrocodone or a
pharmaceutically acceptable salt thereof and about 30 to about 60%
of the hydrocodone or pharmaceutically acceptable salt thereof
dissolves in the stomach of a subject after about 5 to about 10
minutes following oral administration.
[0122] In one embodiment, the hydrocodone salt is hydrocodone
bitartrate. In one embodiment, a composition comprises
acetaminophen or a pharmaceutically acceptable salt thereof and 50%
to about 70% of the acetaminophen or pharmaceutically acceptable
salt thereof dissolves in the stomach of a subject after about 5 to
about 10 minutes following oral administration.
[0123] In one embodiment, the composition comprises promethazine or
a pharmaceutically acceptable salt thereof, hydrocodone or a
pharmaceutically acceptable salt thereof and acetaminophen or a
pharmaceutically acceptable salt thereof, and at least 90% of the
pharmaceutically active agents in the composition dissolve in the
stomach of a subject after about 45 minutes following oral
administration. In one embodiment, the composition is a bilayer
tablet comprising an immediate-release layer and a
controlled-release layer.
[0124] In one embodiment, the immediate release layer comprises
promethazine or a pharmaceutically acceptable salt as the only
pharmaceutically active agent. In another embodiment, the
controlled-release layer comprises hydrocodone or a
pharmaceutically acceptable salt and acetaminophen or a
pharmaceutically acceptable salt as the only pharmaceutical
ingredients.
[0125] In yet another embodiment, the controlled release layer
comprises an opioid analgesic or a non-opioid analgesic as the only
pharmaceutically active agent. In another embodiment, the
controlled release layer comprises an opioid analgesic and a
non-opioid analgesic as the only pharmaceutically active agents. In
another embodiment the immediate release layer comprises an
antiemetic or a stimulant as the only pharmaceutically active
agent. In another embodiment the immediate release layer comprises
an antiemetic and a stimulant as the only pharmaceutically active
agents.
[0126] Immediate-Release Layer
[0127] In one embodiment, the immediate-release layer is capable of
releasing about 70 to about 80% of the one or more pharmaceutically
active agent contained therein in the stomach of a subject in about
5 to about 10 minutes following oral administration. In one
embodiment, the immediate-release layer is capable of releasing
about 90 to about 100% of one or more pharmaceutically active agent
contained therein in the stomach of a subject in about 40
minutes.
[0128] In one embodiment, the one or more pharmaceutically active
agent in the immediate-release layer is an antiemetic. In one
embodiment, the antiemetic is promethazine or a pharmaceutically
acceptable salt thereof. In another embodiment, the antiemetic is
promethazine HCl.
[0129] In one embodiment, an immediate-release layer comprises two
or more agents, including an anti-emetic and a stimulant.
[0130] In some embodiments, the immediate-release layer comprises
one or more excipients, including but not limited to silicified
microcrystalline cellulose (e.g., HD90), croscarmellose sodium
(AC-Di-Sol), magnesium stearate. In one embodiment, the total layer
weight of the immediate-release layer is from about 100 to about
300 mg, such as about 110 mg, about 120 mg, about 130 mg, about 140
mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about
190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg,
about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280
mg, about 290 mg, or about 300 mg.
[0131] In one embodiment, the immediate-release layer comprises
from about 75 mg to about 150 mg of silicified microcrystalline
cellulose, from about 10 mg to about 20 mg croscarmellose sodium,
from about 0.5 mg to 2 mg magnesium stearate. In yet a further
embodiment, the immediate-release layer comprises from about 10 to
about 15 mg promethazine, or a pharmaceutically acceptable salt
thereof. In another embodiment, the immediate-release layer
comprises about 12.5 mg promethazine or a pharmaceutically
acceptable salt thereof. In another embodiment, the
pharmaceutically acceptable salt is promethazine HCl.
[0132] In one embodiment, the immediate-release layer comprise
about 12.5 mg promethazine HCl, about 121.5 mg silicified
microcrystalline cellulose, about 15 mg croscarmellose sodium, and
about 1 mg magnesium stearate.
[0133] In one embodiment, a composition comprising an effective
amount of each of hydrocodone bitartrate, acetaminophen and
promethazine HCl is capable of dissolving in the stomach of a
subject so that an effective plasma concentration of each of
pharmaceutically active ingredient is present in a subject in from
about 5 minutes to about 30 minutes.
[0134] Controlled-Release Layer
[0135] In one embodiment, the controlled-release layer is capable
of releasing about 30 to about 40% of the one or more
pharmaceutically active agent contained therein in the stomach of a
subject in about 5 to about 10 minutes following oral
administration. In another embodiment, the controlled-release layer
is capable of releasing about 90% of the one or more
pharmaceutically active agents are released in about 40 minutes
after oral administration.
[0136] In some embodiment, the controlled-release layer comprises
one or more excipients, including but not limited to silicified
microcrystalline cellulose (e.g., HD90), croscarmellose sodium
(AC-Di-Sol), magnesium stearate. In one embodiment, the total layer
weight of the controlled-release layer is from about 100 to about
300 mg, such as about 110 mg, about 120 mg, about 130 mg, about 140
mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about
190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg,
about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280
mg, about 290 mg, or about 300 mg.
[0137] In one embodiment, a controlled-release layer comprises from
about 75 mg to about 250 mg of silicified microcrystalline
cellulose, from about 10 mg to about 40 mg hydroxyl methyl propyl
cellulose, from about 0.5 mg to 5 mg magnesium stearate, and from
about 0.5 mg to about 5 mg stearic acid.
[0138] In one embodiment, the controlled-release layer comprises
about 152 mg silicified microcrystalline cellulose, about 20 mg
hydroxyl methyl propyl cellulose, about 2.75 mg magnesium stearate,
about 2.75 stearic acid, about 7.5 mg hydrocodone, or a
pharmaceutically acceptable salt thereof and about 325 mg
acetaminophen or a pharmaceutically acceptable salt thereof. In yet
a further embodiment, the controlled-release layer comprises from
about 5 mg to about 12.5 mg hydrocodone or a pharmaceutically
acceptable salt thereof. In one embodiment, the controlled-release
layer comprises about 7.5 mg hydrocodone or a pharmaceutically
acceptable salt thereof. In another embodiment, the opioid
analgesic is oxycodone or a pharmaceutically acceptable salt
thereof. In one embodiment, the pharmaceutically acceptable salt is
oxycodone HCl. In another embodiment, the pharmaceutically
acceptable salt for hydrocodone is hydrocodone bitartrate.
[0139] In yet a further embodiment, the controlled-release layer
further comprises from about 290 mg to about 360 mg acetaminophen
or a pharmaceutically acceptable salt thereof. In one embodiment
the controlled-release layer comprises about 325 mg acetaminophen
or a pharmaceutically acceptable salt thereof.
[0140] In one embodiment, the immediate-release layer comprises
promethazine HCl and the controlled-release layer comprises
hydrocodone bitartrate. In another embodiment, the
controlled-release layer further comprises a non-opioid analgesic
(e.g., acetaminophen).
[0141] In one embodiment, the one or more pharmaceutically active
agents of the controlled-release layer is an opioid analgesic. In
one embodiment, the opioid analgesic is hydrocodone or oxycodone;
or a pharmaceutically acceptable salt thereof. In one embodiment,
the immediate-release layer is about 150 mg in total layer weight
and the controlled-release layer is about 550 mg total weight.
[0142] Furthermore, in one embodiment, the controlled-release layer
comprises about 325 mg acetaminophen, about 7.5 mg hydrocodone
bitartrate, about 152 mg silicified microcrystalline cellulose,
about 20 mg hydroxyl methyl propyl cellulose (HPMC), about 2.75 mg
magnesium stearate, and about 2.75 mg stearic acid; and the
immediate-release layer comprises about 12.5 mg promethazine HCl,
about 121 mg silicified microcrystalline cellulose, about 15 mg
croscarmellose sodium, and about 1 mg magnesium stearate.
[0143] In various embodiments, a bilayer tablet of the invention
can comprise the combinations of pharmaceutically active agents in
Table 1 or Table 2, wherein the controlled-release layer comprises
one or more opioid analgesic agents, triptan agents, non-analgesic
agents, barbiturates or stimulants, and the immediate-release layer
comprises one or more stimulants.
[0144] In one embodiment, a stimulant is present in the
immediate-release layer, controlled-release layer or both layers;
the immediate-release layer comprises one or more antiemetic or
antihistamines; and the controlled-release layer comprises one or
more non-opioid analgesics. In addition, either layer of the
bilayered tablet can comprise one or more anti-abuse agents
disclosed herein.
[0145] In one embodiment, a bilayer tablet of the invention
comprises a controlled-release layer comprising one or more
analgesic agents as the only pharmaceutically active agents in the
controlled-release layer. In another embodiment, a bilayer tablet
of the invention comprises an immediate-release layer comprising an
antiemetic agent as the only pharmaceutically active agent in the
immediate-release layer.
[0146] In another embodiment the controlled release layer further
comprises one or more of: silicified microcrystalline cellulose,
hydroxy methyl propyl cellulose, magnesium stearate, and stearic
acid. In another embodiment the immediate-release layer further
comprises one or more of: silicified microcrystalline cellulose,
croscarmellose sodium and magnesium stearate. In another embodiment
the tablet has a hardness of about 9.5 kilopond and thickness from
about 6.9 to about 7.0 mm. In another embodiment the hydrocodone
salt is hydrocodone bitartrate. In another embodiment the
promethazine salt is promethazine HCL. In another embodiment the
controlled release layer is an inner layer and wherein the
immediate-release layer is an outer layer.
[0147] In one embodiment the opioid analgesic is oxycodone or
pharmaceutically acceptable salt thereof; and the one or more
antiemetic is promethazine or a pharmaceutically acceptable salt
thereof. In another embodiment the effective amount is an amount
effective for treating or preventing pain for a period of about 12
hours immediately following administration to a subject. In another
embodiment the bi-layer tablet comprises an immediate release layer
and a controlled release layer. In another embodiment the immediate
release layer comprises the promethazine or pharmaceutically
acceptable salt thereof, and wherein the controlled release layer
comprises the oxycodone, or a pharmaceutically acceptable salt
thereof. In another embodiment about 70% of the promethazine or
pharmaceutically acceptable salt thereof is capable of dissolving
in a liquid solution in about 5 minutes after contact with the
solution, and wherein about 30% of the oxycodone or
pharmaceutically acceptable salt is capable of dissolving in a
liquid solution in about 10 minutes after contact with the
solution. In another embodiment the controlled release layer
further comprises an antiemetic agent.
[0148] In one embodiment the effective amount of the hydrocodone or
pharmaceutically acceptable salt thereof is an amount effective for
treating or preventing pain for a period of about 12 hours
immediately following administration to a subject. In another
embodiment the controlled release layer comprises about 7.5 mg of
hydrocodone or a pharmaceutically acceptable salt thereof, about
325 mg of acetaminophen or a pharmaceutically acceptable salt
thereof, about 152 mg of silicified microcrystalline cellulose,
about 20 mg of hydroxy methyl propyl cellulose, about 2.7 mg of
magnesium stearate, and about 2.7 mg of stearic acid; and the
immediate release layer comprises about 12.5 mg of promethazine or
a pharmaceutically acceptable salt thereof, about 121.5 mg of
silicified microcrystalline cellulose, about 15 mg of
croscarmellose sodium and about 1 mg of magnesium stearate.
[0149] In another embodiment the composition further comprises an
effective amount of naltrexone or a pharmaceutically acceptable
salt thereof. In another embodiment the composition is in the form
of a bi-layer tablet. In another embodiment the effective amount of
the morphine or pharmaceutically acceptable salt thereof is an
amount effective for treating or preventing pain for a period of
about 12 hours immediately following administration to a
subject.
[0150] In one embodiment the controlled release layer comprises
about 7.5 mg of hydrocodone or a pharmaceutically acceptable salt
thereof, and about 325 mg of acetaminophen or a pharmaceutically
acceptable salt thereof; and further wherein the immediate-release
layer comprises about 12 mg of promethazine or a pharmaceutically
acceptable salt thereof.
[0151] In one embodiment the effective amount is an amount
effective for treating or preventing pain for a period of about 12
hours immediately following administration to a subject.
[0152] In one embodiment the effective amount of the oxycodone or
pharmaceutically acceptable salt thereof is an amount effective for
treating or preventing pain for a period of about 12 hours
immediately following administration to a subject.
[0153] Combination Formulations
[0154] Various embodiments of the invention are directed to
compositions comprising an effective amount of each of an analgesic
and an active agent that is useful for reducing an adverse effect
associated with such one or more opioid analgesics, or one or more
non-opioid analgesic. Various embodiments for compositions of the
invention are provided in Table 1 or Table 2.
[0155] Such additional active agents include antiemetics and
antihistamines. In some embodiments, the analgesics are opioid or
non-opioid analgesics (e.g., hydrocodone or oxycodone, or a
pharmaceutically acceptable salt thereof and acetaminophen or a
pharmaceutically acceptable salt thereof). In a further embodiment,
the active agent which reduces adverse effects of such analgesics
is promethazine or a pharmaceutically acceptable salt thereof.
[0156] In one embodiment, a composition of the invention allows for
higher dosages for said analgesics in the composition, by reducing
adverse effects associated with an opioid or non-opioid analgesic.
For example, in a subject who could not otherwise tolerate a
particular dosage of an opioid analgesic, it is believed that a
composition of the invention comprising an effective amount of each
of an opioid analgesic, a non-opioid analgesic and promethazine or
a pharmaceutically acceptable salt thereof, will reduce an adverse
effects (e.g. nausea or vomiting) associated with an opioid
analgesic, thus allowing for increased dosages to be administered.
Furthermore, administration can be through a single
composition.
[0157] In various embodiments, the analgesic agent of the
composition is an opioid analgesic agent such as hydrocodone,
oxycodone, acetyldihydrocodeinone, diamorphine, codeine, pethidine,
alfentanil, buprenorphine, butorphanol, codeine, dezocine,
fentanyl, hydromorphone, levomethadyl acetate, levorphanol,
meperidine, methadone, morphine sulfate, nalbuphine, oxymorphone,
pentazocine, propoxyphene, remifentanil, sufentanil, tramadol, or a
pharmaceutically acceptable salt thereof. In one embodiment, the
opioid analgesic agent is hydrocodone, oxycodone, propoxyphene, or
fentanyl or a pharmaceutically acceptable salt thereof.
[0158] In another embodiment, a dosage form comprises an opioid
analgesic and one or more antiemetic. In another embodiment, a
dosage form comprises hydrocodone or oxycodone or a
pharmaceutically acceptable salt thereof and one or more
antiemetic, which are disclosed herein.
[0159] In some embodiments, a composition of the invention
comprises an opioid antagonist agent or abuse deterrent agent such
as nalmefene, naloxone, niacin, naltrexone or a pharmaceutically
acceptable salt thereof. The composition can further comprise an
antitussive such as codeine or dextromethorphan, dextrorphan, or a
pharmaceutically acceptable salt thereof.
[0160] As stated above, a pharmaceutically active agent can be in
the form of a pharmaceutically acceptable salt. Each agent
disclosed herein can be used in a composition of the invention as
its free base or its pharmaceutically acceptable salt, prodrug,
analog and complex. In various embodiments of the invention, with
respect to a pharmaceutically active agent in a composition, a
pharmaceutically acceptable salt includes, but is not limited to,
metal salts, such as sodium salts, potassium salts, and lithium
salts; alkaline earth metals, such as calcium salts, magnesium
salts, and the like; organic amine salts, such as triethylamine
salts, pyridine salts, picoline salts, ethanolamine salts,
triethanolamine salts, dicyclohexylamine salts,
N,N'-dibenzylethylenediamine salts, and the like; inorganic acid
salts such as hydrochloride salts, hydrobromide salts, sulfate
salts, phosphate salts, and the like; organic acid salts such as
formate salts, acetate salts, trifluoroacetate salts, maleate
salts, tartrate salts, and the like; sulfonate salts such as
methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate
salts, and the like; and amino acid salts, such as arginate salts,
asparginate salts, glutamate salts, and the like.
[0161] In addition, pharmaceutically acceptable salts include
bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate,
phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate,
pentafluoropropionate, hydrobromide, mucate, oleate, phosphate
dibasic, phosphate monobasic, acetate trihydrate,
bis(heptafuorobutyrate), bis(pentafluoropropionate), bis(pyridine
carboxylate), bis(trifluoroacetate), chlorhydrate, and sulfate
pentahydrate. In one embodiment the agent is hydrocodone, a
pharmaceutically acceptable salt or its thiosemicarbazone,
p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis
(methylcarbamate). In another embodiment the agent is oxycodone, a
pharmaceutically acceptable salt or its thiosemicarbazone,
p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis
(methylcarbamate). In a further embodiment the agent is
acetaminophen, a pharmaceutically acceptable salt or its
thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime,
semicarbazone, or bis (methylcarbamate). In another embodiment an
agent is promethazine, a pharmaceutically acceptable salt or its
thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime,
semicarbazone, or bis (methylcarbamate). Other representative
pharmaceutically acceptable salts include, e.g., water-soluble and
water-insoluble salts, such as the acetate,
amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, butyrate,
calcium edetate, camphorsulfonate, camsylate, carbonate, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts. A hydrate is
another example of a pharmaceutically acceptable salt.
[0162] In some embodiments, a composition of the invention
comprises an effective amount of each of an opioid analgesic agent
and a non-opioid analgesic agent, where the opioid analgesic
agent/non-opioid analgesic agent is codeine/acetaminophen,
codeine/aspirin, codeine/naproxen, codeine/ibuprofen,
hydrocodone/acetaminophen, hydrocodone/ibuprofen,
hydrocodone/naproxen, hydrocodone/aspirin, oxycodone/acetaminophen,
oxycodone/aspirin, oxycodone/naproxen, oxycodone/ibuprofen,
propoxyphene/aspirin, propoxyphene/ibuprofen,
propoxyphene/acetaminophen, or propoxyphene/naproxen, wherein the
opioid analgesic agent or non-opioid analgesic agent is optionally
in the form of a or a pharmaceutically acceptable salt thereof. In
one embodiment, the hydrocodone salt is hydrocodone bitartrate, the
oxycodone salt is oxycodone HCl, and the naproxen salt is naproxen
Na or Mg.
[0163] In some embodiments the compositions disclosed herein may
further comprise one or more of an opioid antagonist agent, abuse
deterrent agent, a barbiturate agent, a stimulant agent, or an
antiemetic agent.
[0164] Therefore, in some embodiments, a composition comprises an
effective amount of an opioid analgesic agent (such as hydrocodone
or oxycodone or a pharmaceutically acceptable salt thereof), a
non-opioid analgesic agent (such as acetaminophen or naproxen or a
pharmaceutically acceptable salt thereof) and an active agent
useful for reducing or eliminating adverse effects, such as an
antihistamine (e.g., promethazine or a pharmaceutically acceptable
salt thereof) or an antiemetic, as described herein. In one
embodiment the composition is in the form of a bi-layer tablet that
comprises an immediate-release layer and a controlled-release
layer. In a further embodiment the immediate-release layer
comprises one or more of an opioid agent, a non-opioid analgesic
agent and an active agent useful for reducing or eliminating
adverse effects. In a further embodiment a controlled-release layer
comprises an effective amount of one or more of an opioid agent, a
non-opioid analgesic agent and an active agent useful for reducing
or eliminating adverse effects associated with administration of an
opioid analgesic agent or non-opioid analgesic agent. In some
embodiments a composition further comprises an effective amount of
an opioid antagonist agent or abuse deterrent agent. In a specific
embodiment the composition comprises hydrocodone or oxycodone, or a
pharmaceutically acceptable salt thereof, acetaminophen or a
pharmaceutically acceptable salt thereof, or naproxen or a
pharmaceutically acceptable salt thereof, and promethazine or a
pharmaceutically acceptable salt thereof.
[0165] Examples of non-opioid analgesic agents useful in the
compositions of the invention include but are not limited to
acetaminophen; a non-steroidal anti-inflammatory drug (NSAID) such
as a salicylate (including, for example, amoxiprin, benorilate,
choline magnesium salicylate, diflunisal, faislamine, methyl
salicylate, magnesium salicylate), an arylalkanoic acid (including,
for example, diclofenac, aceclofenac, acemetacin, bromfenac,
etodolac, indometacin, nabumetone, sulindac, tolmetin), a profen
(including, for example, ibuprofen, carprofen, fenbuprofen,
flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen,
suprofen), a fenamic acid (including, for example mefenamic acid,
meclofenamic acid), an oxicam (including, for example, piroxicam,
lomoxicam, meloxicam, tenoxicam), a pyrazolidine derivative
(including, for example, phenylbutazone, azapropazone, metamizole,
oxyphenbutazone, sulfinprazone) or a pharmaceutically acceptable
salt thereof; a Cox-2 inhibitor (such as valdecoxib, celecoxib,
rofecoxib or a pharmaceutically acceptable salt thereof), a local
analgesic (such as lidocaine, mexiletine or a pharmaceutically
acceptable salt thereof); an anti-depressant (such as
amitriptyline, carbamazepine, gabapentin, pregabalin, amoxapine,
clomipramine, desipramine, dosulepin, doxepin, imipramine,
iprindole, lofepramine, nortriptyline, opipramol, protryptyline,
trimipramine or a pharmaceutically acceptable salt thereof) an
atypical analgesic (such as orphenadrine, cyclobenzaprine,
scopolamine, atropine, gabapentin or a pharmaceutically acceptable
salt thereof), a psychotropic agent (such as tetrahydrocannabinol
or a pharmaceutically acceptable salt thereof), an NMDA receptor
antagonist (such as ketamine, amantadine, dextromethorphan,
dextrorphan, ibogaine, phencyclidine, riluzole, tiletamine,
memantine, dizocilpine, patiganel, remacimide, or a
pharmaceutically acceptable salt thereof), an
.alpha..sub.2-adrenoreceptor agonists (such as clonidine or a
pharmaceutically acceptable salt thereof) and a synthetic drug
having narcotic properties such as tramadol. In one embodiment the
non-opioid analgesic agent is acetaminophen, naproxen or a
pharmaceutically acceptable salt thereof.
[0166] The agent useful for preventing or alleviating an adverse
effect associated with administration of an opioid analgesic or a
non-opioid analgesic, a triptan, barbiturate or morphine narcotic,
includes, for example, an antihistamine including a histamine
agonist and an antagonist which is classified according to receptor
subtype.
[0167] Such antihistamines include H1 agonists and H1 antagonists.
H1 agonists or partial agonists include
2-(m-fluorophenyl)-histamine and H1 antagonists include
chlorpheniramine, scopolamine, mepyramine, terfenadine, astemizole,
and triprolidine. Further antagonists (which may be further
classified by their chemical structures) include the ethanolamines
carbinoxamine, dimenhydrinate, diphenhydramine, and doxylamine; the
ethylaminediamines pyrilamine and tripelennamine; the piperazine
derivatives dydroxyzine, cyclizine, fexofenadine and meclizine; the
alkylamines brompheniramine and chlorpheniramine; and miscellaneous
antagonists cyproheptadine, loratadine, cetrizine. H2 agonists
include dimaprit, impromidine, and amthamine; and H2 antagonists
(useful in the treatment of gastric acid secretion) include
cimetidine, ranitidine, nizatidine, and famotidine; H3 agonists
include R-alpha-methylhistamine, imetit, and immepip and H3
antagonists include thioperamide, iodophenpropit, and clobenpropit;
and H4 agonists include clobenpropit, imetit, and clozapine and H4
antagonists include thioperamide.
[0168] The agent useful for preventing or suppressing a adverse
effect can also include an H1 blocker, such as azelastine,
brompheniramine, buclizine, carbinoxamine, cetrizine,
chlorpheniramine, clemastine, cyclizine, cyproheptadine,
desloratidine, dimenhydrinate, diphenhydramine, emedastine,
fexofenadine, hydroxyzine, ketotifen, levocabastine, loratadine,
meclizine, olopatadine, phenindamine, and promoathazine.
[0169] In various embodiments compositions comprise two, three,
four, five, six or more active agents. In one embodiment at least
one of the active agents is an antiemetic or antihistamine. In
other embodiment, a composition does not comprise promethazine or a
pharmaceutically acceptable salt. As indicated herein, a
composition can comprise pharmaceutically active agents in the
combinations provided in Table 1 or Table 2.
[0170] As indicated above, compositions can comprise an antiemetic
agent including, for example, aprepitant, dronabinol, perphenazine,
palonosetron, trimethyobenzamide, metoclopromide, domperidone,
prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acetylleucine
monoethanolamine, alizapride, azasetron, benzquinamide,
bietanautine, bromopride, buclizine, clebopride, cyclizine,
dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,
metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine,
tropisetron, droperidol, haloperidol, prochloperazine,
metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam,
hyoscine, dexamethasone, emetrol, propofol and a pharmaceutically
acceptable salt or mixtures thereof.
[0171] In another embodiment the composition can comprise an
antitussive agent including, for example, dextromethorphan,
dextrorphan, noscapine, ethyl morphine, codeine, camphor, menthol,
theobromine, guaifenesin, or the like.
[0172] In various embodiments of the invention, a composition
comprises at least two analgesics; and one or more additional
pharmaceutically active agents disclosed in Table 1 or Table 2. In
one embodiment, the composition further comprises one antihistamine
or antiemetic.
[0173] In some embodiments a composition comprises a stimulant
agent. Stimulant agents useful in the methods and compositions of
the invention include, but are not limited to, aminophylline,
caffeine, dyphlline, oxitriphylline, theophhylline, amphetamine,
benzphetamine, dextroamphetamine, diethylpropion, mazindol,
methamphetamine, methylphenidate, dexmethylphenidate, pemoline,
sibutramine, modafinil, atomoxetine, phendimetrizine, phenteramine,
adrafinil, phenylpropanolamine, psuedoephedrine, Synephrine,
amphetaminil, furfenorex, or a combination thereof. In some
embodiments, compositions comprise a stimulant agent that provides
an anti-sedative effect.
[0174] A stimulant agent can be an amphetamine, examples of which
include but are not limited to methamphetamine, levoamphetamine,
dextroamphetamine, 3,5-methyloxy amphetamine,
2,5-dimethoxy-4-methylthioamphetamine,
2,5-dimethoxy-4-ethylthioamphetamine,
2,5-dimethoxy-4-(i)-propylthioamphetamine,
2,5-dimethoxy-4-phenylthioamphetamine,
2,5-dimethoxy-4-(n)-propylthioamphetamine, Brolamfetamine,
2,5-dimethoxy-4-iodoamphetamine, 2,5-Dimethoxy-4-methylamphetamine,
2,5-Dimethoxy-4-butyl-amphetamine,
3,4-Dimethyl-2,5-dimethoxyamphetamine, 2-Phenylethylamine,
propylamphetamine, methylphenidate, lisdexamfetamine,
ethylamphetamine, MDMA (3,4-methylenedioxy-N-methylamphetamine),
MDEA (3,4-methylenedioxy-N-ethylamphetamine), PMA
(p-methoxyamphetamine), DMA
(2-(2,4-Dimethoxy-phenyl)-1-methyl-ethylamine), benzphetamine,
4-FMP (para-fluoroamphetamine), or 4-MTA (4-Methylthioamphetamine),
or a pharmaceutically acceptable salt thereof.
[0175] In one embodiment, a composition is provided that comprises
an effective amount of an opioid (such as hydrocodone,
propoxyphene, fentanyl or oxycodone, or a pharmaceutically
acceptable salt thereof) and a stimulant (such as modafinil or
caffeine, or a pharmaceutically acceptable salt thereof). In some
embodiments a composition further comprises an antiemetic. In one
embodiment, the antiemetic is promethazine or a pharmaceutically
acceptable salt thereof. In yet another embodiment, the composition
further comprises a non-analgesic agent disclosed herein. In one
embodiment, the non-opioid analgesic is acetaminophen or a
pharmaceutically acceptable salt thereof, or naproxen or a
pharmaceutically acceptable salt thereof.
[0176] In a further a composition is in the form of a bilayer
tablet comprising an immediate-release layer and a
controlled-release layer, wherein the immediate-release layer
comprises and/or the chronic-release layer comprise a stimulant
agent. In one embodiment, the controlled-release layer comprises an
opioid agent. In yet a further embodiment, the controlled-release
layer further comprises an effective amount of a second or same
stimulant agent as compared to the immediate-release layer. In yet
another embodiment, the immediate-release layer and/or the
controlled-release layer further comprises an antiemetic agent. In
a further embodiment the immediate-release layer comprises an
effective amount of one or more of an opioid agent, a stimulant
agent and an antiemetic agent. In another further embodiment a
controlled-release layer comprises an effective amount of one or
more of an opioid agent, a stimulant agent, and an antiemetic
agent. In some embodiments the composition further comprises an
effective amount of an opioid antagonist agent or abuse deterrent
agent.
[0177] In a specific embodiment a composition is provided that
comprises hydrocodone or oxycodone, or a pharmaceutically
acceptable salt thereof, modafinil or caffeine or a
pharmaceutically acceptable salt thereof and optionally
promethazine or a pharmaceutically acceptable salt thereof.
[0178] In some embodiments compositions comprise a barbiturate
active agent. Barbiturate agents useful in the methods and
compositions include, but are not limited to, Allobarbital,
Alphenal, Amobarbital, Aprobarbital, Barbexaclone, Barbital,
Brallobarbital, Butabarbital, Butalbital, Butobarbital,
Butallylonal, Crotylbarbital, Cyclobarbital, Cyclopal,
Ethallobarbital, Febarbamate, Heptabarbital, Hexethal,
Hexobarbital, Mephobarbital, Metharbital, Methohexital,
Methylphenobarbital, Narcobarbital, Nealbarbital, Pentobarbital,
Primidone, Probarbital, Propallylonal, Proxibarbal, Proxibarbital,
Reposal, Secbutabarbital, Secobarbital, Sigmodal, Talbutal,
Thialbarbital, Thiamylal, Thiobarbital, Thiobutabarbital,
Thiopental, Valofane, Vinbarbital, Vinylbital, 1,3-dimethoxymethyl
5,5-diphenyl-barbituric acid (DMMDPB), 1-monomethoxymethyl
5,5-diphenylbarbituric acid (MMMDPB), a diphenyl-barbituric acid
(DPB) and their precursors, derivatives and analogs or a
combination thereof and a pharmaceutically acceptable salt
thereof.
[0179] In another embodiment, a composition is provided that
comprises an effective amount of an opioid agent (such as
hydrocodone, propoxyphene, fentanyl or oxycodone, or a
pharmaceutically acceptable salt thereof); a non-opioid agent (such
as acetaminophen or naproxen, or a pharmaceutically acceptable salt
thereof); a barbiturate agent (such as butalbital, or a
pharmaceutically acceptable salt thereof) and optionally an
antiemetic (such as promethazine, or a pharmaceutically acceptable
salt thereof).
[0180] In a further embodiment a composition is in the form of a
bilayer tablet, wherein the composition comprises an effective
amount of each of an opioid agent, a non-opioid analgesic agent, a
barbiturate agent and an antiemetic agent. In one embodiment the
bi-layer tablet comprises an immediate-release layer and a
controlled-release layer. In a further embodiment the
immediate-release layer comprises an effective amount of one or
more of an opioid agent, a non-opioid analgesic agent, a
barbiturate agent and an antiemetic agent. In another further
embodiment a controlled-release layer comprises an effective amount
of one or more of an opioid agent, a barbiturate agent, a
non-opioid analgesic agent, and an antiemetic agent. In some
embodiments a composition further comprises an effective amount of
an opioid antagonist agent or abuse deterrent agent. In a specific
embodiment a composition comprises hydrocodone or oxycodone, or a
pharmaceutically acceptable salt thereof acetaminophen, or a
pharmaceutically acceptable salt thereof, butalbital or a
pharmaceutically acceptable salt thereof and optionally
promethazine or a pharmaceutically acceptable salt thereof.
[0181] In another embodiment an a composition comprises an
effective amount of each of an opioid agent (such as hydrocodone,
propoxyphene, fentanyl or oxycodone or a pharmaceutically
acceptable salt thereof); a barbiturate agent (such as butalbital
or a pharmaceutically acceptable salt thereof); a stimulant agent
(such as modafinil or caffeine or a pharmaceutically acceptable
salt thereof); and optionally a non-opioid agent (such as
acetaminophen or naproxen or a pharmaceutically acceptable salt
thereof). In some embodiments the composition further comprises an
antiemetic (such as promethazine or a pharmaceutically acceptable
salt thereof).
[0182] In one embodiment, such a composition is in the form of a
bi-layer tablet, wherein the composition comprises an effective
amount of an opioid agent, a non-opioid analgesic agent, a
barbiturate agent, a stimulant agent and optionally an antiemetic
agent. In one embodiment the bi-layer tablet comprises an
immediate-release layer and a controlled-release layer. In a
further embodiment the immediate-release layer comprises an
effective amount of one or more of an opioid agent, a non-opioid
analgesic agent, a barbiturate agent, a stimulant agent and an
antiemetic agent. In another further embodiment a
controlled-release layer comprises an effective amount of one or
more of an opioid agent, a non-opioid analgesic agent, a
barbiturate agent, a stimulant agent and an antiemetic agent. In
some embodiments a composition further comprises an effective
amount of an opioid antagonist agent or abuse deterrent agent. In a
specific embodiment a composition comprises hydrocodone,
propoxyphene or oxycodone, or a pharmaceutically acceptable salt
thereof; butalbital, naproxen, caffeine or a pharmaceutically
acceptable salt thereof; and optionally promethazine or a
pharmaceutically acceptable salt thereof.
[0183] In another embodiment a composition comprises an effective
amount of an opioid agent (hydrocodone or oxycodone or a
pharmaceutically acceptable salt thereof); and a barbiturate agent
(such as butalbital or a pharmaceutically acceptable salt thereof).
In some embodiments a composition further comprises an antiemetic
(such as promethazine or a pharmaceutically acceptable salt
thereof). In a further the composition is in the form of a bi-layer
tablet, wherein the composition comprises an effective amount of
each of an opioid analgesic agent, a barbiturate agent, and
optionally an antiemetic agent. In one embodiment the bi-layer
tablet comprises an immediate-release layer and a
controlled-release layer. In a further embodiment the
immediate-release layer comprises an effective amount of each of
one or more of an opioid analgesic agent, a barbiturate agent, or
an antiemetic agent. In another a further embodiment a
controlled-release layer comprises an effective amount of each of
one or more of an opioid analgesic agent, a barbiturate agent, or
an antiemetic agent. In some the composition further comprises an
effective amount of an opioid antagonist agent or abuse deterrent
agent. In a specific embodiment a composition comprises butalbital,
hydrocodone or oxycodone, or a pharmaceutically acceptable salt
thereof and optionally promethazine or a pharmaceutically
acceptable salt thereof.
[0184] In another embodiment a composition comprises an effective
amount of a non-opioid agent (such as acetaminophen, naproxen or
ibuprofen or a pharmaceutically acceptable salt thereof); a
barbiturate agent (such as butalbital or a pharmaceutically
acceptable salt thereof); and an antiemetic (such as promethazine
or a pharmaceutically acceptable salt thereof). In one embodiment,
the composition comprises about 50 mg butalbital or a
pharmaceutically acceptable salt thereof, about 325 mg
N-Acetyl-p-Aminophenol or a pharmaceutically acceptable salt
thereof, and about 12.5 mg promethazine or a pharmaceutically
acceptable salt thereof. In one embodiment, the promethazine salt
is promethazine HCl.
[0185] In another embodiment a composition comprises an effective
amount of each of a non-opioid agent (such as acetaminophen,
naproxen or ibuprofen or a pharmaceutically acceptable salt
thereof); a barbiturate agent (such as butalbital or a
pharmaceutically acceptable salt thereof); and a stimulant agent
(such as modafinil or caffeine or a pharmaceutically acceptable
salt thereof). In some embodiments the composition further
comprises an antiemetic (such as promethazine or a pharmaceutically
acceptable salt thereof). In a further embodiment an effective
amount of a composition is in the form of a bi-layer tablet,
wherein the composition comprises an effective amount of each of a
non-opioid analgesic agent, a barbiturate agent, a stimulant agent
and optionally an antiemetic agent. In one embodiment the bi-layer
tablet comprises an immediate-release layer and a
controlled-release layer. In a further embodiment the
immediate-release layer comprises an effective amount of one or
more of a non-opioid analgesic agent, a barbiturate agent, a
stimulant agent or an antiemetic agent. In another a further
embodiment a controlled-release layer comprises one or more of a
non-opioid analgesic agent, a barbiturate agent, stimulant agent or
an antiemetic agent. In a specific embodiment a composition
comprises butalbital, naproxen, caffeine, or a pharmaceutically
acceptable salt thereof and optionally promethazine or a
pharmaceutically acceptable salt thereof.
[0186] In another embodiment a composition comprises an effective
amount of a barbiturate agent (such as butalbital or a
pharmaceutically acceptable salt thereof) and a stimulant agent
(such as modafinil or caffeine or a pharmaceutically acceptable
salt thereof). In some embodiments the composition further
comprises an antiemetic (such as promethazine or a pharmaceutically
acceptable salt thereof). In another embodiment, a composition is
in the form of a bi-layer tablet, wherein the composition comprises
an effective amount of each of a barbiturate agent, a stimulant
agent and optionally an antiemetic agent. In one embodiment the
bi-layer tablet comprises an immediate-release layer and a
controlled-release layer. In a further embodiment the
immediate-release layer comprises an effective amount of each of
one or more of a barbiturate agent, a stimulant agent or an
antiemetic agent. In another a further embodiment a
controlled-release layer comprises an effective amount of each of
one or more of a barbiturate agent, stimulant agent or an
antiemetic agent. In a specific embodiment a composition comprises
butalbital or a pharmaceutically acceptable salt thereof, caffeine
or a pharmaceutically acceptable salt thereof and optionally
promethazine or a pharmaceutically acceptable salt thereof.
[0187] In another embodiment a composition comprises an effective
amount of a non-opioid agent (such as ibuprofen or naproxen or a
pharmaceutically acceptable salt thereof) and a stimulant agent
(such as modafinil or caffeine or a pharmaceutically acceptable
salt thereof). In some embodiments the composition further
comprises an antiemetic (such as promethazine or a pharmaceutically
acceptable salt thereof). In one embodiment, the composition is in
the form of a bi-layer tablet, wherein the composition comprises an
effective amount of each of a non-opioid agent, a stimulant agent
and optionally an antiemetic agent. In one embodiment the bi-layer
tablet comprises an immediate-release layer and a
controlled-release layer. In a further embodiment the
immediate-release layer comprises an effective amount of each of
one or more of a non-opioid agent, a stimulant agent or an
antiemetic agent. In another further embodiment the
controlled-release layer comprises an effective amount of each of
one or more of a non-opioid agent, stimulant agent or an antiemetic
agent. In a specific embodiment a composition comprises naproxen or
a pharmaceutically acceptable salt thereof and caffeine or a
pharmaceutically acceptable salt thereof and optionally
promethazine or a pharmaceutically acceptable salt thereof.
[0188] The present compositions can comprise one or more beta
blockers, serotonin receptor agonists, vasoconstrictors,
anti-platelet agents, anti-convulsants, triptans, ergots, or
calcitonin-gene-related peptide (CGRP) receptor antagonists.
[0189] Non-limiting examples of beta blockers are acebutolol,
arotinolol, atenolol, betaxolol, bisoprolol, butoxamine,
carvedilol, carteolol, esmolol, carteolol, carvedilol, labetalol,
levobunolol, mepindolol, metoprolol, nebivolol, nadolol,
oxprenolol, penbutolol, propranolol, pindolol, sotalol, and
timolol. In one embodiment, the beta blocker is propanolol.
[0190] Non-limiting examples of serotonin receptor agonists are
buspirone, mescaline, psilocybin, cisapride, triptans, or lysergic
acid diethylamide. Non-limiting examples of vasoconstrictors are
isometheptene mucate, amphetamines, antihistamines, cocaine,
caffeine, pseudoephedrine, ergine, methylphenidate, psilocybin, or
stimulants such as amphakines (e.g., drugs effective to
glutagatergic AMPA receptors and benzoylpiperidine derivatives).
Non-limiting examples of amphetamines and antihistamines are
disclosed herein above.
[0191] Non-limiting examples of anti-platelet agents are
acetylsalycyclic acid, clopidogrel, ticlopidine, cilostazol,
abciximab, eptifibatide, tirofiban defibrotide and
dipyridamole.
[0192] Non-limiting examples of anti-convulsants are topiramate,
divaprex, pehnobarbital, methlyphenobarbital, metharbital,
barbexaclone, stiripentol, clobazam, clonazepam, clorazepate,
diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam,
potassium bromide, felbamate, carbamazepine, oxcarbazepine,
vigabatrin, progabide, tiagabine, gabapentin, prgabalin, ethotoin,
phenytoin, mephenytoin, fosphenytoin, paramethadione,
trimethadione, ethadione, beclaminde, primidone, brivaracetam,
levetiracetam, seletracetam, ethsuximide, phesuximide, mesuximide,
acetazolamide, sulthiame, methazolamide, zonisamide, lamotrigine,
pheneturide, phenacemide, valpromide, valnoctamide and
pharmaceutically acceptable salt thereof.
[0193] Non-limiting examples of calcitonin-gene-related peptide
(CGRP) receptor antagonists are MK-0974, CGRP8-37, BIBN 4096 BS,
quinine, nitrobenzamide, 4-oxobutanamides, cyclopropane
derivatives, and benzimidazolinyl piperidines.
[0194] Non-limiting examples of triptans are naratriptan,
almotriptan, sumatriptan, zolmitriptan, eletriptan, frovatriptan,
or rizatriptan, or a pharmaceutically acceptable salt thereof. In
some embodiments, a oral dosage form (e.g., bilayer tablet) is
provided comprising one or more triptan and one or more antiemetic.
In one embodiment, the triptan is sumatriptan or a pharmaceutically
acceptable salt thereof, and the antiemetic is promethazine or a
pharmaceutically acceptable salt thereof. In a further embodiment,
the composition is a bilayer tablet comprising a controlled-release
layer and an immediate-release layer, wherein the
controlled-release layer comprises an effective amount of the
sumatriptan or a pharmaceutically acceptable salt thereof and the
immediate release layer comprises an effective amount of the
promethazine or a pharmaceutically acceptable salt thereof. In one
embodiment, the sumatriptan salt is sumatriptan succinate.
[0195] Non-limiting examples of ergots are ergotamine,
methysergide, zonisamide and pharmaceutically acceptable salt
thereof. In one embodiment, the compositions comprises: sumatriptan
or a pharmaceutically acceptable salt thereof in a dosage from
about 25 mg to about 100 mg and promethazine or a pharmaceutically
acceptable salt thereof in a dosage of from about 12.5 mg to about
50 mg.
[0196] In various embodiments, compositions of the invention are
administered in a single dosage form which comprises active agents
as disclosed in Table 1 or Table 2 and one or more beta blockers,
serotonin receptor agonists, vasoconstrictors, anti-platelet
agents, anti-convulsants, triptans, ergot alkaloids, and
calcitonin-gene-related peptide (CGRP) receptor antagonists.
[0197] In some embodiments, a single dosage form is a multilayered
tablet which comprises one or more pharmaceutically active agents
which includes one or more beta blockers, serotonin receptor
agonists, vasoconstrictors, anti-platelet agents, anti-convulsants,
triptans, ergot alkaloids, or calcitonin-gene-related peptide
(CGRP) receptor antagonists. In one embodiment, a multilayer tablet
comprises at least one immediate release layer and at least one
controlled-released layer. Compositions of the invention can be
administered using other dosage forms disclosed herein.
[0198] In yet other embodiments, compositions comprising one or
more active agents disclosed herein (e.g., Table 1 or Table 2) of
the invention are administered prior to, concurrent with, or after
administration of one or more beta blockers, serotonin receptor
agonists, vasoconstrictors, anti-platelet agents, anti-convulsants,
triptans, ergot alkaloids, or calcitonin-gene-related peptide
(CGRP) receptor antagonists. In some embodiments the present
methods for treating or preventing pain further comprise
administering an effective amount of one or more beta blockers,
serotonin receptor agonists, vasoconstrictors, anti-platelet
agents, anti-convulsants, triptans, ergots, or CGRP receptor
antagonists.
[0199] Dosage
[0200] In various embodiments compositions of the invention
comprise multiple active agents at the same or different dosages.
In some embodiments, the analgesic components may vary in dosages
as further described herein, and the antihistamine or antiemetic
dosage can be adjusted according to the particular analgesics
used.
[0201] For example, in various embodiments compositions are
provided that comprise an opioid analgesic agent that is present at
from about a dose of about 1.0 mg to about 100 mg, including but
not limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0
mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0,
10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5
mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5
mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg,
23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27
mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg,
31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, 36.5 mg, 37 mg,
37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg,
41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg,
45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg,
49.5 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90
mg, 95 mg, or 100 mg. In one embodiment the opioid analgesic agent
is hydrocodone or oxycodone or salt thereof. In another embodiment
the opioid analgesic agent is present in a bi-layer tablet that
comprises an immediate release and a controlled release layer.
[0202] In another embodiment a composition is provided that
comprises a non-opioid analgesic that is present at a dose from
about 200 mg to about 1000 mg, including but not limited to 200 mg,
205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245
mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg,
290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326
mg, 326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg,
330 mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5
mg, 334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg,
337.5 mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341
mg, 341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg,
345 mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5
mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg,
352.5 mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356
mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg,
360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5
mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg,
367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372
mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg,
376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5
mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg,
383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387
mg, 387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg,
391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5
mg, 395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg,
398.5 mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg,
425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465
mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg,
510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550
mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg,
595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635
mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg,
685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725
mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg,
770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810
mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg,
855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895
mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg,
940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980
mg, 985 mg, 990 mg, 995 mg, or 1000 mg. In one embodiment the
non-opioid analgesic agent is present in a bi-layer tablet that
comprises an immediate release and a controlled release layer.
[0203] In another embodiment the compositions comprise an
antiemetic or antihistamine agent (e.g., promethazine) present at a
dose from about 0.5 mg to about 200 mg of promethazine or a
pharmaceutically acceptable salt thereof, including but not limited
to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg,
4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5
mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5
mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg,
17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21
mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,
25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg,
29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38
mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg,
48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85
mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg,
130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170
mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one
embodiment the antiemetic or antihistamine agent is present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer.
[0204] In one embodiment, the compositions of the invention
comprise an opioid analgesic agent (such as hydrocodone), a
pharmaceutically acceptable salt or its thiosemicarbazone,
p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis
(methylcarbamate) (each of the foregoing being a hydrocodone agent
or derivative); acetaminophen; and promethazine or salt thereof.
Furthermore, the opioid analgesic agent is present in a range of
from about 1.0 mg to about 100 mg, including but not limited to 1
mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg,
7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg,
12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5
mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg,
20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24
mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg,
28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg,
32.5 mg, 33 mg, 33.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg,
38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg,
42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg,
46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, 55
mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100
mg.
[0205] Furthermore, in various embodiments, the compositions of the
invention comprise acetaminophen or a pharmaceutically acceptable
salt thereof is present in the composition at a range of from about
200 mg to about 1000 mg, including but not limited to 200 mg, 205
mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,
250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290
mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,
326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330
mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg,
334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5
mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg,
341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345
mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg,
349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5
mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,
356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360
mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,
364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5
mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg,
372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376
mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,
380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5
mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,
387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391
mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg,
395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5
mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425
mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,
470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510
mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg,
555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595
mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,
640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685
mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,
730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770
mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg,
815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855
mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,
900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940
mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,
985 mg, 990 mg, 995 mg, or 1000 mg. In addition, the promethazine
or salt thereof is present in the composition at a dose between
about 0.5 mg to about 200 mg, including but not limited to 0.5 mg,
1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0
mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg,
9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg,
13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg,
17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg,
21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,
25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg,
29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38
mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg,
48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85
mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg,
130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170
mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one
embodiment hydrocodone or a salt thereof, acetaminophen or a salt
thereof, and promethazine or a salt thereof are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer. In another embodiment the immediate
release layer comprises promethazine or a salt thereof and the
controlled release layer comprises hydrocodone or a salt thereof
and acetaminophen or a salt thereof.
[0206] In various embodiments, the compositions of the invention
comprise an opioid analgesic agent (such as hydrocodone or
oxycodone or a pharmaceutically acceptable salt thereof),
acetaminophen or a pharmaceutically acceptable salt thereof and
promethazine or a pharmaceutically acceptable salt thereof, wherein
the composition comprises the respective agents, opioid analgesic
agent: acetaminophen or a salt thereof: promethazine or a
pharmaceutically acceptable salt thereof in a ratio by weight of
about (1 to 2):(40 to 45):(1 to 2), such as about 1:40:1, 1:40:1.1,
1:40:1.2, 1:40:1.3, 1:40:1.4, 1:40:1.5, 1:40:1.6, 1:40:1.7,
1:40:1.8, 1:40:1.9, 1:40:2, 1.1:40:1, 1.2:40:1, 1.3:40:1, 1.4:40:1,
1.5:40:1, 1.6:40:1, 1.7:40:1, 1.8:40:1, 1.9:40:1, 2:40:1, 1:41:1,
1:41:1.1, 1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41:1.5, 1:41:1.6,
1:41:1.7, 1:41:1.8, 1:41:1.9, 1:41:2, 1.1:41:1, 1.2:41:1, 1.3:41:1,
1.4:41:1, 1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1, 2:41:1,
1:42:1, 1:42:1.1, 1:42:1.2, 1:42:1.3, 1:42:1.4, 1:42:1.5, 1:42:1.6,
1:42:1.7, 1:42:1.8, 1:42:1.9, 1:42:2, 1.1:42:1, 1.2:42:1, 1.3:42:1,
1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9:42:1, 2:42:1,
1:43:1, 1:43:1.1, 1:43:1.2, 1:43:1.3, 1:43:1.4, 1:43:1.5, 1:43:1.6,
1:43:1.7, 1:43:1.8, 1:43:1.9, 1:43:2, 1.1:43:1, 1.2:43:1, 1.3:43:1,
1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 1.9:43:1, 2:43:1,
1:43.1:1, 1:43.1:1.1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1:1.4,
1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:1.9,
1:43.1:2, 1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1,
1.5:43.1:1, 1.6:43.1:1, 1.7:43.1:1, 1.8:43.1:1, 1.9:43.1:1,
2:43.1:1, 1:43.2:1, 1:43.2:1.1, 1:43.2:1.2, 1:43.2:1.3, 1:43.2:1.4,
1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7, 1:43.2:1.8, 1:43.2:1.9,
1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:1, 1.4:43.2:1,
1.5:43.2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 1.9:43.2:1,
2:43.2:1, 1:43.3:1, 1:43.3:1.1, 1:43.3:1.2, 1:43.3:1.3, 1:43.3:1.4,
1:43.3:1.5, 1:43.3:1.6, 1:43.3:1.7, 1:43.3:1.8, 1:43.3:1.9,
1:43.3:2, 1.1:43.3:1, 1.2:43.3:1, 1.3:43.3:1, 1.4:43.3:1,
1.5:43.3:1, 1.6:43.3:1, 1.7:43.3:1, 1.8:43.3:1, 1.9:43.3:1,
2:43.3:1, 1:43.4:1, 1:43.4:1.1, 1:43.4:1.2, 1:43.4:1.3, 1:43.4:1.4,
1:43.4:1.5, 1:43.4:1.6, 1:43.4:1.7, 1:43.4:1.8, 1:43.4:1.9,
1:43.4:2, 1.1:43.4:1, 1.2:43.4:1, 1.3:43.4:1, 1.4:43.4:1,
1.5:43.4:1, 1.6:43.4:1, 1.7:43.4:1, 1.8:43.4:1, 1.9:43.4:1,
2:43.4:1, 1:43.5:1, 1:43.5:1.1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:1.4,
1:43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:1.9,
1:43.5:2, 1.1:43.5:1, 1.2:43.5:1, 1.3:43.5:1, 1.4:43.5:1,
1.5:43.5:1, 1.6:43.5:1, 1.7:43.5:1, 1.8:43.5:1, 1.9:43.5:1,
2:43.5:1, 1:43.6:1, 1:43.6:1.1, 1:43.6:1.2, 1:43.6:1.3, 1:43.6:1.4,
1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7, 1:43.6:1.8, 1:43.6:1.9,
1:43.6:2, 1.1:43.6:1, 1.2:43.6:1, 1.3:43.6:1, 1.4:43.6:1,
1.5:43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 1.9:43.6:1,
2:43.6:1, 1:43.7:1, 1:43.7:1.1, 1:43.7:1.2, 1:43.7:1.3, 1:43.7:1.4,
1:43.7:1.5, 1:43.7:1.6, 1:43.7:1.7, 1:43.7:1.8, 1:43.7:1.9,
1:43.7:2, 1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 1.4:43.7:1,
1.5:43.7:1, 1.6:43.7:1, 1.7:43.7:1, 1.8:43.7:1, 1.9:43.7:1,
2:43.7:1, 1:43.8:1, 1:43.8:1.1, 1:43.8:1.2, 1:43.8:1.3, 1:43.8:1.4,
1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7, 1:43.8:1.8, 1:43.8:1.9,
1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1, 1.4:43.8:1,
1.5:43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 1.9:43.8:1,
2:43.8:1, 1:43.9:1, 1:43.9:1.1, 1:43.9:1.2, 1:43.9:1.3, 1:43.9:1.4,
1:43.9:1.5, 1:43.9:1.6, 1:43.9:1.7, 1:43.9:1.8, 1:43.9:1.9,
1:43.9:2, 1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 1.4:43.9:1,
1.5:43.9:1, 1.6:43.9:1, 1.7:43.9:1, 1.8:43.9:1, 1.9:43.9:1,
2:43.9:1, 1:44:1, 1:44:1.1, 1:44:1.2, 1:44:1.3, 1:44:1.4, 1:44:1.5,
1:44:1.6, 1:44:1.7, 1:44:1.8, 1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1,
1.3:44:1, 1.4:44:1, 1.5:44:1, 1.6:44:1, 1.7:44:1, 1.8:44:1,
1.9:44:1, 2:44:1, 1:45:1, 1:45:1.1, 1:45:1.2, 1:45:1.3, 1:45:1.4,
1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8, 1:45:1.9, 1:45:2, 1.1:45:1,
1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1, 1.6:45:1, 1.7:45:1,
1.8:45:1, 1.9:45:1, or 2:45:1. For example, in one embodiment, the
ratio of amounts for each active agent is about (1):(43.33):(1.67)
for hydrocodone or a salt thereof: acetaminophen or a salt thereof:
promethazine or a pharmaceutically acceptable salt thereof,
respectively. In one embodiment a pharmaceutically acceptable salt
of hydrocodone, acetaminophen orpromethazine is provided. In one
embodiment an opioid analgesic agent (such as hydrocodone or
oxycodone or a salt thereof), acetaminophen or a salt thereof; and
promethazine or a salt thereof are present in a bi-layer tablet
that comprises an immediate release and a controlled release
layer.
[0207] In another embodiment, the composition comprises oxycodone,
a pharmaceutically acceptable salt or its thiosemicarbazone,
p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis
(methylcarbamate) (each of the foregoing being a hydrocodone agent
or derivative); acetaminophen or a salt thereof; and promethazine
or a salt thereof. Furthermore, the oxycodone or a salt thereof is
present in a range of about 1 mg to about 200 mg, including but not
limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5.0 mg,
5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5
mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg,
14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg,
18 mg, 18.5 mg, 19 mg, 19.5 mg or 20 mg, 30 mg, 40 mg, 50 mg, 70
mg, 100 mg, 130 mg, 160, 190 mg, 200 mg. Furthermore, the
acetaminophen or a salt thereof is in a range of between about 200
mg to about 1000 mg, including but not limited to 200 mg, 205 mg,
210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250
mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg,
295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,
326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330
mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg,
334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5
mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg,
341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345
mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg,
349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5
mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,
356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360
mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,
364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5
mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg,
372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376
mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,
380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5
mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,
387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391
mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg,
395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5
mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425
mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,
470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510
mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg,
555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595
mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,
640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685
mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,
730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770
mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg,
815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855
mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,
900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940
mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,
985 mg, 990 mg, 995 mg, or 1000 mg. The compositions can further
comprise between about 0.5 mg to about 200 mg of an antihistamine
(e.g., promethazine or a salt thereof), including but not limited
to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg,
4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5
mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5
mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg,
17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21
mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,
25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg,
29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38
mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg,
48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85
mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg,
130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170
mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one
embodiment oxycodone or a salt thereof, acetaminophen or a salt
thereof and promethazine or a salt thereof are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer.
[0208] In one embodiment, the composition comprises promethazine or
a salt thereof in an amount of 12.5 mg. In one embodiment, the
compositions of the invention comprise oxycodone or a salt thereof,
acetaminophen or a salt thereof and promethazine or a salt thereof,
wherein the composition comprises the agents in a weight ratio of
about (1 to 2):(40 to 45):(1 to 2), respectively. In one embodiment
a pharmaceutically acceptable salt of oxycodone, acetaminophen
orpromethazine is provided. For example, in one embodiment, the
weight ratio of amounts for each active agent is about
(1):(43.33):(1.67) for oxycodone or a salt thereof, acetaminophen
or a salt thereof and promethazine or a salt thereof, respectively.
In one embodiment, the compositions of the invention comprise an
antihistamine (e.g., promethazine or a salt thereof) at a lower
dosage than that which the antihistamine is administered alone. In
one embodiment, the antihistamine is provided in the composition at
a dosage to prevent sedation, which may be observed with relatively
higher dosages of promethazine or a salt thereof. Thus in some
embodiments, promethazine is provided at 0.5 mg, 1.0 mg, 1.5 mg,
2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0
mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg,
10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg,
14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg,
18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg,
22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg,
26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31
mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg,
41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50
mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg,
100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140
mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg,
185 mg, 190 mg, 195 mg, or 200 mg. Therefore, an antihistamine or
antiemetic (e.g., promethazine or a salt thereof) can be provided
at a dosage that is effective for reducing adverse affects
associated with the opioid analgesic or non-opioid analgesic, but
is at a relative low enough dosage (e.g., given the subject's
weight) to prevent sedation associated with the antihistamine or
antiemetic. Examples of adverse effects include acute liver
toxicity, allergic reactions such as swelling, difficulty
breathing, closing of throat, abdominal pain, nausea, unusual
bleeding or bruising. In one embodiment oxycodone or a salt
thereof, acetaminophen or a salt thereof; and promethazine or a
salt thereof are present in a bi-layer tablet that comprises an
immediate release and a controlled release layer.
[0209] In one embodiment, the compositions of the invention
comprise 6-8 mg of hydrocodone or a salt thereof (such as about 6.0
mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg,
6.9 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7
mg, 7.8 mg, 7.9 mg, or 8.0 mg,), 310-330 mg of acetaminophen (such
as about 310 mg, 315 mg, 320 mg, or 325 mg), and 5-13 mg of
promethazine or a salt thereof (such as about 10 mg, 10.5 mg, 11.0
mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0, mg, 13.5 mg, 14.0 mg, 14.5 mg,
or 15 mg). In a further embodiment a pharmaceutically acceptable
salt of hydrocodone, acetaminophen or promethazine is provided. The
hydrocodone and the acetaminophen can be formulated using
conventional technologies to provide for an extended time release
over a desired dosage interval. All or some of the promethazine can
be formulated for immediate release to help abate common adverse
effects associated with the hydrocodone and acetaminophen including
nausea, vomiting, other gastric upsets, skin rashes, allergic
reactions such as swelling, difficulty breathing, closing of
throat, abdominal pain, unusual bleeding or bruising, sedation, CNS
depression, or respiratory depression. In one embodiment
hydrocodone, acetaminophen; and promethazine are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer.
[0210] In one embodiment, the compositions of the invention
comprise from 1% to 20% by weight of an antihistamine (such as 1%,
1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%,
8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%,
14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%,
19.5%, or 20%); from 10% to 80% by weight a non-opioid analgesic
(such as 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%,
14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%,
20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%,
25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%,
31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%,
36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%,
42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%,
47.5%, 48%, 48.5%, 49%, 49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%,
53%, 53.5%, 54%, 54.5%, 55%, 55.5%, 56%, 56.5%, 57%, 57.5%, 58%,
58.5%, 59%, 59.5%, 60%, 60.5%, 61%, 61.5%, 62%, 62.5%, 63%, 63.5%,
64%, 64.5%, 65%, 65.5%, 66%, 66.5%, 67%, 67.5%, 68%, 68.5%, 69%,
69.5%, 70%, 70.5%, 71%, 71.5%, 72%, 72.5%, 73%, 73.5%, 74%, 74.5%,
75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%, 79.5%, 80%);
and from 1% to 20% by weight of an opioid analgesic (such as 1%,
1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%,
8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%,
14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%,
19.5%, or 20%). In one embodiment an opioid analgesic agent, a
non-opioid analgesic and an antihistamine are present in a bi-layer
tablet that comprises an immediate release and a controlled release
layer.
[0211] In one embodiment, the compositions of the invention
comprise 6-8 mg of oxycodone HCL (such as about 7.5 mg), 310-330 mg
of acetaminophen (such as about 325 mg), and 6-15 mg of
promethazine HCL (such as about 12.5 mg). The oxycodone HCL and the
acetaminophen can be formulated using conventional technologies to
provide for an extended time release over a desired dosage
interval. All or some of the promethazine can be formulated for
immediate release. In one embodiment the composition is in the form
of a bi-layer tablet comprising an immediate-release layer
comprising promethazine HCL and a controlled-release layer and a
controlled release layer comprising acetaminophen and oxycodone or
a salt thereof.
[0212] In one embodiment, administration of the composition
disclosed herein that comprises an antiemetic agent (such as
promethazine or a salt thereof) can produce an outcome in a
subject, such as reduced, abated or eliminated adverse effects
associated with the administration of an opioid agent or non-opioid
agent, such as oxycodone HCL, hydrocodone bitartrate and
acetaminophen. Reduced, abated or eliminated adverse effects
include but are not limited to including nausea, vomiting, other
gastric upsets, skin rashes, allergic reactions such as swelling,
difficulty breathing, closing of throat, abdominal pain, unusual
bleeding or bruising, sedation, CNS depression, or respiratory
depression or any combination thereof.
[0213] The dosages and concentrations of active agents in the
compositions may be varied as desired, as further described herein.
Depending on the subject and/or condition being treated and on the
administration route, the active agent in a composition can
generally be administered in dosages of 0.01 mg to 500 mg per kg
body weight per day, e.g. about 20 mg/day for an average person.
The dosage can be adjusted based on the mode of administration. A
typical dosage may be one administration daily or multiple
administrations daily.
[0214] Of course for controlled-release dosage forms the unit dose
can be designed for administration over a defined period of time.
In some embodiments, dosage for one or a combination of agents can
be from about 0.01 to 5 mg, 1 to 10 mg, 5 to 20 mg, 10 to 50 mg, 20
to 100 mg, 50 to 150 mg, 100 to 250 mg, 150 to 300 mg, 250 to 500
mg, 300 to 600 mg or 500 to 1000 mg V/kg body weight. Dose levels
can vary as a function of the specific compound, the severity of
the symptoms and the susceptibility of the subject to adverse
effects.
[0215] In another embodiment a composition comprises multiple
active agents at the same or different dosages, where the
composition comprises an effective amount of: an opioid analgesic;
an antiemetic or antihistamine; and a stimulant. In some
embodiments the composition may further comprise a barbiturate or a
non-opioid active agent, or both. The dosage can be adjusted
according to the particular actives selected.
[0216] In one embodiment, a composition comprises an effective
amount of: an opioid analgesic; an antiemetic or antihistamine; and
a stimulant. In this embodiment the antiemetic or an antihistamine
(e.g., promethazine or a salt thereof), that is present at about
0.5 mg to about 60 mg, including but not limited to a dose of about
0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5
mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg,
9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg,
13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17
mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg,
21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,
25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg,
29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38
mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg,
48 mg, 49 mg, 50 mg, 55 mg, 60 mg. In one embodiment, the
antiemetic or antihistamine is promethazine or a salt thereof. In
various other embodiments, the antihistamine or antiemetic is one
described herein above. As described herein, in some embodiments,
the antihistamine or antiemetic is a component of an
immediate-release formulation. For example, in a further
embodiment, the immediate-release is in a capsule, a tablet, a
transdermal means, or achieved through injection, intramuscular
administration or other means disclosed herein. In one embodiment
an opioid analgesic agent, a stimulant and an antihistamine are
present in a bi-layer tablet that comprises an immediate release
and a controlled release layer. In one embodiment the stimulant and
an antihistamine are present in the immediate release layer and the
opioid analgesic agent is present in the controlled release layer.
In another embodiment an opioid analgesic agent, a non-opioid
analgesic, a stimulant and an antihistamine are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer. In one embodiment the stimulant and an
antihistamine are present in the immediate release layer and the
opioid analgesic agent and a non-opioid analgesic are present in
the controlled release layer.
[0217] In a further embodiment, a composition of the invention
comprises: an effective amount of an opioid analgesic agent; an
antiemetic or antihistamine agent; and a stimulant agent or a
non-opioid agent, or both. In one embodiment each agent is present
at a dose of about 0.5 mg to about 20 mg, 5 mg to 30 mg, 10 mg to
100 mg, including but not limited to about 0.5 mg, 1.0 mg, 1.5 mg,
2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0
mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5
mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg,
16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25
mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In one embodiment an
opioid analgesic agent, a stimulant and an antihistamine are
present in a bi-layer tablet that comprises an immediate release
and a controlled release layer. In one embodiment the stimulant and
an antihistamine are present in the immediate release layer and the
opioid analgesic agent is present in the controlled release
layer.
[0218] In yet a further embodiment, the composition comprising: an
effective amount of an opioid analgesic, a stimulant and optionally
an antiemetic or antihistamine. In one embodiment the composition
comprises a stimulant at a dose of about 1 mg to about 350 mg, 5 mg
to 25 mg, 10 mg to 50 mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250
mg, 75 mg to 350 mg, including but not limited to about 1.0 mg, 1.0
mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg,
7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg,
12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5
mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg,
20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80
mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg,
170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250
mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg,
340 mg, or 350 mg. In one embodiment an opioid analgesic agent, a
stimulant and an antihistamine are present in a bi-layer tablet
that comprises an immediate release and a controlled release layer.
In one embodiment the stimulant and an antihistamine are present in
the immediate release layer and the opioid analgesic agent is
present in the controlled release layer.
[0219] In various embodiments, a composition of the invention
comprises: an opioid analgesic, a stimulant, and an antiemetic or
antihistamine, wherein the relative ratio by weight of each of an
opioid: a stimulant: an antiemetic or antihistamine is about (1 to
2):(40 to 45):(1 to 2), such as about 1:40:1, 1:40:1.1, 1:40:1.2,
1:40:1.3, 1:40:1.4, 1:40:1.5, 1:40:1.6, 1:40:1.7, 1:40:1.8,
1:40:1.9, 1:40:2, 1.1:40:1, 1.2:40:1, 1.3:40:1, 1.4:40:1, 1.5:40:1,
1.6:40:1, 1.7:40:1, 1.8:40:1, 1.9:40:1, 2:40:1, 1:41:1, 1:41:1.1,
1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41:1.5, 1:41:1.6, 1:41:1.7,
1:41:1.8, 1:41:1.9, 1:41:2, 1.1:41:1, 1.2:41:1, 1.3:41:1, 1.4:41:1,
1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1, 2:41:1, 1:42:1,
1:42:1.1, 1:42:1.2, 1:42:1.3, 1:42:1.4, 1:42:1.5, 1:42:1.6,
1:42:1.7, 1:42:1.8, 1:42:1.9, 1:42:2, 1.1:42:1, 1.2:42:1, 1.3:42:1,
1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9:42:1, 2:42:1,
1:43:1, 1:43:1.1, 1:43:1.2, 1:43:1.3, 1:43:1.4, 1:43:1.5, 1:43:1.6,
1:43:1.7, 1:43:1.8, 1:43:1.9, 1:43:2, 1.1:43:1, 1.2:43:1, 1.3:43:1,
1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 1.9:43:1, 2:43:1,
1:43.1:1, 1:43.1:1.1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1:1.4,
1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:1.9,
1:43.1:2, 1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1,
1.5:43.1:1, 1.6:43.1:1, 1.7:43.1:1, 1.8:43.1:1, 1.9:43.1:1,
2:43.1:1, 1:43.2:1, 1:43.2:1.1, 1:43.2:1.2, 1:43.2:1.3, 1:43.2:1.4,
1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7, 1:43.2:1.8, 1:43.2:1.9,
1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:1, 1.4:43.2:1,
1.5:43.2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 1.9:43.2:1,
2:43.2:1, 1:43.3:1, 1:43.3:1.1, 1:43.3:1.2, 1:43.3:1.3, 1:43.3:1.4,
1:43.3:1.5, 1:43.3:1.6, 1:43.3:1.7, 1:43.3:1.8, 1:43.3:1.9,
1:43.3:2, 1.1:43.3:1, 1.2:43.3:1, 1.3:43.3:1, 1.4:43.3:1,
1.5:43.3:1, 1.6:43.3:1, 1.7:43.3:1, 1.8:43.3:1, 1.9:43.3:1,
2:43.3:1, 1:43.4:1, 1:43.4:1.1, 1:43.4:1.2, 1:43.4:1.3, 1:43.4:1.4,
1:43.4:1.5, 1:43.4:1.6, 1:43.4:1.7, 1:43.4:1.8, 1:43.4:1.9,
1:43.4:2, 1.1:43.4:1, 1.2:43.4:1, 1.3:43.4:1, 1.4:43.4:1,
1.5:43.4:1, 1.6:43.4:1, 1.7:43.4:1, 1.8:43.4:1, 1.9:43.4:1,
2:43.4:1, 1:43.5:1, 1:43.5:1.1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:1.4,
1:43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:1.9,
1:43.5:2, 1.1:43.5:1, 1.2:43.5:1, 1.3:43.5:1, 1.4:43.5:1,
1.5:43.5:1, 1.6:43.5:1, 1.7:43.5:1, 1.8:43.5:1, 1.9:43.5:1,
2:43.5:1, 1:43.6:1, 1:43.6:1.1, 1:43.6:1.2, 1:43.6:1.3, 1:43.6:1.4,
1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7, 1:43.6:1.8, 1:43.6:1.9,
1:43.6:2, 1.1:43.6:1, 1.2:43.6:1, 1.3:43.6:1, 1.4:43.6:1,
1.5:43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 1.9:43.6:1,
2:43.6:1, 1:43.7:1, 1:43.7:1.1, 1:43.7:1.2, 1:43.7:1.3, 1:43.7:1.4,
1:43.7:1.5, 1:43.7:1.6, 1:43.7:1.7, 1:43.7:1.8, 1:43.7:1.9,
1:43.7:2, 1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 1.4:43.7:1,
1.5:43.7:1, 1.6:43.7:1, 1.7:43.7:1, 1.8:43.7:1, 1.9:43.7:1,
2:43.7:1, 1:43.8:1, 1:43.8:1.1, 1:43.8:1.2, 1:43.8:1.3, 1:43.8:1.4,
1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7, 1:43.8:1.8, 1:43.8:1.9,
1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1, 1.4:43.8:1,
1.5:43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 1.9:43.8:1,
2:43.8:1, 1:43.9:1, 1:43.9:1.1, 1:43.9:1.2, 1:43.9:1.3, 1:43.9:1.4,
1:43.9:1.5, 1:43.9:1.6, 1:43.9:1.7, 1:43.9:1.8, 1:43.9:1.9,
1:43.9:2, 1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 1.4:43.9:1,
1.5:43.9:1, 1.6:43.9:1, 1.7:43.9:1, 1.8:43.9:1, 1.9:43.9:1,
2:43.9:1, 1:44:1, 1:44:1.1, 1:44:1.2, 1:44:1.3, 1:44:1.4, 1:44:1.5,
1:44:1.6, 1:44:1.7, 1:44:1.8, 1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1,
1.3:44:1, 1.4:44:1, 1.5:44:1, 1.6:44:1, 1.7:44:1, 1.8:44:1,
1.9:44:1, 2:44:1, 1:45:1, 1:45:1.1, 1:45:1.2, 1:45:1.3, 1:45:1.4,
1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8, 1:45:1.9, 1:45:2, 1.1:45:1,
1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1, 1.6:45:1, 1.7:45:1,
1.8:45:1, 1.9:45:1, or 2:45:1. In one embodiment an opioid
analgesic agent, a stimulant and an antihistamine are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer. In one embodiment the stimulant and an
antihistamine are present in the immediate release layer and the
opioid analgesic agent is present in the controlled release
layer.
[0220] In another embodiment, compositions are provided that
comprise an effective amount of an opioid (such as hydrocodone,
fentanyl or oxycodone or a salt thereof); a non-opioid (such as
acetaminophen or naproxen salt thereof); and a barbiturate (such as
butalbital or a salt thereof). In some embodiments the compositions
further comprise an antiemetic (such as promethazine or a salt
thereof). In some embodiments the composition further comprises a
stimulant agent. In some embodiments the barbiturate is present at
a dose of 1 mg to about 350 mg, 5 mg to 25 mg, 10 mg to 50 mg, 25
to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 mg,
including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg,
3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5
mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0
mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17
mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg,
35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110
mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg,
200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280
mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg.
[0221] In another embodiment the compositions comprise an effective
amount of an opioid (such as hydrocodone, fentanyl or oxycodone or
a salt thereof); a non-opioid agent (such as acetaminophen or
naproxen or a salt thereof); and a barbiturate (such as butalbital
or a salt thereof). In one embodiment the opioid agent (such as
hydrocodone or oxycodone or a salt thereof) is present in a range
of about 1 mg to about 200 mg, including but not limited to 1.0 mg,
1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5
mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg,
11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0
mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg,
19.5 mg or 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 100 mg, 130 mg, 160,
190 mg, 200 mg. Furthermore, the non-opioid agent (such as
acetaminophen or naproxen or a salt thereof) is present in a range
of between about 200 mg to about 1000 mg, including but not limited
to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg,
240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280
mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg,
325 mg, 326 mg, 326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329
mg, 329.5 mg, 330 mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg,
333 mg, 333.5 mg, 334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5
mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg,
340.5 mg, 341 mg, 341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344
mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg,
348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5
mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg,
355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359
mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg,
363 mg, 363.5 mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5
mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg,
371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375
mg, 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg,
379 mg, 379.5 mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5
mg, 383 mg, 383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg,
386.5 mg, 387 mg, 387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390
mg, 390.5 mg, 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg,
394 mg, 394.5 mg, 395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5
mg, 398 mg, 398.5 mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415
mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg,
460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500
mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg,
545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585
mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg,
630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675
mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg,
720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760
mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg,
805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845
mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg,
890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930
mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg,
975 mg, 980 mg, 985 mg, 990 mg, 995 mg, or 1000 mg. Additionally,
the barbiturate (e.g., butalbital or a salt thereof) is present at
a dose between about 0.5 mg to about 200 mg, including but not
limited to, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg,
4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0
mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0
mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg,
16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg,
20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg,
24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg,
28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg,
36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45
mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg,
120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160
mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200
mg. In one embodiment an opioid analgesic agent, a non-opioid
agent, and a barbiturate agent are present in a bi-layer tablet
that comprises an immediate release and a controlled release layer.
In a further embodiment the bi-layer tablet comprises an antiemetic
agent, such as an antihistamine. In one embodiment the
antihistamine is present in the immediate release layer and the
opioid analgesic agent, non-opioid agent, and barbiturate agent are
present in the controlled release layer.
[0222] In another embodiment compositions are provided that
comprise an effective amount of a barbiturate agent (such as
butalbital or a salt thereof); a non-opioid agent (such as
acetaminophen or naproxen or a salt thereof); and a stimulant agent
(such as caffeine or a salt thereof). In one embodiment the
barbiturate agent (such as butalbital or a salt thereof); is
present in a range of about 0.5 mg to about 200 mg, including but
not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5
mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg,
8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg,
12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg,
16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20
mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg,
24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg,
28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg,
36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45
mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,
75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg,
120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160
mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200
mg. Furthermore, the non-opioid agent (such as acetaminophen or
naproxen or a salt thereof) is present in a range of between about
200 mg to about 1000 mg, including but not limited to 200 mg, 205
mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,
250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290
mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,
326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330
mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg,
334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5
mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg,
341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345
mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg,
349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5
mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,
356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360
mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,
364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5
mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg,
372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376
mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,
380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5
mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,
387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391
mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg,
395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5
mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425
mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,
470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510
mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg,
555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595
mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,
640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685
mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,
730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770
mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg,
815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855
mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,
900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940
mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,
985 mg, 990 mg, 995 mg, or 1000 mg. Additionally, the stimulant
agent (e.g., caffeine) is present at a dose from about 0.5 mg to
about 200 mg including but not limited to 0.5 mg, 1.0 mg, 1.5 mg,
2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0
mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg,
10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg,
14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg,
18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg,
22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg,
26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31
mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg,
41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50
mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg,
100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140
mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg,
185 mg, 190 mg, 195 mg, or 200 mg. In one embodiment a stimulant
agent, a non-opioid agent, and a barbiturate agent are present in a
bi-layer tablet that comprises an immediate release and a
controlled release layer. In one embodiment the stimulant is
present in the immediate release layer and the non-opioid analgesic
agent and barbiturate are present in the controlled release layer.
In a further embodiment the bi-layer tablet comprises an antiemetic
agent, such as an antihistamine (e.g., promethazine). In one
embodiment the stimulant and an antihistamine are present in the
immediate release layer and the non-opioid analgesic agent and
barbiturate are present in the controlled release layer.
[0223] In another embodiment compositions are provided that
comprise an effective amount of a barbiturate and a stimulant. In
one embodiment the composition comprises a stimulant at a dose of
about 1 mg to about 350 mg (such as 5 mg to 25 mg, 10 mg to 50 mg,
25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 mg)
including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg,
3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5
mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0
mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17
mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg,
35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110
mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg,
200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280
mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg.
Additionally, the barbiturate agent (such as butalbital or a salt
thereof); is present in a range of about 0.5 mg to about 200 mg,
including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5
mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg,
7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg,
11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg,
15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19
mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg,
23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg,
27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33
mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg,
43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60
mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105
mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg,
150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190
mg, 195 mg, or 200 mg. In one embodiment, a barbiturate agent, and
a stimulant are present in a bi-layer tablet that comprises an
immediate release and a controlled release layer. In a further
embodiment the bi-layer tablet further comprises an antiemetic
agent, such as an antihistamine (e.g. promethazine or a salt
thereof). In one embodiment the stimulant and an antihistamine are
present in the immediate release layer and the barbiturate agent is
present in the controlled release layer.
[0224] In another embodiment the compositions comprise an effective
amount of a non-opioid agent (such as naproxen or ibuprofen or a
salt thereof) and a stimulant (such as caffeine or a salt thereof).
In some embodiments the non-opioid agent (such as naproxen or
ibuprofen or a salt thereof) is present in a range of between about
200 mg to about 1000 mg, including but not limited to 200 mg, 205
mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,
250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290
mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,
326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330
mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg,
334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5
mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg,
341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345
mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg,
349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5
mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,
356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360
mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,
364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5
mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg,
372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376
mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,
380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5
mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,
387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391
mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg,
395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5
mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425
mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,
470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510
mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg,
555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595
mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,
640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685
mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,
730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770
mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg,
815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855
mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,
900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940
mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,
985 mg, 990 mg, 995 mg, or 1000 mg. In these embodiments the
compositions comprise a stimulant at a dose of about 1 mg to about
350 mg, (such as 5 mg to 25 mg, 10 mg to 50 mg, 25 to 100 mg, 50 to
150 mg, 100 mg to 250 mg, or 75 mg to 350 mg), including but not
limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg,
5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5
mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg,
14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg,
18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,
45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,
130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210
mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg,
300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg. In one
embodiment a non-opioid agent and a stimulant are formulated as a
bi-layer tablet that comprises an immediate release and a
controlled release layer. In one example naproxen and caffeine are
formulated in a bi-layer tablet. In one embodiment the caffeine is
present in the immediate release layer and naproxen is present in
the controlled release layer.
[0225] In one embodiment, the compositions of the invention
comprise an effective amount of propoxyphene or a salt thereof and
a non-opioid agent (such as naproxen or a salt thereof). In some
embodiments the composition further comprises an antiemetic (such
as promethazine or a salt thereof). In some embodiments the
compositions further comprise a stimulant agent. In one embodiment,
the propoxyphene or salt thereof is present in a range of about 1.0
mg to about 100 mg, including but not limited to 11.0 mg, 1.5 mg,
2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0
mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5
mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg,
16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg,
20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg,
24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg,
28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg,
32.5 mg, 33 mg, 33.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg,
38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg,
42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg,
46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, 55
mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100
mg.
[0226] Furthermore, the non-opioid agent is in a range of about 200
mg to about 1000 mg, including but not limited to 200 mg, 205 mg,
210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250
mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg,
295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,
326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330
mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg,
334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5
mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg,
341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345
mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg,
349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5
mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,
356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360
mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,
364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5
mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg,
372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376
mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,
380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5
mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,
387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391
mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg,
395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5
mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425
mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,
470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510
mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg,
555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595
mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,
640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685
mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,
730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770
mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg,
815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855
mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,
900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940
mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg,
985 mg, 990 mg, 995 mg, or 1000 mg. In one embodiment propoxyphene
or a salt thereof and naproxen (such as naproxen sodium or naproxen
magnesium) are present in a bi-layer tablet. In a further
embodiment, the composition comprises an antiemetic or an
antihistamine (e.g., promethazine or a salt thereof). In one
embodiment the antihistamine is present in the immediate release
layer and propoxyphene and naproxen are present in the controlled
release layer.
[0227] In another embodiment, the compositions described herein
comprise an effective amount of an antiemetic or an antihistamine
(e.g., promethazine or a salt thereof), that is present in the
range of at about 0.5 mg to about 60 mg, including but not limited
to a dose of about 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg,
3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5
mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5
mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5
mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg,
20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24
mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg,
28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg,
36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45
mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg. In one
embodiment, the antiemetic or antihistamine is promethazine or a
salt thereof. In various other embodiments, the antihistamine or
antiemetic is another described herein above. As described herein,
in some embodiments, the antihistamine or antiemetic is a component
of an immediate-release formulation. For example, in a further
embodiment, the immediate-release is in a lollipop, capsule, a
tablet, a transdermal means, through injection, intramuscular
administration or other means disclosed herein.
[0228] Dosage Forms
[0229] Oral Dosage Forms
[0230] In one embodiment the invention relates to methods and
compositions formulated for oral delivery to a subject in need. In
one embodiment a composition is formulated so as to deliver one or
more pharmaceutically active agents to a subject through a mucosa
layer in the mouth or esophagus. In another embodiment the
composition is formulated to deliver one or more pharmaceutically
active agents to a subject through a mucosa layer in the stomach
and/or intestines.
[0231] In one embodiment compositions are provided in modified
release dosage forms (such as immediate release, controlled release
or both), which comprise an effective amount of an opioid analgesic
(such as oxycodone or hydrocodone or a salt thereof), a non-opioid
analgesic (such as acetaminophen, naproxen or ibuprofen or a salt
thereof) and an antihistamine (such as promethazine or a salt
thereof); and one or more release controlling excipients as
described herein. Suitable modified release dosage vehicles
include, but are not limited to, hydrophilic or hydrophobic matrix
devices, water-soluble separating layer coatings, enteric coatings,
osmotic devices, multiparticulate devices, and combinations
thereof. The compositions may also comprise non-release controlling
excipients.
[0232] In another embodiment compositions are provided in enteric
coated dosage forms. The compositions can also comprise non-release
controlling excipients.
[0233] In another embodiment compositions are provided in
effervescent dosage forms. The compositions can also comprise
non-release controlling excipients.
[0234] In another embodiment compositions can be provided in a
dosage form that has at least one component that can facilitate the
immediate release of an active agent, and at least one component
that can facilitate the controlled release of an active agent. In a
further embodiment the dosage form can be capable of giving a
discontinuous release of the compound in the form of at least two
consecutive pulses separated in time from 0.1 up to 24 hours. The
compositions can comprise one or more release controlling and
non-release controlling excipients, such as those excipients
suitable for a disruptable semi-permeable membrane and as swellable
substances.
[0235] In another embodiment compositions are provided in a dosage
form for oral administration to a subject, which comprise one or
more pharmaceutically acceptable excipients or carriers, enclosed
in an intermediate reactive layer comprising a gastric
juice-resistant polymeric layered material partially neutralized
with alkali and having cation exchange capacity and a gastric
juice-resistant outer layer.
[0236] In one embodiment the compositions are in the form of
enteric-coated granules, as controlled-release capsules for oral
administration. The compositions can further comprise cellulose,
disodium hydrogen phosphate, hydroxypropyl cellulose, hypromellose,
lactose, mannitol, and sodium lauryl sulfate.
[0237] In another embodiment the compositions are in the form of
enteric-coated pellets, as controlled-release capsules for oral
administration. The compositions can further comprise glyceryl
monostearate 40-50, hydroxypropyl cellulose, hypromellose,
magnesium stearate, methacrylic acid copolymer type C, polysorbate
80, sugar spheres, talc, and triethyl citrate.
[0238] In another embodiment the compositions are enteric-coated
controlled-release tablets for oral administration. The
compositions can further comprise carnauba wax, crospovidone,
diacetylated monoglycerides, ethylcellulose, hydroxypropyl
cellulose, hypromellose phthalate, magnesium stearate, mannitol,
sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide,
and yellow ferric oxide.
[0239] In another embodiment the compositions can further comprise
calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron
oxide, mannitol, methacrylic acid copolymer, polysorbate 80,
povidone, propylene glycol, sodium carbonate, sodium lauryl
sulfate, titanium dioxide, and triethyl citrate.
[0240] The compositions provided herein can be in unit-dosage forms
or multiple-dosage forms. Unit-dosage forms, as used herein, refer
to physically discrete units suitable for administration to human
or non-human animal subjects and packaged individually. Each
unit-dose can contain a predetermined quantity of an active
ingredient(s) sufficient to produce the desired therapeutic effect,
in association with the required pharmaceutical carriers or
excipients. Examples of unit-dosage forms include, but are not
limited to, ampules, syringes, and individually packaged tablets
and capsules. Unit-dosage forms may be administered in fractions or
multiples thereof. A multiple-dosage form is a plurality of
identical unit-dosage forms packaged in a single container, which
can be administered in segregated unit-dosage form. Examples of
multiple-dosage forms include, but are not limited to, vials,
bottles of tablets or capsules, or bottles of pints or gallons. In
another embodiment the multiple dosage forms comprise different
pharmaceutically active agents. For example a multiple dosage form
can be provided which comprises a first dosage element comprising
an immediate release form of an antihistamine (such as in a liquid
form) and a second dosage element comprising an opioid and/or non
opioid analgesic, which can be in a modified release form (such as
immediate release, controlled release, or extended release
form).
[0241] In this example a pair of dosage elements can make a single
unit dosage. In one embodiment a kit is provided comprising
multiple unit dosages, wherein each unit comprises a first dosage
element comprising an immediate release form of an antihistamine
(such as in a liquid form) and a second dosage element comprising
an opioid or non-opioid analgesic or both, which can be in a
modified release form (such as immediate release or controlled
release, or both). In another embodiment the kit further comprises
a set of instructions. In yet a further embodiment the
antihistamine is promethazine or a pharmaceutically acceptable salt
thereof, the opioid analgesic is oxycodone or hydrocodone or
pharmaceutically acceptable salt thereof, the non-opioid analgesic
is acetaminophen or a pharmaceutically acceptable salt thereof.
[0242] In one embodiment compositions can be formulated in various
dosage forms for oral, parenteral, and topical administration. The
compositions may also be formulated as a modified release dosage
form, including immediate-, delayed-, extended-, prolonged-,
sustained-, pulsatile-, controlled-, extended, accelerated- and
fast-, targeted-, programmed-release, and gastric retention dosage
forms. These dosage forms can be prepared according to known
methods and techniques (see, Remington: The Science and Practice of
Pharmacy, supra; Modified-Release Drug Delivery Technology,
Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel
Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which is herein
incorporated by reference in its entirety).
[0243] In various embodiments of the invention, the compositions
are in one or more dosage form. For example, a composition can be
administered in a solid or liquid form. Examples of solid dosage
forms include but are not limited to discrete units in capsules or
tablets, as a powder or granule, or present in a tablet
conventionally formed by compression molding. Such compressed
tablets may be prepared by compressing in a suitable machine the
three or more agents and a pharmaceutically acceptable carrier. The
molded tablets can be optionally coated or scored, having indicia
inscribed thereon and can be so formulated as to cause immediate,
substantially immediate, slow, controlled or extended release of
the opioid analgesics (such as oxycodone or hydrocodone) and/or the
non-opioid analgesics (such as acetaminophen) and or the
antihistamine (such as promethazine). Furthermore, dosage forms of
the invention can comprise acceptable carriers or salts known in
the art, such as those described in the Handbook of Pharmaceutical
Excipients, American Pharmaceutical Association (1986),
incorporated by reference herein in its entirety.
[0244] In one embodiment, one or more pharmaceutically active
agents are mixed with a pharmaceutical excipient to form a solid
preformulation composition comprising a homogeneous mixture of
compounds described herein. When referring to these compositions as
"homogeneous", it is meant that the agents are dispersed evenly
throughout the composition so that the composition can be
subdivided into unit dosage forms such as tablets or capsules. This
solid preformulation composition can then subdivided into unit
dosage forms of the type described above comprising from, for
example, about 1.0 mg to about 15 mg of an opioid, such as
hydrocodone or oxycodone or a pharmaceutically acceptable salt
thereof.
[0245] The compositions can be formulated, in the case of capsules
or tablets, to be swallowed whole, for example with water. The
inclusion of the side-effect-reducing agent such as an
antihistamine or antiemetic to abate common symptoms of nausea and
vomiting are believed beneficial in that promethazine or a salt
thereof, or the like will eliminate or minimize the amount of
discomfort. Adverse effects reduced or eliminated include but are
not limited to nausea, vomiting, other gastric upsets, skin rashes,
allergic reactions such as swelling, difficulty breathing, closing
of throat, abdominal pain, unusual bleeding or bruising, CNS
suppression and respiratory suppression.
[0246] Frequently, subjects taking opioids have adverse effects
including vomiting that can occur shortly after taking a first or
subsequent dose. As a consequence, a portion of the opioid dose is
subsequently lost, making it difficult to accurately gauge
replacement dosages for the subject, and for subjects outside of a
hospital or clinic environment, there might not be any alternative
form of pain medication readily available. As a consequence,
subjects experiencing gastric discomfort such as vomiting will lack
the beneficial effects of the opioid analgesic and experience the
additional discomfort and enhanced pain associated with vomiting.
This problem is solved by also administering promethazine or a salt
thereof, which reduces side-effects.
[0247] The dosage forms described herein can be manufactured using
processes that are well known to those of skill in the art. For
example, for the manufacture of bi-layered tablets, the agents can
be dispersed uniformly in one or more excipients, for example,
using high shear granulation, low shear granulation, fluid bed
granulation, or by blending for direct compression. Excipients
include diluents, binders, disintegrants, dispersants, lubricants,
glidants, stabilizers, surfactants and colorants. Diluents, also
termed "fillers", can be used to increase the bulk of a tablet so
that a practical size is provided for compression. Non-limiting
examples of diluents include lactose, cellulose, microcrystalline
cellulose, mannitol, dry starch, hydrolyzed starches, powdered
sugar, talc, sodium chloride, silicon dioxide, titanium oxide,
dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate,
alumina and kaolin. Binders can impart cohesive qualities to a
tablet formulation and can be used to help a tablet remain intact
after compression. Non-limiting examples of suitable binders
include starch (including corn starch and pregelatinized starch),
gelatin, sugars (e.g., glucose, dextrose, sucrose, lactose and
sorbitol), celluloses, polyethylene glycol, waxes, natural and
synthetic gums, e.g., acacia, tragacanth, sodium alginate, and
synthetic polymers such as polymethacrylates and
polyvinylpyrrolidone. Lubricants can also facilitate tablet
manufacture; non-limiting examples thereof include magnesium
stearate, calcium stearate, stearic acid, glyceryl behenate, and
polyethylene glycol. Disintegrants can facilitate tablet
disintegration after administration, and non-limiting examples
thereof include starches, alginic acid, crosslinked polymers such
as, e.g., crosslinked polyvinylpyrrolidone, croscarmellose sodium,
potassium or sodium starch glycolate, clays, celluloses, starches,
gums and the like. Non-limiting examples of suitable glidants
include silicon dioxide, talc and the like. Stabilizers can inhibit
or retard drug decomposition reactions, including oxidative
reactions. Surfactants can also include and can be anionic,
cationic, amphoteric or nonionic. If desired, the tablets can also
comprise nontoxic auxiliary substances such as pH buffering agents,
preservatives, e.g., antioxidants, wetting or emulsifying agents,
solubilizing agents, coating agents, flavoring agents, and the
like.
[0248] Controlled-release formulations can comprise one or more
combination of excipients that slow the release of the agents by
coating or temporarily bonding or decreasing their solubility of
the active agents. Examples of these excipients include cellulose
ethers such as hydroxypropylmethylcellulose (e.g., Methocel K4M) or
silicified microcrystalline cellulose, polyvinylacetate-based
excipients such as, e.g., Kollidon SR, and polymers and copolymers
based on methacrylates and methacrylic acid such as, e.g., Eudragit
NE 30D. In one embodiment of the invention, the opioid analgesic or
non-opioid agents (e.g., hydrocodone or oxycodone or a salt
thereof, and acetaminophen or a salt thereof) are formulated for
extended or controlled-release while the promethazine or a salt
thereof is formulated for immediate release. In another embodiment,
all agents are formulated for extended or controlled-release.
[0249] Immediate-release formulations can comprise one or more
combination of excipients that allow for a rapid release of a
pharmaceutically active agent (such as from 1 minute to 1 hour
after administration), such as an anti-emetic or an antihistamine.
In one embodiment an immediate release excipient can be
microcrystalline cellulose, sodium carboxymethyl cellulose, sodium
starch glycolate, corn starch, colloidal silica, Sodium Laurel
Sulphate, Magnesium Stearate, Prosolve SMCC (HD90), croscarmellose
Sodium, Crospovidone NF, Avicel PH200, and combinations of such
excipients.
[0250] Pharmaceutical carriers or vehicles suitable for
administration of the compounds provided herein include all such
carriers known to those skilled in the art to be suitable for the
particular mode of administration. In addition, the compositions
can one or more components that do not impair the desired action,
or with components that supplement the desired action, or have
another action. As noted above, the compositions can comprise
additional (e.g., a fourth, fifth, sixth, etc.) additional active
agents.
[0251] In one embodiment, the compositions comprise three or more
pharmaceutically active agents wherein at least one active agent is
formulated in an immediate release form. In this embodiment the
immediate-release form can be included in an amount that is
effective to shorten the time to its maximum concentration in the
blood. By way of example, certain immediate-release pharmaceutical
preparations are taught in United States Patent Publication US
2005/0147710A1 entitled, "Powder Compaction and Enrobing" which is
incorporated herein in its entirety by reference.
[0252] In a further embodiment, a component of an immediate-release
form or layer is a component that reduces abates or eliminates
and/or suppresses an adverse effect associated with one or more
opioid analgesics.
[0253] For example, the immediate-release active can be an
antihistamine or an antiemetic, which reduces, abates or eliminates
an adverse effect associated with opioid and/or non-opioid
analgesics described herein.
[0254] In a further embodiment, all or less than the entire amount
of the antiemetic or antihistamine agent is formulated in
immediate-release form, as described herein.
[0255] A variety of known methods and materials may be used to
bring about the immediate release. For instance, placement of the
agent along an exterior of a tablet (e.g., coating the exterior or
formulating the outer layer with the agent) and/or combined with
forming a tablet by compressing the powder using low compaction can
produce immediate-release of the agent from the composition.
[0256] In a specific embodiment, an effective amount of the
promethazine or a salt thereof in immediate-release form may be
coated onto a substrate. For example, where the extended release of
one or more analgesics from a formulation is due to a
controlled-release coating, an immediate-release layer comprising
promethazine or a salt thereof can overcoat the controlled-release
coating. In another example, an immediate-release layer can be
coated onto the surface of a substrate wherein an opioid, a
non-opioid agent, a barbiturate, or a stimulant is incorporated in
a controlled release matrix. Where a plurality of
controlled-release substrates (e.g., multiparticulate systems
including pellets, spheres, beads and the like) are incorporated
into a hard gelatin capsule, a side-effect-reducing compound can be
incorporated into the gelatin capsule via inclusion of an amount of
immediate-release promethazine or a salt thereof, as a powder or
granulate within the capsule. Alternatively, the gelatin capsule
itself can be coated with an immediate-release layer of
promethazine. One skilled in the art recognizes still other
alternative means of incorporating an immediate release
side-effect-reducing compound into the unit dose. By including an
effective amount of immediate-release side-effect-reducing compound
in the unit dose, the experience of adverse effects including
nausea, vomiting, other gastric upsets, skin rashes, allergic
reactions such as swelling, difficulty breathing, closing of
throat, abdominal pain, unusual bleeding or bruising, skin rashes,
sedation, CNS depression, or respiratory depression in subjects can
be significantly reduced.
[0257] In one embodiment, the composition comprises three or more
active agents wherein at least one active agent is in
controlled-release form. The controlled-release form can be in an
amount that is effective to protect the agent from rapid
elimination from the body. Certain preparations relating to the
controlled release of a pharmaceutical are taught in United States
Patent Publication US 2005/0147710A1 entitled, "Powder Compaction
and Enrobing" which is incorporated herein in its entirety by
reference. Examples of time release coated beads are disclosed in
U.S. Application Publication No. 20080131517.
[0258] In a further embodiment, at least one pharmaceutically
active agent in a controlled-release form is an opioid analgesic
agent. In one embodiment of the invention, compositions comprise
one or more carriers that protect the agents against rapid
elimination from the body, such as time-release formulations or
coatings. Such carriers include controlled-release formulations,
including, for example, microencapsulated delivery systems. The
active agents can be included in the pharmaceutically acceptable
carrier in amounts sufficient to treat a subject's pain, with
reduced adverse effects.
[0259] In certain embodiments the compositions are in oral-dosage
form and comprise a matrix that includes, for example, a
controlled-release material and an opioid or non-opioid analgesic.
In certain embodiments, the matrix is compressible into a tablet
and can be optionally overcoated with a coating that can control
the release of the opioid or non-opioid analgesic from the
composition. In this embodiment blood levels of analgesics are
maintained within a therapeutic range over an extended period of
time. In certain alternate embodiments, the matrix is
encapsulated.
[0260] Tablets or capsules containing a composition described
herein can be coated or otherwise compounded to provide a dosage
form affording the advantage of prolonged action. For example, the
tablet or capsule can contain an inner dosage and an outer dosage
component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer
that serves to resist disintegration in the stomach and permit the
inner component to pass intact into the duodenum or to be
controlled in release. For controlled extended release, the capsule
can also have micro drilled holes.
[0261] A coating comprising a side-effect-reducing compound, in
immediate release form, can be added to the outside of a
controlled-release tablet core to produce a final dosage form. Such
a coating can be prepared by admixing a compound like promethazine
with polyvinylpyrrolidone (PVP) 29/32 or hydroxypropyl
methylcellulose (HPMC) and water/isopropyl alcohol and triethyl
acetate. Such an immediate-release coating can be spray coated onto
the tablet cores. The immediate-release coating can also be applied
using a press-coating process with a blend consisting of 80% by
weight promethazine and 20% by weight of lactose and hydroxypropyl
methylcellulose type 2910. Press-coating techniques are known in
the art and are described in U.S. Pat. No. 6,372,254, which is
herein incorporated by reference in its entirety.
[0262] The immediate-release or controlled-release dosage forms
described herein can also take the form of a bi-layered tablet,
which comprises a first layer and a second layer. The first layer
comprises a first drug that is an analgesic, antitussive,
antihistamine, and antiemetic. The second layer comprises a second
drug that is an analgesic, antitussive, antihistamine, and
antiemetic. The second drug is the same as or different from the
first drug. The bi-layered tablet can provide a plasma
concentration within the therapeutic range of the second drug over
a period which is coextensive with at least about 70% of the period
(e.g., 12 hours) within which the bi-layered tablet provides a
plasma concentration within the therapeutic range of the first
drug.
[0263] In a further embodiment of the bi-layered tablet, one layer
is an immediate release layer and the other layer is a
controlled-release layer. In one example a bi-layered is formulated
using the methods disclosed in U.S. Pat. No. 4,820,522, which is
herein incorporated by reference in its entirety.
[0264] In one embodiment of the bi-layered tablet described herein,
both layers can comprise an opioid analgesic, a non-opioid
analgesic and a compound to reduce or suppress adverse effects.
[0265] In a further embodiment of the bi-layered tablet described
herein, the immediate-release layer comprises promethazine or a
salt thereof and the controlled release layer comprises hydrocodone
or oxycodone or a pharmaceutically acceptable salt thereof. In one
embodiment the immediate or controlled release layer can further
comprise acetaminophen or naproxen or a salt thereof.
[0266] In one embodiment of the multi-layered tablet, the second
drug can have a plasma half-life that differs from the plasma
half-life of the first drug by at least about 2 hours.
[0267] In another embodiment, an effective amount of the antiemetic
agent or antihistamine in an immediate-release form may be coated
onto a substrate. For example, where the one or more opioid
analgesics and one or more stimulant are components of a
controlled-release formulation, an immediate-release layer
comprising the antiemetic agent or antihistamine can overcoat the
controlled-release formulation.
[0268] In another embodiment, the immediate-release layer can be
coated onto the surface of a substrate having a controlled release
matrix. Where a plurality of controlled-release substrates
comprising an effective unit dose of a pharmaceutically active
agent (e.g., multiparticulate systems including pellets, spheres,
beads and the like) are incorporated into a hard gelatin capsule,
another agent can be incorporated into the gelatin capsule via
inclusion of an amount of immediate-release agent as a powder or
granulate within the capsule. Alternatively, the gelatin capsule
itself can be coated with an immediate-release layer. One skilled
in the art recognizes still other alternative means of
incorporating the immediate release side-effect-reducing compound
into the unit dose. Therefore, in one embodiment, by including an
effective amount of an antiemetic agent or antihistamine (and
optionally including a stimulant) in the unit dose, the subject is
prepared for the eventual and subsequent release of one or more
opioid analgesic in the controlled-release layer, where the
antiemetic agent or antihistamine reduces the incidence of or
intensity of adverse effects associated with an opioid agent
including but not limited to nausea, vomiting, other gastric
upsets, skin rashes, allergic reactions such as swelling,
difficulty breathing, closing of throat, abdominal pain, unusual
bleeding or bruising, skin rashes, sedation, CNS depression, or
respiratory depression in subjects can be significantly
reduced.
[0269] The immediate-release or controlled-release dosage forms
described herein can also take the form of a bi-layered tablet,
which can comprise an immediate-release layer and a
controlled-release layer. In one embodiment the immediate release
layer comprises an antiemetic agent or antihistamine, and
optionally a stimulant or a non-opioid analgesic, or both. In one
embodiment, the first layer can comprise one, two, three or more
active agents.
[0270] The controlled release layer can comprise an opioid
analgesic or non-opioid analgesic or stimulant. Such classes of
active agents are described herein above.
[0271] The immediate-release or controlled release dosage forms
described herein can also take the form of pharmaceutical particles
manufactured by a variety of methods, including but not limited to
high-pressure homogenization, wet or dry ball milling, or small
particle precipitation (nano spray). Other methods to make a
suitable powder formulation are the preparation of a solution of
active ingredients and excipients, followed by precipitation,
filtration, and pulverization, or followed by removal of the
solvent by freeze-drying, followed by pulverization of the powder
to the desired particle size.
[0272] In one embodiment the particles have a final size of 3-1000
.mu.m, such as at most 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60,
70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,
650, 700, 750, 800, 850, 900, 950, 1000 .mu.m. In another
embodiment the pharmaceutical particles have a final size of 10-500
.mu.m. In one embodiment the pharmaceutical particles have a final
size of 50-600 .mu.m. In another embodiment the pharmaceutical
particles have a final size of 100-800 .mu.m. These dosage forms
can include immediate-release particles in combination with
controlled-release particles in a ratio sufficient useful for
delivering the desired dosages of active agents. In an alternative
embodiment, a dosage unit can be divided into or exclusively
included into both immediate release and controlled release
particles.
[0273] In a further embodiment the dosage form can be an
effervescent dosage form. Effervescent means that the dosage form,
when mixed with liquid, including water and saliva, evolves a gas.
Some effervescent agents (or effervescent couple) evolve gas by
means of a chemical reaction which takes place upon exposure of the
effervescent disintegration agent to water and/or to saliva in the
mouth. This reaction can be the result of the reaction of a soluble
acid source and an alkali monocarbonate or carbonate source. The
reaction of these two general compounds produces carbon dioxide gas
upon contact with water or saliva. An effervescent couple (or the
individual acid and base separately) can be coated with a solvent
protective or enteric coating to prevent premature reaction. Such a
couple can also be mixed with previously lyophilized particles
(such as one or more pharmaceutically active agents coated with a
solvent protective or enteric coating. The acid sources may be any
which are safe for human consumption and may generally include food
acids, acid and hydrite antacids such as, for example: citric,
tartaric, amalic, fumeric, adipic, and succinics. Carbonate sources
include dry solid carbonate and bicarbonate salt such as, for
example, sodium bicarbonate, sodium carbonate, potassium
bicarbonate and potassium carbonate, magnesium carbonate and the
like. Reactants which evolve oxygen or other gasses and which are
safe for human consumption are also included. In one embodiment
citric acid and sodium bicarbonate is used.
[0274] In another embodiment the dosage form can be in a candy form
(e.g., matrix), such as a lollipop or lozenge. In one embodiment
one or more pharmaceutically active agents is dispersed within a
candy matrix. In one embodiment the candy matrix comprises one or
more sugars (such as dextrose or sucrose). In another embodiment
the candy matrix is a sugar-free matrix. The choice of a particular
candy matrix is subject to wide variation. Conventional sweeteners
such as sucrose may be utilized, or sugar alcohols suitable for use
with diabetic patients, such as sorbitol or mannitol might be
employed. Other sweeteners, such as the aspartanes, can also be
easily incorporated into a composition in accordance with
compositions described herein. The candy base may be very soft and
fast dissolving, or may be hard and slower dissolving. Various
forms will have advantages in different situations.
[0275] A containing candy mass comprising at least one
pharmaceutically active agent can be orally administered to a
subject in need thereof so that the agent will be released into the
subject's mouth as the candy mass dissolves. The drug rapidly
enters the subject bloodstream, and importantly, the blood in the
veins draining from the mouth and the pharyngeal and esophageal
areas passes through a substantial portion of the body (so that the
drug can be absorbed) before the blood passes through the liver
(where the drug may be inactivated). A subject in need thereof can
include a human adult or child in pain, such as a child in sickle
cell crisis, a child undergoing bone marrow transplant or a lumbar
puncture procedure, a child with cancer (e.g., metastasic cancer,
leukemia or lymphoma).
[0276] In some embodiments of the invention the candy matrix
(lollipop or lozenge) comprises a composition that lacks a
stimulant. In one embodiment said formulation may have a sedative
effect in addition to providing pain relief to a subject in need
thereof. In some other embodiments the candy matrix (lollipop or
lozenge) comprises a composition that comprises a stimulant. In
these embodiments the composition provides an anti-sedative effect
in addition to providing pain relief to a subject in need
thereof.
[0277] In one embodiment a candy mass is prepared that comprises
one or more layers which may comprise different pharmaceutically
active agents and or rates of dissolution. In one embodiment a
multilayer candy mass (such as a lollipop) comprises an outer layer
with a concentration of one or more pharmaceutically active agents
differing from that of one or more inner layers. Such a drug
delivery system has a variety of applications. By way of example,
it may be desirable to quickly get a predetermined dose of a first
pharmaceutically active agent into the bloodstream to obtain a
desired effect and then use a different inner layer to deliver one
or more other agents.
[0278] The choices of matrix and the concentration of the drug in
the matrix can be important factors with respect to the rate of
drug uptake. A matrix that dissolves quickly can deliver drug into
the patient's mouth for absorption more quickly than a matrix that
is slow to dissolve. Similarly, a candy matrix that contains one or
more pharmaceutically active agents in a high concentration can
release more of the one or more pharmaceutically active agents in a
given period of time than a candy having a low concentration. In
one embodiment a candy matrix such as one disclosed in U.S. Pat.
No. 4,671,953 or US Application 2004/0213828 (which are herein
incorporated by reference in their entirety) is used to deliver the
pharmaceutically active agents disclosed herein.
[0279] The immediate-release or extended release dosage forms
described herein can also take the form of pharmaceutical particles
manufactured by a variety of methods, including but not limited to
high-pressure homogenization, wet or dry ball milling, or small
particle precipitation (e.g., nGimat's NanoSpray). Other methods
useful to make a suitable powder formulation are the preparation of
a solution of active ingredients and excipients, followed by
precipitation, filtration, and pulverization, or followed by
removal of the solvent by freeze-drying, followed by pulverization
of the powder to the desired particle size. In one embodiment the
pharmaceutical particles have a final size of 3-1000 .mu.m, such as
at most 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90,
100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,
750, 800, 850, 900, 950, 1000 .mu.m. In another embodiment the
pharmaceutical particles have a final size of 10-500 .mu.m. In
another embodiment the pharmaceutical particles have a final size
of 50-600 .mu.m. In another embodiment the pharmaceutical particles
have a final size of 100-800 .mu.m. These dosage forms can include
immediate-release particles in combination with controlled-release
particles in a ratio sufficient useful for delivering the desired
dosages of active agents. For example, the immediate-release
particles can comprise about 12.5 mg of promethazine or a salt
thereof, and the controlled-release particles can comprise about
7.5 mg of hydrocodone or oxycodone or a salt thereof, and about 325
mg of acetaminophen or a salt thereof.
[0280] In another embodiment, the agents are released from a
multi-layered tablet that comprises at least a first layer, a
second layer and a third layer. Wherein, the layers containing a
pharmaceutically active agent can be optionally separated by one or
more layers of inert materials. In one embodiment the layers
containing a pharmaceutically active agent have similar rates of
release, e.g., all are immediate release or all are
controlled-release. In an alternative embodiment the layers have
different rates of release. In this embodiment at least one layer
is an immediate release layer and at least one layer is a
controlled release layer. For example in one embodiment the
multilayer tablet comprises at least three layers, each of which
contains a different agent, such as: layer one contains
promethazine or a salt thereof; layer two comprises hydrocodone or
oxycodone or a salt thereof; and layer three comprises
acetaminophen or a salt thereof. In this embodiment the
promethazine layer may be immediate-release, while the other two
layers may be controlled-release.
[0281] Transdermal Dosage Forms
[0282] In another embodiment, the invention relates to a method of
use and a system for the transdermal delivery of one or more
pharmaceutically active agents into a subject. In one embodiment a
portion of the skin of a subject is sealed with a thin, film layer
of a base material to occlude the skin and transport a desired
dosage of at least one pharmaceutically active agent across the a
layer, which can be from a rate-controlling system in contact with
the thin layer. The rate-controlling system can be a thin
rate-controlling membrane interposed between one or more agents and
the thin layer. In another embodiment a reservoir delivers at least
one pharmaceutically active agent to the layer for delivery into a
subject. In some embodiments the pharmaceutically active agents to
be delivered are: an opioid analgesic, a non-opioid analgesic and
an antihistamine; or pharmaceutically acceptable salts, solvates,
or prodrugs thereof; one or more pharmaceutically acceptable
excipients or carriers.
[0283] In one embodiment, the rate-controlling system or reservoir
comprises at least one pharmaceutically active agent to be
delivered, is dispersed in a base material and contained within a
container system. In one embodiment at least one pharmaceutically
active agent is dissolved in the base material. In another
embodiment at least one pharmaceutically active agent is uniformly
dispersed in the base material. In another embodiment, the
rate-controlling system or reservoir comprises microparticles of at
least one pharmaceutically active agent to be delivered suspended
in a base material and contained within a container system. In one
embodiment the base material is a viscous material. The container
system may comprise a macroporous, non-rate-controlling face
membrane with an impervious backing to form a pool or patch-like
system of desired face membrane area with the face of the membrane
placed over and in contact with the thin, occluding, viscous layer
on the skin. The thin viscous layer may be coated or placed on the
skin repeatedly, and the patch system placed on top of the thin,
viscous layer or the viscous layer formed in situ by exudation
through the membrane face when the patch or pool system is placed
in position on the skin. In one embodiment the patch or pool
container system generally is retained in a transdermal position by
the use of a peripheral adhesive layer about the patch or pool. In
one embodiment, the face or transport area of the membrane is
covered prior to use by a removable cover such as a peelable strip
of impervious sheet material. In another embodiment, microcapsules
containing a drug for delivery may be suspended in a viscous base
material, and the composition then spread as a layer over the skin
of the user with or without a covering material.
[0284] In other embodiments U.S. Pat. Nos. 4,906,463; 4,588,580;
4,685,911, 4,626,539, 4,834,978 and 5,635,204 disclose useful
transdermal patches which may be used for the practice methods and
compositions described herein, which are herein incorporated by
reference in their entirety.
[0285] In one embodiment the compositions are administered to a
subject via a transdermal patch.
[0286] Suppository Dosage Form
[0287] In another embodiment, the compositions are in the form of a
suppository. In one embodiment the suppository is useful for
vaginal or rectal administration. In some embodiments the
suppository is effervescent.
[0288] In some embodiments the suppository base material contains
hydrophobic or hydrophilic media, each of which can melt at body
temperature. In one embodiment the suppository base material used
can be cocoa butter or similar material. In another embodiment the
suppository base material can be a moist polymer is then mixed with
the one or more pharmaceutically active agents and compressed into
the desired form. In one embodiment at least one pharmaceutically
active agent is dissolved in the suppository base material. In
another embodiment at least one pharmaceutically active agent is
uniformly dispersed in the suppository base material. In another
embodiment, the suppository base material comprises microparticles
of at least one pharmaceutically active agent to be delivered
suspended in the suppository base material. In some embodiments
(such as vaginal suppositories) the suppository is effervescent. In
some embodiments the effervescing properties are imparted for the
purpose of enhancing the rapid disintegration properties of the
suppository.
[0289] In other embodiments U.S. Pat. Nos. 4,265,875 and 4,853,211
disclose useful suppositories which may be used for the practice of
methods and compositions described herein, which are herein
incorporated by reference in their entirety.
[0290] Abuse Safeguard Dosage Forms
[0291] Adverse-Effect Agents
[0292] In one embodiment, the present compositions can safeguard
against abuse of the opioid analgesic agent. For example, a
composition disclosed herein can further comprise an effective
amount of an adverse-effect agent or antagonist agent that reduces
or eliminates one or more of: (1) the capacity of the opioid
analgesic agent to produce the kind of physical dependence in which
withdrawal causes sufficient distress to bring about drug-seeking
behavior; (2) the ability to suppress withdrawal symptoms caused by
withdrawal from the opioid analgesic agent; and (3) the induction
of euphoria. Useful adverse-effect agents include, but are not
limited to, opioid antagonists. When there is a potential for an
overdose, then an antidote of the opioid analgesic agent can be
used as the adverse-effect agent.
[0293] The phrase "adverse-effect agent" is also meant to encompass
all pharmaceutically acceptable salts of the adverse-effect
agent.
[0294] Opioid antagonists that can be used as an adverse-effect
agent include, but are not limited to, naloxone, naltrexone,
nalmefene, cyclazacine, levallorphan, or a salt thereof, and
mixtures thereof. In certain embodiments, the opioid antagonist is
naloxone, naltrexone or a pharmaceutically acceptable salt
thereof.
[0295] In some embodiments, the opioid agent and the opioid
antagonist are present in a ratio of opioid antagonist to opioid
agent (analgesic) which is analgesically effective when the
combination is administered orally, but which is aversive in a
physically dependent subject. In this manner, the combination
product (antagonist/agonist) could in essence be therapeutic to one
population (patients in pain), while being unacceptable (aversive)
in a different population (e.g., physically dependent subjects)
when orally administered at the same dose or at a higher dose than
the usually prescribed dosage, e.g., about 2-3 times the usually
prescribed dose of the opioid. Thus, the oral dosage form would
have less potential for parenteral as well as oral abuse. In one
embodiment where the opioid is hydrocodone or oxycodone or a salt
thereof and the antagonist is naltrexone or a salt thereof, the
ratio of naltrexone or a salt thereof to hydrocodone or a salt
thereof is from about 0.02-0.35:1 by weight, and in some
embodiments from about 0.05-0.2:1 by weight. In one embodiment the
ratio of naltrexone or a salt thereof is in an amount from about
0.5 to about 4 mg per 15 mg of hydrocodone or a salt thereof. In
another embodiment the ratio of naltrexone or a salt thereof is in
an amount from about 0.75 mg to about 3 mg per 15 mg hydrocodone or
a salt thereof. In another example where the opioid antagonist is
naltrexone or a salt thereof and the opioid agent is hydromorphone
or a salt thereof, the ratio of naltrexone or a salt thereof to
hydromorphone or a salt thereof can be from about 0.14:1 to about
1.19:1, or from about 0.222:1 to about 0.889:1. In another example
where the opioid antagonist is naltrexone or a salt thereof and the
opioid agent is oxycodone or a salt thereof, the ratio of
naltrexone or a salt thereof to oxycodone or a salt thereof is
about 0.03:1 to about 0.3:1, or from about 0.056:1 to about
0.222:1.
[0296] In one embodiment, the opioid is hydrocodone, hydromorphone,
oxycodone, fentanyl, or a pharmaceutically acceptable salt
thereof.
[0297] In some embodiments, an opioid antagonist is administered in
an amount (i) which does not cause a reduction in the level of
analgesia elicited from the dosage form upon oral administration to
a non-therapeutic level and (ii) which provides at least a mildly
negative, "aversive" experience in physically dependent subjects
(e.g., precipitated abstinence syndrome) when the subjects attempt
to take at least twice the usually prescribed dose at a time (and
often 2-3 times that dose or more), as compared to a comparable
dose of the opioid without the opioid antagonist present. In
certain embodiments, an amount of naltrexone or a salt thereof is
included in the oral dosage form and is less positively reinforcing
(e.g., less "liked") to a non-physically dependent opioid addict
than a comparable oral dosage form without the antagonist included.
In one embodiment the composition provides effective analgesia when
orally administered.
[0298] In some embodiments the oral dosage form can be administered
on a twice-a-day or a once-a-day basis.
[0299] The composition can be formulated as a controlled oral
formulation in any suitable tablet, coated tablet or
multiparticulate formulation known to those skilled in the art. The
controlled release dosage form can optionally include a carrier
which is incorporated into a matrix or can be applied as a
controlled release coating.
[0300] In embodiments in which the opioid analgesic is hydrocodone
(or a pharmaceutically acceptable salt thereof), the extended
release oral dosage forms may include analgesic doses from about 4
mg to about 60 mg of hydrocodone or a salt thereof per dosage unit.
In a controlled release oral dosage forms where hydromorphone or a
salt thereof is the therapeutically active opioid, it can be
included in an amount from about 2 mg to about 64 mg hydromorphone
hydrochloride. In yet another embodiment, the opioid analgesic is
oxycodone and the controlled release oral dosage forms include from
about 2.5 mg to about 800 mg oxycodone HCL. Alternatively, the
dosage form may contain molar equivalent amounts of other salts of
the opioids useful in compositions described herein.
[0301] In other embodiments U.S. Pat. Nos. 6,228,863; 6,475,494;
7,201,920; and U.S. Pat. Nos. 7,172,767, 7,201,920 disclose useful
opioid agent/opioid antagonist formulations which can be used for
the methods and compositions described herein, which are herein
incorporated by reference in their entirety.
[0302] In another embodiment, one or more non-opioid analgesic
agents, in addition to the opioid antagonist, can be included in
the dosage form. Such non-opioid drugs can provide additional
analgesia, and include, for example, aspirin; acetaminophen;
non-steroidal anti-inflammatory drugs ("NSAIDS"), e.g., ibuprofen,
naproxen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor
antagonists, e.g., a morphinan such as dextromethorphan or
dextrorphan, or ketamine; cycooxygenase-II inhibitors ("COX-II
inhibitors"); and/or glycine receptor antagonists.
[0303] Abuse Deterrent Agents
[0304] In another embodiment the compositions comprising an opioid
analgesic safeguards against abuse by further comprising one or
more abuse deterrent agents. The choice of which abuse deterrent
agent to include in a composition can be varied depending on the
route of administration and intended method of treatment. For
example different abuse deterrent agents can be used in conjunction
with same pharmaceutically active agents depending on if they are
formulated as an oral dosage form or a transdermal dosage form.
Similarly, compositions intended to treat a cancer associated pain
in a subject can comprise a different abuse deterrent agent than a
composition intended to treat headache associated pain in a
subject.
[0305] In one embodiment the abuse deterrent agent is formulated as
a gel-forming agent, and optionally comprises one or more mucous
membrane irritants or nasal passageway tissue irritants. In another
embodiment, the compositions described herein include a composition
comprising an analgesic, one or more gel-forming agents and one or
more emetics as described herein. In another embodiment, the
compositions comprise an opioid analgesic, one or more mucous
membrane irritants or nasal passageway tissue irritants and one or
more emetics as described herein. In one particular embodiment, the
compositions comprise an analgesic, one or more gel-forming agents,
one or more mucous membrane irritants and/or nasal passageway
tissue irritants, and one or more emetics.
[0306] Suitable gel-forming agents include compounds that, upon
contact with a solvent (e.g., water), absorb the solvent and swell,
thereby forming a viscous or semi-viscous substance that
significantly reduces and/or minimizes the amount of free solvent
which can contain an amount of solublized drug, and which can be
drawn into a syringe. The gel can also reduce the overall amount of
drug extractable with the solvent by entrapping the drug in a gel
matrix. In one embodiment, typical gel-forming agents include
pharmaceutically acceptable polymers, typically hydrophilic
polymers, such as hydrogels.
[0307] In some embodiments, the polymers exhibit a high degree of
viscosity upon contact with a suitable solvent. The high viscosity
can enhance the formation of highly viscous gels when attempts are
made by an abuser to crush and dissolve the contents of a dosage
form in an aqueous vehicle and inject it intravenously.
[0308] More specifically, in certain embodiments the polymeric
material described herein provides viscosity to the dosage form
when it is tampered. In such embodiments, when an abuser crushes
and dissolves the dosage form in a solvent (e.g., water or saline),
a viscous or semi-viscous gel is formed. The increase in the
viscosity of the solution discourages the abuser from injecting the
gel intravenously or intramuscularly by preventing the abuser from
transferring sufficient amounts of the solution to a syringe to
cause a desired "high" once injected.
[0309] Suitable polymers include one or more pharmaceutically
acceptable polymers selected from any pharmaceutical polymer that
will undergo an increase in viscosity upon contact with a solvent.
Polymers can include polyethylene oxide, polyvinyl alcohol,
hydroxypropyl methyl cellulose and carbomers.
[0310] In another embodiment the compositions comprise an abuse
deterrent agent that is a mucous membrane irritant or nasal
passageway tissue irritant, or both. These irritants are designed
to deter abuse via the improper administration of a dosage form
comprising an opioid (e.g., crushing and snorting). In one
embodiment, suitable mucous membrane irritants or nasal passageway
tissue irritants include compounds that are generally considered
pharmaceutically inert, yet can induce irritation. Such compounds
include, but are not limited to surfactants. In one embodiment,
suitable surfactants include sodium lauryl sulfate, poloxamer,
sorbitan monoesters and glyceryl monooleates. Other suitable
compounds are believed to be within the knowledge of a practitioner
skilled in the relevant art, and can be found in the Handbook of
Pharmaceutical Excipients, 4th Ed. (2003), the entire content of
which is hereby incorporated by reference.
[0311] In one embodiment the irritant can be present in amount of
from 1 to 10 percent by weight on a solid basis, such as from about
1 to 5 percent by weight on a solid basis. In another embodiment,
the amount of irritant can be present in an amount from 1 to 3
percent by weight.
[0312] In another embodiment, the irritant can deter abuse of a
dosage form when a potential abuser tampers with a dosage form
described herein. Specifically, in such embodiments, when an abuser
crushes the dosage form, the irritant is exposed. The irritant
discourages inhalation of the crushed dosage form by inducing pain
and/or irritation of the abuser's mucous membrane and/or nasal
passageway tissue. In one embodiment, the irritant discourages
inhalation (e.g., via snorting through the nose) by inducing pain
and/or irritation of the abuser's nasal passageway tissue.
[0313] In one embodiment, the compositions described herein
comprise one or more mucous membrane irritants that cause
irritation of mucous membranes located anywhere on or in the body,
including membranes of the mouth, eyes and intestinal tract. Such
compositions can deter abuse via oral, intra-ocular or rectal or
vaginal routes.
[0314] In another embodiment the compositions comprise an abuse
deterrent agent that is an emetic or emesis inducing agent. In one
embodiment the emetic can be a pharmaceutically acceptable inert
excipient that only induces emesis after a certain threshold amount
is ingested. In another embodiment, the emetic can be a
pharmaceutically active emetic.
[0315] In one embodiment, the amount of emetic present in the
compositions described herein can be tied directly to the amount of
drug in the composition. Thus, by controlling the quantity of the
emetic compound in the composition, emesis can be avoided if normal
prescription directions are followed. However, if an overdosage
occurs by ingesting more than a prescribed quantity of a drug in a
composition described herein, the amount of ingested emetic can
exceed the threshold amount necessary to induce emesis.
[0316] In some embodiments, the threshold amount of emetic for
inducing emesis can be reached when the normal prescription
directions are inappropriately increased by factors of 2, 3, 4, 5,
6, 7, or 8 times, or more. Thus, in some embodiments, the amount of
emetic present in a composition described herein is an amount such
that the amount of emetic ingested does not exceed the threshold
amount necessary for inducing emesis until a subject ingests 2, 3,
4, 5, 6, 7, or 8 or more times the amount of drug normally
prescribed. In some embodiments, emesis can preclude death or
serious illness in the subject.
[0317] In one embodiment, the emetic is zinc sulfate. Zinc sulfate
is an excipient, which can induce emesis when more than about 0.6
to 2.0 gm is ingested, typically more than about 0.6 gm, or about 5
to 25 percent by weight on a solid basis, more typically about 5 to
10 percent by weight. Accordingly, compositions described herein
can be easily designed to induce emesis if a prescribed dosage is
exceeded and/or if prescription directions are not followed for
dosage forms containing a composition described herein. Typically,
suitable embodiments include less than about 0.6 to 2.0 gm of zinc
sulfate.
[0318] For example a dosage form can induce emesis only after a
pre-determined number of dosage forms are ingested (such as 4, 5, 6
or more), in this case the amount of zinc sulfate in each dosage
form should not exceed about 0.19 gm. Thus, if three dosage forms
are ingested, the amount of emetic can be 0.57 gm, which is less
than a typical threshold amount of the particular emetic. However,
if a fourth dosage form having 0.19 gm. of zinc sulfate is
ingested, the amount of emetic exceeds the threshold amount, and
emesis is induced.
[0319] In another embodiment the compositions comprise an effective
amount of an abuse deterrent agent that induces flushing, (i.e.
redness of the skin, including redness of the skin of one or more
of the face, neck, chest, back and trunk and legs) and/or itching
and/or discomfort and/or temporary pain (a flushing/pain inducing
agent or flushing inducing agent), and/or generalized pruritic,
and/or intense warmth, and/or chills when administered at or in
excess of a threshold amount.
[0320] With respect to flushing, discomfort and pain inducing
agents, a threshold amount is an amount below which one or more
adverse effects is absent or below which a subject may experience a
beneficial effect.
[0321] In one embodiment, the flushing agent or itching agent or
pain-inducing agent is a drug. In certain embodiments, the drug is
obtainable "over the counter" and in certain embodiments, the "over
the counter" drug is a vitamin. In yet another embodiment, the
vitamin is niacin. In another embodiment, the present invention
includes vitamin.
[0322] Accordingly, in one embodiment the amount of flushing,
itching, or pain inducing agent present in a composition described
herein can be tied directly to the amount of drug in the
composition. Thus, by controlling the quantity of the flushing,
itching, or pain inducing agent in the composition, flushing,
itching, or pain can be avoided if normal prescription directions
are followed. However, if an overdosage occurs by ingesting more
than a prescribed quantity of a drug in a composition described
herein (e.g., by ingesting more than the prescribed dose), the
total amount of flushing, itching, or pain inducing agent can, in
certain embodiments, exceed the threshold amount necessary to
induce flushing, itching, or pain thereby inducing flushing,
itching, or pain.
[0323] In one embodiment, compositions and methods described herein
includes about 10 mg to about 500 mg of the flushing, itching, or
pain inducing agent. In yet another embodiment, a composition
comprises about 15 mg to about 150 mg of a flushing, itching, or
pain agent. In another embodiment, a composition comprises 15, 30,
45, 60, 75, 90 or 105 mg of a flushing, itching, or pain inducing
agent. In one embodiment, compositions and methods described herein
includes a flushing, itching, or pain inducing agent in an amount
of about 1% to 25%, typically about 3% to 15%, more typically about
1%, 3%, 6%, 9%, 12%, 15% or 20% by weight, including or excluding
the weight of any analgesic and/or other drug susceptible to
abuse.
[0324] In some embodiments of dosage forms having a controlled
release layer or formulation, the amount of flushing inducing agent
(and in other embodiments, the amount of any abuse deterrent
component or opioid antagonist described herein), can exceed the
threshold amount present in an immediate release form. This is
because in controlled release formulations, the amount of drug
which is susceptible to abuse is typically higher than in an
immediate release formulation and the flushing inducing agent (or
other abuse deterrent component) becomes bioavailable at a slower
rate than the immediate release form. Thus, the amount of abuse
deterrent component which is bioavailble typically also remains
below the amount sufficient to cause an abuse deterrent effect.
However, if the dosage form is tampered with (e.g., ground, chewed
or crushed), a large portion of the abuse deterrent component
becomes immediately bioavailable, thus inducing one or more abuse
deterrent effects.
[0325] Examples of abuse deterrent agents that can be used in
compositions described herein are disclosed in US Patent
Application Nos: US20060177380A1; US20060110327A1; and
US20070231268A1, which are herein incorporated by reference in its
entirety.
[0326] Abuse Deterrence via Chemical Modification of Active
Agents
[0327] In another embodiment the compositions comprise an opioid
agent that is conjugated to a chemical moiety. The chemical moiety
can be any chemical substance that can be attached to the opioid
agent in a manner that renders it pharmacologically inactive.
Analgesics and stimulants produce their pharmacological effects
through binding to specific receptors or uptake proteins. The
attachment of certain chemical moieties can therefore prevent the
active substance from binding its receptor(s) or recognition site
on its uptake protein. Further, without being bound by theory, the
covalent modification is believed to prevent the pharmacological
effect by preventing the drug from crossing the blood-brain
barrier. The attachment of the chemical moiety to the opioid agent
can also prevent or substantially delay the absorption of the
compound, particularly when the compound is delivered by routes
other than oral administration.
[0328] In one embodiment of the invention, the chemical moiety is
attached to the opioid agent in a manner in which it is not readily
released by conditions found in the mouth (saliva), the intranasal
cavity, the surface of the lungs, or in the serum. Extreme acid
conditions encountered in the stomach are not present elsewhere in
humans. Therefore, any acid dependent release mechanism will occur
only after oral administration. Although, degradative enzymes are
present in the aforementioned environments, they are not generally
present in the high concentrations found in the intestinal tract.
Thus, release of the opioid agent by enzymatic cleavage will not
occur rapidly when the novel compounds are administered by routes
other than oral delivery.
[0329] In another embodiment of the invention, the opioid agent is
attached to a polymer of serine (or other amino acid containing a
hydroxyl side chain e.g. threonine, tyrosine) via side chain
hydroxyl groups. Alternatively, attachment is to a polymer of
glutamic acid through the carboxyl group of the delta carbon of
glutamic acid. The resulting ester (carbonate) linkages can be
hydrolysed by lipases (esterases) encountered in the small
intestine. Esterases are not present at high levels in saliva or on
the mucosal surfaces of the nasal cavity, lungs, or oral cavity.
Thus, opioid agents attached to polyglutamic acid by this method
would not be rapidly released by saliva or when delivered
intranasally or by inhalation.
[0330] In another embodiment of the invention, the opioid agent is
attached to an oligopeptide, which can consist of between one and
five amino acids. In a further embodiment of the invention the
amino acids are a heterogenous mixture of the twenty naturally
occurring amino acids. Hydrophilic amino acids will tend to prevent
passive absorption of the analgesic peptide conjugate through nasal
membranes. In one embodiment of the invention that hydrophilic
amino acids be included in the oligopeptide. In another embodiment
of the invention that lipophilic amino acids be attached closer to
the analgesic for optimum stability. Both lipophilic and
hydrophilic properties (i.e., amphiphilic) can be satisfied with
between three and five amino acids. In a further embodiment of the
invention, the oligopeptide that is attached to the analgesic can
be an amphiphilic tripeptide.
[0331] Amphiphilic amino acids/oligopeptides may contain (i)
hydrophobic amino acids, located in positions next to the active
agent to provide increased stability; (ii) amino acid sequences
designed to be cleaved by intestinal enzymes (e.g. pepsin, trypsin,
chymotrypsin, elastase, carboxypeptidases A and B, etc.) provide
for increased bioavailability; (iii) peptides longer than three
amino acids for increased stability, increased anti-abuse e.g. less
membrane permeability, and potentially more efficient intestinal
digestion, e.g., major intestinal enzymes target proteins and
polypeptides, (iv) or mixtures thereof. In one embodiment the
carrier portion of the conjugate is designed for intestinal
cleavage.
[0332] In another embodiment the cleavage specificity is directed
to pepsin and/or chymotrypsin. Examples of carriers include XXXAA
or XXAAA, where X is selected from any amino acid, except Arg, Lys,
His, Pro, and Met and A is selected from Tyr, Phe, Trp, or Leu.
Examples of other carriers are selected from XXXPheLeu wherein X is
Glu; XXXPheLeu wherein X is Gly; XXPheLeuLeu wherein X is Glu; and
XXPheLeuLeu wherein X is Gly.
[0333] In another embodiment the cleavage specificity is directed
to trypsin. Examples of more carriers include XXXAA or XXAAA
wherein X is any amino acid except Pro and Cys and A is Arg or Lys.
Examples of yet more carriers are selected from XXXArgLeu wherein X
is Glu; XXXArgLeu wherein X is Gly; XXArgLeuLeu wherein X is Gly;
XXXArgLeuLeu wherein X is Gly.
[0334] Examples of chemical modifications to opioid agents that can
be used in compositions described herein are disclosed in US Patent
Application No: 20050080012, which is herein incorporated by
reference in its entirety.
[0335] In another embodiment, one or more adverse-effect-reducing
active agents in addition to the opioid antagonist agent or abuse
deterrent component can be included in the dosage form.
Adverse-effect-reducing active agents include but are not limited
to promethazine, dolasetron, granisetron, ondansetron, tropisetron,
palonosetron, domperidone, droperidol, haloperidol, chlorpromazine,
prochloperazine, metoclopramide, alizapride, cyclizine,
diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis,
dronabinol, nabilone, midazolam, lorazepam, hyoscine,
dexamethasone, trimethobenzamide, emetrol and propofol.
[0336] Additives
[0337] The present compositions can further comprise suitable
additives, including, but not limited to, diluents, binders,
surfactants, lubricants, glidants, coating materials, plasticizers,
coloring agents, flavoring agents, or pharmaceutically inert
materials. Examples of diluents include, for example, cellulose;
cellulose derivatives such as microcrystalline cellulose and the
like; starch; starch derivatives such as corn starch, cyclodextrin
and the like; sugar; sugar alcohol such as lactose, D-mannitol and
the like; inorganic diluents such as dried aluminum hydroxide gel,
precipitated calcium carbonate, magnesium aluminometasilicate,
dibasic calcium phosphate and the like.
[0338] Examples of binders include, for example,
hydroxypropylcellulose, methylcellulose,
hydroxypropylmethylcellulose, povidone, dextrin, pullulane,
hydroxypropyl starch, polyvinyl alcohol, scacia, agar, gelatin,
tragacanth, macrogol and the like.
[0339] Examples of surfactants include, for example, sucrose esters
of fatty acids, polyoxyl stearate, polyoxyethylene hydrogenated
castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan
sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan
monopalmitate, sorbitan monolaurate, polysorbate, glyceryl
monostearate, sodium lauryl sulfate, lauromacrogol and the
like.
[0340] Examples of lubricants include, for example, stearic acid,
calcium stearate, magnesium stearate, talc and the like.
[0341] Examples of glidants include, for example, dried aluminum
hydroxide gel, magnesium silicate and the like.
[0342] Examples of coating materials include, for example,
hydroxypropylmethyl cellulose 2910, aminoalkyl methacrylate
copolymer E, polyvinylacetal diethylaminoacetate, macrogol 6000,
titanium oxide and the like. Examples of plasticizers include, for
example, triethyl citrate, triacetin, macrogol 6000 and the
like.
[0343] Administration
[0344] Described herein are methods for preventing an adverse
effect such as nausea, vomiting, other gastric upsets, skin rashes,
itching, allergic reactions such as swelling, difficulty breathing,
closing of throat, abdominal pain, unusual bleeding or bruising,
skin rashes, sedation, CNS depression, or respiratory depression in
a subject receiving, or in need of, opioid analgesic therapy. The
prevention of an adverse effect can be accomplished by the
administration of an effective amount of promethazine or other
antihistamine with the chosen analgesic agent or agents. In one
embodiment, the invention provides methods for treating pain,
comprising administering to a subject in need thereof an effective
amount of an opioid analgesic agent, a non-opioid analgesic agent,
an agent that reduces side effects of the opioid analgesic agent
and optionally a stimulant agent. In one embodiment, the non-opioid
analgesic agent is acetaminophen. In another embodiment, the agent
that reduces an adverse effect is promethazine. In another
embodiment, the invention provides methods for treating pain,
comprising administering to a subject in need thereof an effective
amount of an opioid analgesic agent, a non-opioid analgesic agent,
a barbiturate agent, an agent that reduces side effects of the
opioid analgesic agent and optionally a stimulant agent. In another
embodiment, the invention provides methods for treating pain,
comprising administering to a subject in need thereof an effective
amount of an opioid analgesic agent, a barbiturate agent, an agent
that reduces side effects of the opioid analgesic agent and
optionally a stimulant agent. In another embodiment, the invention
provides methods for treating pain, comprising administering to a
subject in need thereof an effective amount of an a non-opioid
analgesic agent, a barbiturate agent, an agent that reduces side
effects of the opioid analgesic agent and optionally a stimulant
agent. In another embodiment, the invention provides methods for
treating pain, comprising administering to a subject in need
thereof an effective amount of an opioid analgesic agent, an agent
that reduces side effects of the opioid analgesic agent and
optionally a stimulant agent.
[0345] The administration can continue for only a relatively short
time in the case of an acute condition requiring opioid therapy or
for long periods in the case of conditions requiring chronic use of
opioid analgesics. The dosing of analgesics can be dependent upon
the condition being treated, the subject's individual perception of
pain and the use of the opioid on a set time schedule as a
prophylactic to prevent the onset of pain or on an as needed basis
in response to perceived pain. The choice of selecting a dosage of
a composition that contains suitable amount of promethazine can be
dependent upon the extent and severity of the adverse effects
including nausea, vomiting, other gastric upsets, skin rashes,
allergic reactions such as swelling, difficulty breathing, closing
of throat, abdominal pain, unusual bleeding or bruising, skin
rashes, sedation, CNS depression, or respiratory depression in a
subject, upon the sensitivity to side-effect-reducing compounds
such as promethazine in a subject, upon the likelihood of subject
losing medication by vomiting, and/or on an as needed basis in
response to perceived adverse effects. The dosage can be assessed
by a prescribing professional evaluating the subject, the condition
treated, the analgesic to be used, diet and the expected duration
of therapy.
[0346] In one embodiment, compositions and methods described herein
provides for a method for treating a subject suffering from or
susceptible to pain, comprising administering to said subject an
effective amount of a composition comprising an effective amount of
a first component which is a non-opioid analgesic, or a
pharmaceutically acceptable salt thereof, an effective amount of a
second component which is a non-opioid analgesic, or a
pharmaceutically acceptable salt thereof and an effective amount of
a third component which is an antihistamine.
[0347] In another embodiment, a method for treating a subject is
provided comprising administering an effective amount of a
composition comprising: an effective amount of a first
pharmaceutically active agent which is an opioid analgesic, or a
pharmaceutically acceptable salt thereof; an effective amount of a
second pharmaceutically active agent which is a non-opioid
analgesic, or a pharmaceutically acceptable salt thereof; and an
effective amount of a third pharmaceutically active agent which is
an antihistamine or an anti-emetic. In one embodiment the at least
one adverse effect is nausea, vomiting, other gastric upsets, skin
rashes, allergic reactions such as swelling, difficulty breathing,
closing of throat, itching, abdominal pain, unusual bleeding or
bruising, skin rashes, sedation, CNS depression, or respiratory
depression. In one embodiment the non-opioid analgesic is
acetaminophen or analogue thereof. In one embodiment, the
antihistamine is promethazine. In one embodiment, the opioid
analgesic is hydrocodone. In another embodiment the opioid
analgesic is oxycodone. In another embodiment, the invention
provides methods for preventing or ameliorating an adverse effect
associated with administration of an analgesic, comprising
administering to a subject in need thereof an effective amount of
an opioid analgesic agent, a non-opioid analgesic agent, an agent
that reduces side effects of the opioid analgesic agent and
optionally a stimulant agent. In one embodiment, the non-opioid
analgesic agent is acetaminophen. In another embodiment, the agent
that reduces an adverse effect is promethazine. In another
embodiment, the invention provides methods for preventing or
ameliorating an adverse effect associated with administration of an
analgesic, comprising administering to a subject in need thereof an
effective amount of an opioid analgesic agent, a non-opioid
analgesic agent, a barbiturate agent, an agent that reduces side
effects of the opioid analgesic agent and optionally a stimulant
agent. In another embodiment, the invention provides methods for
preventing or ameliorating an adverse effect associated with
administration of an analgesic, comprising administering to a
subject in need thereof an effective amount of an opioid analgesic
agent, a barbiturate agent, an agent that reduces side effects of
the opioid analgesic agent and optionally a stimulant agent. In
another embodiment, the invention provides methods for preventing
or ameliorating an adverse effect associated with administration of
an analgesic, comprising administering to a subject in need thereof
an effective amount of an a non-opioid analgesic agent, a
barbiturate agent, an agent that reduces side effects of the opioid
analgesic agent and optionally a stimulant agent. In another
embodiment, the invention provides methods for preventing or
ameliorating an adverse effect associated with administration of an
analgesic, comprising administering to a subject in need thereof an
effective amount of an opioid analgesic agent, an agent that
reduces side effects of the opioid analgesic agent and optionally a
stimulant agent.
[0348] In another embodiment, compositions and methods described
herein provides for a method for preventing an adverse effect such
as nausea, vomiting, and a skin rash in a subject receiving or in
need of opioid therapy by the administration of an effective amount
of acetaminophen or analogue thereof and promethazine with the
opioid analgesic agent. In one embodiment, the opioid analgesic is
hydrocodone. In another embodiment the opioid analgesic is
oxycodone. In one embodiment, administration of a composition
comprising a non-opioid analgesic and an antihistamine enhances the
reduction or elimination of adverse effects associated with an
opioid analgesic. For example, addition of promethazine and
acetaminophen/ibuprofen reduces or eliminates an adverse effect
associated with an opioid analgesic in a synergistic manner
[0349] It is believed that administration of a composition of the
invention would result in treatment of the subject which includes
elimination or reduction of an adverse effect associated with
analgesics (e.g., opioids) and enhance the beneficial uses of such
analgesics. Such an adverse effect can otherwise render
administration of certain analgesics intolerable, due to for
example vomiting, nausea, and skin rashes. Therefore, various
embodiments of the methods of the invention are directed to target
populations of subjects that are susceptible to such an adverse
effect(s), thus allowing such subjects to benefit from the
pain-alleviating effects of analgesic-based pain relief,
administration of which would otherwise be intolerable.
[0350] For example, by reducing the risk of vomiting, the risk of
subject losing the analgesics (and losing the pain-relieving
beneficial effects of analgesics) by vomiting is minimized.
Furthermore, administration can be adjusted to provide the dose of
side-effect-reducing compound to match the subject's analgesic
ingestion without separate intervention by the health care
professionals. Adding one or more additional active agents, such as
promethazine, to the present compositions is believed to result in
a composition having reduced potential for abuse and diversion.
[0351] Routes of Administration
[0352] In various embodiments, the active agents are formulated to
be administered through oral dosage forms (e.g., tablets, capsules,
gels, lollipops), inhalations, nasal sprays, patches, absorbing
gels, liquids, liquid tannates, suppositories, injections, I.V.
drips, other delivery methods, or a combination thereof to treat
subjects. Administration may be performed in a variety of ways,
including, but not limited to orally, subcutaneously,
intravenously, intranasally, intraotically, transdermally,
topically (e.g., gels, salves, lotions, creams, etc.),
intraperitoneally, intramuscularly, intrapulmonary (e.g., AERx.RTM.
inhalable technology commercially available from Aradigm, or
Inhance, pulmonary delivery system commercially available from
Inhale Therapeutics), vaginally, parenterally, rectally, or
intraocularly.
[0353] To prepare the present compositions, an effective amount of
active agents can be mixed with a suitable pharmaceutically
acceptable carrier. Upon mixing of the compounds, the resulting
composition can be a solid, a half-solid, a solution, suspension,
or an emulsion. Such compositions can be prepared according to
methods known to those skilled in the art. The forms of the
resulting compositions can depend upon a variety of factors,
including the intended mode of administration and the solubility of
the compounds in the selected carrier or vehicle. The effective
concentration of analgesics is sufficient for lessening or
alleviating pain. In one embodiment of the invention, the
components of the present compositions are at least one opioid
analgesic agent (e.g., hydrocodone/oxycodone), one non-opioid
analgesic agent (e.g., acetaminophen), and one antihistamine agent
(e.g., promethazine). In other embodiments, administration
comprises administration of an antihistamine (e.g., promethazine)
separately, prior to, or during administration of the analgesic
formulations described herein (e.g., which comprises hydrocodone
and acetaminophen). In another embodiment the components of the
present compositions are at least one opioid analgesic agent, a
non-opioid analgesic agent, an agent that reduces side effects of
the opioid analgesic agent and a stimulant agent. In another
embodiment, the components of the present compositions are at least
one opioid analgesic agent, a non-opioid analgesic agent, a
barbiturate agent, an agent that reduces side effects of the opioid
analgesic agent and optionally a stimulant agent. In another
embodiment, the components of the present compositions are at least
one opioid analgesic agent, a barbiturate agent, an agent that
reduces side effects of the opioid analgesic agent and optionally a
stimulant agent. In another embodiment, the components of the
present compositions are at least one non-opioid analgesic agent, a
barbiturate agent, an agent that reduces side effects of the opioid
analgesic agent and optionally a stimulant agent. In another
embodiment, components of the present compositions are at least one
opioid analgesic agent, an agent that reduces side effects of the
opioid analgesic agent and optionally a stimulant agent.
[0354] The agents of the compositions and methods described herein
can be administered by the nasal inhalation route using
conventional nebulizers or by oxygen aerosolization to provide
convenient pain relief with reduced adverse effects. The agents can
be suspended or dissolved in a pharmacologically acceptable
inhalation carrier. Examples of such carriers are distilled water,
water/ethanol mixtures, and physiological saline solution.
Conventional additives including sodium chloride, glucose, citric
acid and the like may be employed in these dosage forms to
stabilize or to provide isotonic media. In one embodiment of the
invention, the compositions suitable for nasal inhalation by oxygen
aerosolization administration comprise hydrocodone or oxycodone,
acetaminophen, and promethazine. In other embodiments, an
antihistamine (e.g., promethazine) can be administered separately,
prior to, or during administration of the compositions described
herein (e.g., those comprising hydrocodone and acetaminophen).
[0355] The agents described herein can also be administered as a
self-propelled dosage unit in aerosol form suitable for inhalation
therapy. Suitable means for employing the aerosol inhalation
therapy technique are described, for example, in U.S. Pat. No.
6,913,768 to Couch et al., which is incorporated herein by
reference in its entirety. The agent can be suspended in an inert
propellant such as a mixture of dichlorodifluoromethane and
dichlorotetrafluoroethane, together with a co-solvent such as
ethanol, together with flavoring materials and stabilizers. In one
embodiment of the invention, the agents useful for a self-propelled
dosage unit in aerosol form administration are hydrocodone or
oxycodone, acetaminophen, and promethazine. In a further embodiment
the dosage unit may further comprise an agent such as a
bronchodilator (e.g., albuterol).
[0356] The agents of the compositions and methods described herein
can also be administered as nasal spray/drop compositions, which
can conveniently and safely be applied to subjects to effectively
treat pain with reduced adverse effects. The compositions may
further comprise a water soluble polymer such as
polyvinylpyrrolidone, together with other medications such as
sumatriptan, together with bioadhesive material. In one embodiment
of the invention, the components of a composition for nasal spray
or drop administration are hydrocodone or oxycodone agent,
acetaminophen, and promethazine, or a pharmaceutically acceptable
salt thereof.
[0357] The compositions described herein can also be administered
topically to the skin of a subject. The agents can be mixed with a
pharmaceutically acceptable carrier or a base which is suitable for
topical application to skin to form a dermatological composition.
Suitable examples of carrier or base include, but not limited to,
water, glycols, alcohols, lotions, creams, gels, emulsions, and
sprays. A dermatological composition comprising an analgesic agent
can be integrated into a topical dressing, medicated tape, dermal
patch absorbing gel and cleansing tissues. In one embodiment of the
invention, the dermatological composition comprises hydrocodone or
oxycodone, acetaminophen, and promethazine.
[0358] The compositions described herein can also be in liquid or
liquid tannate form. The liquid formulations can comprise, for
example, an agent in water-in-solution and/or suspension form; and
a vehicle comprising polyethoxylated castor oil, alcohol and/or a
polyoxyethylated sorbitan mono-oleate with or without flavoring.
Each dosage form comprises an effective amount of an active agent
and can optionally comprise pharmaceutically inert agents, such as
conventional excipients, vehicles, fillers, binders, disintegrants,
pH adjusting substances, buffer, solvents, solubilizing agents,
sweeteners, coloring agents and any other inactive agents that can
be included in pharmaceutical dosage forms for oral administration.
Examples of such vehicles and additives can be found in Remington's
Pharmaceutical Sciences, 17th edition (1985). Therefore, in one
embodiment a liquid composition of the invention comprises an
opioid analgesic (e.g., hydrocodone or oxycodone), a non-opioid
analgesic (e.g., acetaminophen) and an antihistamine (e.g.,
promethazine). In another embodiment a liquid composition of the
invention comprises at least one opioid analgesic agent, a
non-opioid analgesic agent, an agent that reduces side effects of
the opioid analgesic agent and a stimulant agent. In another
embodiment, a liquid composition of the invention comprises at
least one opioid analgesic agent, a non-opioid analgesic agent, a
barbiturate agent, an agent that reduces side effects of the opioid
analgesic agent and optionally a stimulant agent. In another
embodiment, a liquid composition of the invention comprises at
least one opioid analgesic agent, a barbiturate agent, an agent
that reduces side effects of the opioid analgesic agent and
optionally a stimulant agent. In another embodiment, a liquid
composition of the invention comprises at least one non-opioid
analgesic agent, a barbiturate agent, an agent that reduces side
effects of the opioid analgesic agent and optionally a stimulant
agent. In another embodiment, a liquid composition of the invention
comprises at least one opioid analgesic agent, an agent that
reduces side effects of the opioid analgesic agent and optionally a
stimulant agent.
[0359] The compositions described herein can also be administered
in a suppository form, comprising an outer layer containing the
composition in a suppository base. The suppository base may, for
example, be any conventional suppository base material such as
glycogelatin, polyethylene glycol, fractionated palm kernel oil, or
one or more natural, synthetic or semi synthetic hard fats such as
cocoa butter. Therefore, in one embodiment of the invention, the
base material is mixed with an opioid analgesic (e.g.,
hydrocodone/oxycodone), a non-opioid analgesic (e.g.,
acetaminophen) and an antihistamine (e.g., promethazine).
[0360] The compositions described herein can also be administered
in injection-ready stable liquids for injection or I.V. drip. For
example, saline or other injection-ready liquid can be mixed with
an opioid analgesic (e.g., hydrocodone or oxycodone), a non-opioid
analgesic (e.g., acetaminophen) and an antihistamine (e.g.,
promethazine). In one embodiment a composition disclosed herein is
administered by a subject administered injection. For example a
subject can administer the composition via a hand-held injection
device such as a pen type injector. In one example a subject can
use a device or component disclosed in U.S. Pat. Nos. 6,146,361;
5,536,249; or 5,954,700 (which are herein incorporated by reference
in their entirety) to administer a pharmaceutical composition
disclosed herein.
[0361] Treatment or Prevention of Pain
[0362] The present compositions and methods are useful for treating
or preventing pain. Accordingly the present invention includes
methods for treating or preventing pain, comprising administering
to a subject in need thereof a composition of the invention. Pain
treatable or preventable includes, but is not limited to, pain
associated with cancer, chronic or acute pain, headache pain,
migraine headache, chronic headache, surgical procedure, acute or
chronic physical injury, bone fracture or crush injuries, spinal
cord injury, inflammatory disease (e.g., pancreatitis),
noninflammatory neuropathic or dysfunctional pain conditions, or a
combination thereof.
[0363] Various methods of drug administration known in the art or
disclosed herein are utilized to deliver a composition of present
invention to a subject in need thereof.
[0364] In some embodiments, methods of treatment or prevention
comprising administering a composition of the invention are for
treating pain or preventing pain. In some embodiments, the pain
treatable or preventable via administration of a composition of the
invention includes but is not limited to headache pain, and/or
headache related symptoms as further described herein below.
[0365] Treatment or Prevention of Headache
[0366] The present compositions and methods are useful for treating
or preventing a headache. Preventable or treatable headaches
include but are not limited to migraine headaches (with or without
aura), cluster headaches, chronic headaches, tension type
headaches, Hemicrania Continua, new daily persistent, chronic
tension type headaches or any combination thereof. In one
embodiment, a method for treating or preventing a headache
comprises administering to a subject in need thereof a composition
of the invention. Each of such compositions if fully described
herein.
[0367] Migraines and cluster headaches are both important,
well-known, and extensively studied medical problem. In many cases,
they completely incapacitate a sufferer for the duration of the
headache. Their physiological embodiments, causative and
aggravating factors, and current Treatments are discussed in detail
in numerous scientific articles, and in full-length medical
textbooks such as Headache in Clinical Practice (edited by S.
Silberstein et al., Oxford Univ. Press, 1998); The Headaches, by J.
Olesen; and Headache Disorders: A Management Guide for
Practitioners, by A. Rapoport and F. Sheftell (W. B. Saunders,
Philadelphia, 1996), which are herein incorporated by reference in
their entirety. In addition, various definitions, categories, and
diagnostic standards are defined by standardized criteria that have
been approved and issued by the International Headache Society
(IHS), which were published as a supplement to the journal
Cephalalgia (Cephalalgia. 2004; 24 Suppl 1:9-160) and is herein
incorporated by reference in its entirety.
[0368] In one embodiment a composition of the invention is
administered to a subject to treat, eliminate or prevent at least
one headache symptom. An effective amount is a dosage sufficient to
reduce at least one symptom associate with a headache. Headache
symptoms include: (1) frequency, which can be evaluated over a span
of time, such as number of such headaches per week, per month, or
per year; (2) duration, which evaluates (usually in hours) how long
a headache lasts, from the time it begins to develop into a
migraine or cluster headache, until it has been resolved; and (3)
severity (also referred to as intensity), which is based on
subjective estimates of the severity or intensity of pain or other
symptoms (such as nausea) being suffered by patients during such
headaches. In one embodiment a composition is used in a method to
reduce the frequency, duration or severity of a preventable or
treatable headache.
Treatment or Prevention of Photophobia
[0369] In one embodiment, the invention provides methods for
treating or preventing photophobia, comprising administering to a
subject in need thereof a composition of the invention. In one
embodiment the composition comprises an effective amount of each of
an opioid analgesic and an antiemetic, as disclosed herein above.
In one embodiment, the antiemetic is promethazine or a
pharmaceutically acceptable salt thereof and the opioid analgesic
is hydrocodone, oxycodone or a pharmaceutically acceptable salt
thereof. In a further embodiment, the composition is in the form of
a bilayer tablet that comprises an immediate-release layer and a
controlled-release layer. In another embodiment the
immediate-release layer comprises promethazine or a
pharmaceutically acceptable salt thereof, and the
controlled-release layer comprises hydrocodone, oxycodone or a
pharmaceutically acceptable salt thereof. In a further embodiment,
the photophobia is associated with a migraine headache.
[0370] In another embodiment, the invention provides methods for
treating or preventing photophobia, comprising administering to a
subject in need thereof a composition comprising an effective
amount of a triptan and an effective amount of an antiemetic. In a
further embodiment the triptan is a sumatriptan or a
pharmaceutically acceptable salt thereof, and the antiemetic is
promethazine or a pharmaceutically acceptable salt thereof. In one
embodiment, the sumatriptan salt is sumatriptan succinate.
[0371] In yet a further embodiment, the composition is in the form
of a bilayer tablet that comprises an immediate-release layer and a
controlled-release layer. In another embodiment of the invention
the controlled-release layer comprises sumatriptan or a
pharmaceutically acceptable salt thereof, and the immediate-release
layer comprises promethazine or a pharmaceutically acceptable salt
thereof.
EXAMPLES
Example 1
[0372] Example of an analgesic composition comprising Hydrocodone
Bitartrate, Acetaminophen and Promethazine Hydrochloride
TABLE-US-00001 Analgesic Composition A Agents mg/Tablet Hydrocodone
Bitartrate 7.5 mg Acetaminophen 325 mg Promethazine Hydrochloride
12.5 mg
Example 2
[0373] In one example, the composition of Example 1 is formulated
in the form of a bi-layer tablet having an immediate-release layer
comprising 12.5 mg of promethazine hydrochloride and having a
controlled-release layer comprising 7.5 mg of hydrocodone
bitartrate and 325 mg of acetaminophen.
Example 3
[0374] The composition of Example 1 is orally administered with
water to a subject having a tendency to exhibit adverse effects of
opioid administration, such as gastric upset, nausea, vomiting,
skin rash, sedation, CNS depression, or respiratory depression.
Such subjects, upon taking the composition set forth in Example 1
will receive an effective amount of promethazine in their blood
stream. The promethazine will reduce the adverse effects that such
a target population would otherwise exhibit.
Example 4
[0375] Example of an analgesic composition comprising Oxycodone
Hydrochloride, Acetaminophen and Promethazine Hydrochloride
TABLE-US-00002 Analgesic Composition B Agents mg/Tablet Oxycodone
HCl 5 mg or 7.5 mg Acetaminophen 325 mg Promethazine Hydrochloride
12.5 mg
Example 5
[0376] In one example, the composition of Example 4 is in the form
of a bi-layer tablet having an immediate-release layer comprising
12.5 mg of promethazine hydrochloride, and having a
controlled-release layer comprising 5 or 7.5 mg of oxycodone HCl
and 325 mg of acetaminophen.
Example 6
[0377] The composition of Example 5 is orally administered with
water to a subject having a tendency to exhibit adverse effects of
opioid administration, such as gastric upset, nausea, vomiting,
skin rash, sedation, CNS depression, or respiratory depression.
Such subjects, upon taking the composition set forth in Example 5
will receive an effective amount of promethazine which will reduce
the adverse effects that such a target population would otherwise
exhibit.
Example 7
[0378] Example of an abuse safeguard drug formulation comprising
Hydrocodone Bitartrate, Acetaminophen and Promethazine
Hydrochloride.
TABLE-US-00003 Analgesic Composition C Agents mg/Tablet Hydrocodone
Bitartrate 7.5 mg Acetaminophen 325 mg Promethazine HCl 12.5 mg
Naltrexone 0.75 mg
Example 8
[0379] In one example, the composition of Example 7 is in the form
of a bi-layered tablet having an immediate-release layer comprising
12.5 mg of promethazine hydrochloride, and having a
controlled-release layer comprising 7.5 mg of hydrocodone
bitartrate and 325 mg of acetaminophen.
Example 9
[0380] The composition of Example 7 is orally administered with
water to a subject having a tendency to exhibit adverse effects of
opioid administration, such as gastric upset, nausea, vomiting,
skin rash, sedation, CNS depression, or respiratory depression.
Such subjects, upon taking the composition set forth in Example 7
will receive an effective amount of promethazine in their blood
stream. The promethazine will reduce the adverse effects that such
a target population would otherwise exhibit.
Example 10
[0381] Example of an abuse safeguard drug formulation comprising
Oxycodone HCl, Acetaminophen and Promethazine HCl.
TABLE-US-00004 Analgesic Composition D Agents mg/Tablet Oxycodone
HCl 5 mg or 7.5 mg Acetaminophen 325 mg Promethazine HCl 12.5 mg
Naltrexone 0.5 mg or 0.75 mg
Example 11
[0382] In one example, the composition of Example 10 is in the form
of a bi-layer tablet having an immediate-release layer comprising
12.5 mg of promethazine hydrochloride, and having a
controlled-release layer comprising 5 or 7.5 mg of oxycodone HCl
and 325 mg of acetaminophen.
Example 12
[0383] The composition of Example 10 is orally administered with
water to a subject having a tendency to exhibit adverse effects of
opioid administration, such as gastric upset, nausea, vomiting,
skin rash, sedation, CNS depression, or respiratory depression.
Such subjects, upon taking the composition set forth in Example 10
will receive an effective amount of promethazine in their blood
stream. The promethazine will reduce the adverse effects that such
a target population would otherwise exhibit.
Example 13
[0384] Example of a bi-layer tablet analgesic composition
comprising Hydrocodone or a Pharmaceutically Acceptable Salt
Thereof, Acetaminophen and Promethazine or a Pharmaceutically
Acceptable Salt Thereof. In one example, a bi-layer tablet
comprises: (1) a controlled-release layer comprising (a) from about
6.5 mg to about 8.5 mg of hydrocodone or a pharmaceutically
acceptable salt thereof, (b) from about 290 to about 360 mg of
acetaminophen or a pharmaceutically acceptable salt thereof, (c)
from about 135 mg to about 170 mg of silicified microcrystalline
cellulose, (d) from about 17 mg to about 23 mg of hydroxy methyl
propyl cellulose, (e) from about 1 mg to about 4 mg of magnesium
stearate, and (f) from about 1 mg to about 4 mg of stearic acid;
and (2) an immediate-release layer comprising (a) from about 11 mg
to about 14 mg of promethazine or a pharmaceutically acceptable
salt thereof, (b) from about 100 mg to about 140 mg of silicified
microcrystalline cellulose, (c) from about 12 mg to about 18 mg of
croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg of
magnesium stearate. In another example, a bi-layer tablet's
controlled-release layer comprises about 7.5 mg of hydrocodone or a
pharmaceutically acceptable salt thereof, about 325 mg of
acetaminophen or a pharmaceutically acceptable salt thereof, about
152 mg of silicified microcrystalline cellulose, about 20 mg of
hydroxy methyl propyl cellulose, about 2.7 mg of magnesium
stearate, and about 2.7 mg of stearic acid; and tablet's immediate
release layer comprises about 12.5 mg of promethazine or a
pharmaceutically acceptable salt thereof, about 121.5 mg of
silicified microcrystalline cellulose, about 15 mg of
croscarmellose sodium and about 1 mg of magnesium stearate.
[0385] Analgesic Composition F.1
TABLE-US-00005 Ingredient Quantity/Tablet (mg) Top Layer -
Immediate Release Layer Promethazine HCl 12.5 mg Prosolve SMCC
(HD90) 121.5 mg Croscarmellose Sodium 15 mg Crospovidone NF 15 mg
Avicel PH200 21.5 mg Magnesium Stearate 1 mg Total Top Layer Weight
186.5 mg Bottom Layer- Controlled-Release Layer Acetaminophen 89.5%
360.5 mg Hydrocodone Bitartrate 7.5 mg Silicified Microcrystalline
Cellulose 150 mg Hydroxy Methyl Propyl Cellulose 10 mg
Croscarmellose Sodium 23 mg Magnesium Stearate 15 mg Total Bottom
Layer Weight 566 mg
[0386] Analgesic Composition F.2
TABLE-US-00006 Ingredient Quantity/Tablet (mg) Top Layer -
Immediate Release Layer Promethazine HCl 12.5 mg Silicified
Microcrystalline Cellulose 121.5 mg Croscarmellose Sodium 15 mg
Magnesium Stearate 1 mg Total Top Layer Weight 150.0 mg Bottom
Layer- Controlled-Release Layer Acetaminophen 89.05% 364.96 mg
Hydrocodone bitartrate 7.5 mg Silicified Microcrystalline Cellulose
152.04 mg Hydroxy Methyl Propyl Cellulose 20 mg Stearic Acid 2.75
mg Magnesium Stearate 2.75 mg Total Bottom Layer Weight 566 mg
Example 14
[0387] The composition of Example 13 is orally administered with
water to a subject having a tendency to exhibit adverse effects of
opioid administration, such as gastric upset, nausea, vomiting,
skin rash, sedation, CNS depression, or respiratory depression.
Such subjects, upon taking the composition set forth in Example 13
will receive an effective amount of promethazine in their blood
stream. The promethazine will reduce the adverse effects that such
a target population would otherwise exhibit.
Example 15
[0388] Dissolution Data
[0389] Dissolution apparatus was a USP Rotating Paddle Apparatus 2
with an automated sampling station (e.g., VK-8000 or equivalent).
Dissolution fluid was 900 mL of de-aerated 0.01 N HCl, maintained
at 37.0+/-0.5.degree. C. during dissolution procedure. The fluid
was prepared by diluting 5 mL of concentrated HCl in 6000 mL of
de-aerated water, and mixed. To measure peaks, a dual wavelength
detector (e.g., Hitachi L-2420) was used, or alternatively, two
separate chromatographic systems can be used in order to measure
the peaks at two different wavelengths.
[0390] Standard Solution Preparation: Each ingredient was weighed
(e.g., 21 mg of hydrocodone bitrartrate) into a 50 mL volumetric
flask, and diluted to volume with dissolution media. The resulting
solution was mixed to form a stock solution. Different ingredients
were similarly prepared to provide stock solutions (e.g.,
promethazine HCl, acetaminophen). 2 mL each of stock standard
solutions were diluted with dissolution fluid and mixed to produce
a final standard solution. For example, the concentration of
hydrocodone bitartrate was about 0.0084 mg/mL, promethazine HCl was
about 0.014 mg/mL, and acetaminophen was about 0.36 mg/mL.
[0391] Dissolution test solutions were prepared in 900 mL of 0.01 N
HCl using the USP Rotating Paddle Apparatus at 50 WM. An aliquot of
the dissolution solution was filtered and a 50-pL aliquot was
chromatographed on a 50-mm.times.4.6-mm (i.d.) Waters sunFire.TM.
C.sub.18, 3.5-.mu.m particle size column using a gradient HPLC
method. Mobile phase A consisted of water/acetonitrile/TFA,
950/50/2 (v/v/v) and mobile phase B consisted of
water/acetonitrile/TFA, 50/950/1.5 (v/v/v). The flow rate was 2.0
mL/minute. For example, the amount of acetaminophen released was
determined at 300 nm by comparing the area obtained for the peak
due to acetaminophen in the chromatogram of the dissolution test
solution to that obtained for the corresponding peak in a
chromatogram of a standard solution. The amount of hydrocodone
bitartrate released was determined at 230 nm by comparing the area
obtained for the peak due to hydrocodone bitartrate in the
chromatogram of the dissolution test solution to that obtained for
the corresponding peak in a chromatogram of a standard solution.
The amount of promethazine HCl released was determined at 230 nm by
comparing the area obtained for the peak due to promethazine HCl in
the chromatogram of the dissolution test solution to that obtained
for the corresponding peak in a chromatogram of a standard
solution.
[0392] Paddle speed was 50 rpm; pull volume was 10 mL (no
replacement); Pull points: 5, 10, 15, 20, 25, 30, 45 and 60
minutes. The amount of each component dissolved in the dissolution
medium was determined by HPLC. The method can use a high purity,
bonded C18 stationary phase and a binary mobile phase consisting of
an appropriate buffer and organic modifier.
[0393] Dissolution Procedure. 900 mL of dissolution fluid preheated
to 37.degree. C. was placed into each vessel. Tablets of Analgesic
Composition F.2 above were weighed and placed in vessels
respectively. At prescribed time intervals, 5 mL aliquot of the
dissolution fluid was drawn using the automated sampling station
equipped with a 35 .mu.m full flow filter connected to a sampling
probe. Filtrate was allowed to cool to room temperature, to produce
a final sample solution. Fluid withdrawn was not replaced. Samples
were injected in HPLC for analysis after a baseline was
established. Peak area responses were measured for each component:
acetaminophen peak eluted at about 1.5 minutes; hydrocodone
bitartrate eluted at about 3.3 minutes and promethazine HCl eluted
at about 4.8 minutes. The resolution between each peak was
calculated, as well as the tailing factor. The mean and % RSD
values for the acetaminophen peak areas at 300 nm were measured;
promethazine HCl and hydrocodone bitartrate at 230 nm. The five
replicate injections were not more than 2.0% RSD. 50 .mu.L aliquots
of standard and sample solutions were subjected to liquid
chromatography. A typical chromatogram of a standard solution is
illustrated in FIG. 1.
[0394] The amount of a pharmaceutically active agent in a tablet is
determined by comparing the area obtained for the peak due to the
agent in a chromatogram of the dissolution test solution to that
obtained for the corresponding peak in a chromatogram of a standard
solution. For example the standard peaks are provided in FIG. 3,
while the test solutions are provide in FIG. 4.
Example 16
[0395] The compositions of Table 1 or Table 2 can be formulated in
formulated in a variety of dosage forms (e.g., tablets, capsules,
geld, lollipops), parenteral, intraspinal infusion, inhalations,
nasal sprays, transdermal patches, iontophoresis transport,
absorbing gels, liquids, liquid tannates, suppositories,
injections, I.V. drips, other delivery methods, or a combination
thereof to treat subjects. In some embodiments each agent disclosed
in Table 1 or Table 2 can be present in a composition as its
pharmaceutically acceptable salt. In one embodiment the hydrocodone
of the compositions of Table 1 is in the form of hydrocodone
bitartrate; in another embodiment the oxycodone of the compositions
of Table 1 is in the form of oxycodone hydrochloride; in another
embodiment the ibuprofen of the compositions of Table 1 is in the
form of ibruprofen sodium; in another embodiment the naproxen of
the compositions of Table 1 is in the form of naproxen sodium; in
another embodiment the promethazine of the compositions of Table 1
or Table 2 is in the form of promethazine hydrochloride; and in
another embodiment the naltrexone of the compositions of Table 1 is
in the form of naltrexone hydrochloride. In some embodiments a
dosage form comprising an effective amount of promethazine or a
pharmaceutically acceptable salt thereof will be orally
administered to a subject having a tendency to exhibit one or more
adverse effect of opioid administration, such as gastric upset,
nausea, vomiting, skin rash, sedation, CNS depression, or
respiratory depression in response to opioid administration. In one
embodiment one or more of compositions of Table 1 or Table 2 are in
the form of a bi-layer tablet comprising an immediate release layer
and a controlled release layer. In one embodiment the
controlled-release layer comprises hydrocodone, oxycodone,
propoxyphene, ibuprofen, acetaminophen, naproxen or a
pharmaceutically acceptable salt thereof and the immediate-release
layer comprises promethazine or a pharmaceutically acceptable salt
thereof.
TABLE-US-00007 TABLE 1 Multi-drug Compositions Composition Opioid
Abuse No. Opioid agent Non-opioid agent Antiemetic agent
Barbiturate agent Stimulant agent antagonist agent deterrent agent
1 Hydrocodone Acetaminophen -- -- -- -- -- 2 Hydrocodone --
Promethazine -- -- -- -- 3 Hydrocodone -- -- Butalbital -- -- -- 4
Hydrocodone -- -- -- Modafinil -- -- 5 Hydrocodone -- -- --
Caffeine -- -- 6 Hydrocodone -- -- -- -- Naltrexone -- 7
Hydrocodone -- -- -- -- -- Niacin 8 Hydrocodone Acetaminophen
Promethazine -- -- -- -- 9 Hydrocodone Acetaminophen -- Butalbital
-- -- -- 10 Hydrocodone Acetaminophen -- -- Modafinil -- -- 11
Hydrocodone Acetaminophen -- -- Caffeine -- -- 12 Hydrocodone
Acetaminophen -- -- -- Naltrexone -- 13 Hydrocodone Acetaminophen
-- -- -- -- Niacin 14 Hydrocodone -- Promethazine Butalbital -- --
-- 15 Hydrocodone -- Promethazine -- Modafinil -- -- 16 Hydrocodone
-- Promethazine -- Caffeine -- -- 17 Hydrocodone -- Promethazine --
-- Naltrexone -- 18 Hydrocodone -- Promethazine -- -- -- Niacin 19
Hydrocodone -- -- Butalbital Modafinil -- -- 20 Hydrocodone -- --
Butalbital Caffeine -- -- 21 Hydrocodone -- -- Butalbital --
Naltrexone -- 22 Hydrocodone -- -- Butalbital -- -- Niacin 23
Hydrocodone -- -- -- Modafinil Naltrexone -- 24 Hydrocodone -- --
-- Caffeine Naltrexone -- 25 Hydrocodone -- -- -- Modafinil --
Niacin 26 Hydrocodone -- -- -- Caffeine -- Niacin 27 Hydrocodone --
-- -- -- Naltrexone Niacin 28 Hydrocodone Acetaminophen
Promethazine Butalbital -- -- -- 29 Hydrocodone Acetaminophen
Promethazine -- Modafinil -- -- 30 Hydrocodone Acetaminophen
Promethazine -- Caffeine -- -- 31 Hydrocodone Acetaminophen
Promethazine -- -- Naltrexone -- 32 Hydrocodone Acetaminophen
Promethazine -- -- -- Niacin 33 Hydrocodone Acetaminophen --
Butalbital Modafinil -- -- 34 Hydrocodone Acetaminophen --
Butalbital Caffeine -- -- 35 Hydrocodone Acetaminophen --
Butalbital -- Naltrexone -- 36 Hydrocodone Acetaminophen --
Butalbital -- -- Niacin 37 Hydrocodone Acetaminophen -- --
Modafinil Naltrexone -- 38 Hydrocodone Acetaminophen -- --
Modafinil -- Niacin 39 Hydrocodone Acetaminophen -- -- Caffeine
Naltrexone -- 40 Hydrocodone Acetaminophen -- -- Caffeine -- Niacin
41 Hydrocodone Acetaminophen -- -- -- Naltrexone Niacin 42
Hydrocodone -- Promethazine Butalbital Modafinil -- -- 43
Hydrocodone -- Promethazine Butalbital Caffeine -- -- 44
Hydrocodone -- Promethazine Butalbital -- Naltrexone -- 45
Hydrocodone -- Promethazine Butalbital -- -- Niacin 46 Hydrocodone
-- Promethazine -- Modafinil Naltrexone -- 47 Hydrocodone --
Promethazine -- Caffeine Naltrexone -- 48 Hydrocodone --
Promethazine -- Modafinil -- Niacin 49 Hydrocodone -- Promethazine
-- Caffeine -- Niacin 50 Hydrocodone -- Promethazine -- --
Naltrexone Niacin 51 Hydrocodone -- -- Butalbital Modafinil
Naltrexone -- 52 Hydrocodone -- -- Butalbital Caffeine Naltrexone
-- 53 Hydrocodone -- -- Butalbital Modafinil -- Niacin 54
Hydrocodone -- -- Butalbital Caffeine -- Niacin 55 Hydrocodone --
-- Butalbital -- Naltrexone Niacin 56 Hydrocodone -- -- --
Modafinil Naltrexone Niacin 57 Hydrocodone -- -- -- Caffeine
Naltrexone Niacin 58 Hydrocodone Acetaminophen Promethazine
Butalbital Modafinil -- -- 59 Hydrocodone Acetaminophen
Promethazine Butalbital Caffeine -- -- 60 Hydrocodone Acetaminophen
Promethazine Butalbital -- Naltrexone -- 61 Hydrocodone
Acetaminophen Promethazine Butalbital -- -- Niacin 62 Hydrocodone
Acetaminophen Promethazine -- Modafinil Naltrexone -- 63
Hydrocodone Acetaminophen Promethazine -- Caffeine Naltrexone -- 64
Hydrocodone Acetaminophen Promethazine -- Modafinil -- Niacin 65
Hydrocodone Acetaminophen Promethazine -- Caffeine -- Niacin 66
Hydrocodone Acetaminophen Promethazine -- -- Naltrexone Niacin 67
Hydrocodone Acetaminophen -- Butalbital Modafinil Naltrexone -- 68
Hydrocodone Acetaminophen -- Butalbital Caffeine Naltrexone -- 69
Hydrocodone Acetaminophen -- Butalbital Modafinil -- Niacin 70
Hydrocodone Acetaminophen -- Butalbital Caffeine -- Niacin 71
Hydrocodone Acetaminophen -- Butalbital -- Naltrexone Niacin 72
Hydrocodone Acetaminophen -- -- Modafinil Naltrexone Niacin 73
Hydrocodone Acetaminophen -- -- Caffeine Naltrexone Niacin 74
Hydrocodone -- Promethazine Butalbital Modafinil Naltrexone -- 75
Hydrocodone -- Promethazine Butalbital Caffeine Naltrexone -- 76
Hydrocodone -- Promethazine Butalbital Modafinil -- Niacin 77
Hydrocodone -- Promethazine Butalbital Caffeine -- Niacin 78
Hydrocodone -- Promethazine Butalbital -- Naltrexone Niacin 79
Hydrocodone -- -- Butalbital Caffeine Naltrexone Niacin 80
Hydrocodone Acetaminophen Promethazine Butalbital Modafinil
Naltrexone -- 81 Hydrocodone Acetaminophen Promethazine Butalbital
Caffeine Naltrexone -- 82 Hydrocodone Acetaminophen Promethazine
Butalbital Modafinil -- Niacin 83 Hydrocodone Acetaminophen
Promethazine Butalbital Caffeine -- Niacin 84 Hydrocodone --
Promethazine Butalbital Modafinil Naltrexone Niacin 85 Hydrocodone
-- Promethazine Butalbital Caffeine Naltrexone Niacin 86
Hydrocodone Acetaminophen -- Butalbital Modafinil Naltrexone Niacin
87 Hydrocodone Acetaminophen -- Butalbital Caffeine Naltrexone
Niacin 88 Hydrocodone Acetaminophen Promethazine -- Modafinil
Naltrexone Niacin 89 Hydrocodone Acetaminophen Promethazine --
Caffeine Naltrexone Niacin 90 Hydrocodone Acetaminophen
Promethazine Butalbital -- Naltrexone Niacin 91 Hydrocodone
Acetaminophen Promethazine Butalbital Modafinil Naltrexone Niacin
92 Hydrocodone Acetaminophen Promethazine Butalbital Caffeine
Naltrexone Niacin 93 Hydrocodone Naproxen -- -- -- -- -- 94
Hydrocodone -- Promethazine -- -- -- -- 95 Hydrocodone -- --
Butalbital -- -- -- 96 Hydrocodone -- -- -- Modafinil -- -- 97
Hydrocodone -- -- -- Caffeine -- -- 98 Hydrocodone -- -- -- --
Naltrexone -- 99 Hydrocodone -- -- -- -- -- Niacin 100 Hydrocodone
Naproxen Promethazine -- -- -- -- 101 Hydrocodone Naproxen --
Butalbital -- -- -- 102 Hydrocodone Naproxen -- -- Modafinil -- --
103 Hydrocodone Naproxen -- -- Caffeine -- -- 104 Hydrocodone
Naproxen -- -- -- Naltrexone -- 105 Hydrocodone Naproxen -- -- --
-- Niacin 106 Hydrocodone -- Promethazine Butalbital -- -- -- 107
Hydrocodone -- Promethazine -- Modafinil -- -- 108 Hydrocodone --
Promethazine -- Caffeine -- -- 109 Hydrocodone -- Promethazine --
-- Naltrexone -- 110 Hydrocodone -- Promethazine -- -- -- Niacin
111 Hydrocodone -- -- Butalbital Modafinil -- -- 112 Hydrocodone --
-- Butalbital Caffeine -- -- 113 Hydrocodone -- -- Butalbital --
Naltrexone -- 114 Hydrocodone -- -- Butalbital -- -- Niacin 115
Hydrocodone -- -- -- Modafinil Naltrexone -- 116 Hydrocodone -- --
-- Caffeine Naltrexone -- 117 Hydrocodone -- -- -- Modafinil --
Niacin 118 Hydrocodone -- -- -- Caffeine -- Niacin 119 Hydrocodone
-- -- -- -- Naltrexone Niacin 120 Hydrocodone Naproxen Promethazine
Butalbital -- -- -- 121 Hydrocodone Naproxen Promethazine --
Modafinil -- -- 122 Hydrocodone Naproxen Promethazine -- Caffeine
-- -- 123 Hydrocodone Naproxen Promethazine -- -- Naltrexone -- 124
Hydrocodone Naproxen Promethazine -- -- -- Niacin 125 Hydrocodone
Naproxen -- Butalbital Modafinil -- -- 126 Hydrocodone Naproxen --
Butalbital Caffeine -- -- 127 Hydrocodone Naproxen -- Butalbital --
Naltrexone -- 128 Hydrocodone Naproxen -- Butalbital -- -- Niacin
129 Hydrocodone Naproxen -- -- Modafinil Naltrexone -- 130
Hydrocodone Naproxen -- -- Modafinil -- Niacin 131 Hydrocodone
Naproxen -- -- Caffeine Naltrexone -- 132 Hydrocodone Naproxen --
-- Caffeine -- Niacin 133 Hydrocodone Naproxen -- -- -- Naltrexone
Niacin 134 Hydrocodone -- Promethazine Butalbital Modafinil -- --
135 Hydrocodone -- Promethazine Butalbital Caffeine -- -- 136
Hydrocodone -- Promethazine Butalbital -- Naltrexone -- 137
Hydrocodone -- Promethazine Butalbital -- -- Niacin 138 Hydrocodone
-- Promethazine -- Modafinil Naltrexone -- 139 Hydrocodone --
Promethazine -- Caffeine Naltrexone -- 140 Hydrocodone --
Promethazine -- Modafinil -- Niacin 141 Hydrocodone -- Promethazine
-- Caffeine -- Niacin 142 Hydrocodone -- Promethazine -- --
Naltrexone Niacin 143 Hydrocodone -- -- Butalbital Modafinil
Naltrexone -- 144 Hydrocodone -- -- Butalbital Caffeine Naltrexone
-- 145 Hydrocodone -- -- Butalbital Modafinil -- Niacin 146
Hydrocodone -- -- Butalbital Caffeine -- Niacin 147 Hydrocodone --
-- Butalbital -- Naltrexone Niacin 148 Hydrocodone -- -- --
Modafinil Naltrexone Niacin 149 Hydrocodone -- -- -- Caffeine
Naltrexone Niacin 150 Hydrocodone Naproxen Promethazine Butalbital
Modafinil -- -- 151 Hydrocodone Naproxen Promethazine Butalbital
Caffeine -- -- 152 Hydrocodone Naproxen Promethazine Butalbital --
Naltrexone -- 153 Hydrocodone Naproxen Promethazine Butalbital --
-- Niacin 154 Hydrocodone Naproxen Promethazine -- Modafinil
Naltrexone -- 155 Hydrocodone Naproxen Promethazine -- Caffeine
Naltrexone -- 156 Hydrocodone Naproxen Promethazine -- Modafinil --
Niacin 157 Hydrocodone Naproxen Promethazine -- Caffeine -- Niacin
158 Hydrocodone Naproxen Promethazine -- -- Naltrexone Niacin 159
Hydrocodone Naproxen -- Butalbital Modafinil Naltrexone -- 160
Hydrocodone Naproxen -- Butalbital Caffeine Naltrexone -- 161
Hydrocodone Naproxen -- Butalbital Modafinil -- Niacin 162
Hydrocodone Naproxen -- Butalbital Caffeine -- Niacin 163
Hydrocodone Naproxen -- Butalbital -- Naltrexone Niacin 164
Hydrocodone Naproxen -- -- Modafinil Naltrexone Niacin 165
Hydrocodone Naproxen -- -- Caffeine Naltrexone Niacin 166
Hydrocodone -- Promethazine Butalbital Modafinil Naltrexone -- 167
Hydrocodone -- Promethazine Butalbital Caffeine Naltrexone -- 168
Hydrocodone -- Promethazine Butalbital Modafinil -- Niacin 169
Hydrocodone -- Promethazine Butalbital Caffeine -- Niacin 170
Hydrocodone -- Promethazine Butalbital -- Naltrexone Niacin 171
Hydrocodone -- -- Butalbital Caffeine Naltrexone Niacin 172
Hydrocodone Naproxen Promethazine Butalbital Modafinil Naltrexone
-- 173 Hydrocodone Naproxen Promethazine Butalbital Caffeine
Naltrexone -- 174 Hydrocodone Naproxen Promethazine Butalbital
Modafinil -- Niacin 175 Hydrocodone Naproxen Promethazine
Butalbital Caffeine -- Niacin 176 Hydrocodone -- Promethazine
Butalbital Modafinil Naltrexone Niacin 177 Hydrocodone --
Promethazine Butalbital Caffeine Naltrexone Niacin 178 Hydrocodone
Naproxen -- Butalbital Modafinil Naltrexone Niacin 179 Hydrocodone
Naproxen -- Butalbital Caffeine Naltrexone Niacin 180 Hydrocodone
Naproxen Promethazine -- Modafinil Naltrexone Niacin 181
Hydrocodone Naproxen Promethazine -- Caffeine Naltrexone Niacin 182
Hydrocodone Naproxen Promethazine Butalbital -- Naltrexone Niacin
183 Hydrocodone Naproxen Promethazine Butalbital Modafinil
Naltrexone Niacin 184 Hydrocodone Naproxen Promethazine Butalbital
Caffeine Naltrexone Niacin 185 Hydrocodone Ibuprofen -- -- -- -- --
186 Hydrocodone -- Promethazine -- -- -- -- 187 Hydrocodone -- --
Butalbital -- -- -- 188 Hydrocodone -- -- -- Modafinil -- -- 189
Hydrocodone -- -- -- Caffeine -- -- 190 Hydrocodone -- -- -- --
Naltrexone -- 191 Hydrocodone -- -- -- -- -- Niacin 192 Hydrocodone
Ibuprofen Promethazine -- -- -- -- 193 Hydrocodone Ibuprofen --
Butalbital -- -- -- 194 Hydrocodone Ibuprofen -- -- Modafinil -- --
195 Hydrocodone Ibuprofen -- -- Caffeine -- -- 196 Hydrocodone
Ibuprofen -- -- -- Naltrexone -- 197 Hydrocodone Ibuprofen -- -- --
-- Niacin 198 Hydrocodone -- Promethazine Butalbital -- -- -- 199
Hydrocodone -- Promethazine -- Modafinil -- -- 200 Hydrocodone --
Promethazine -- Caffeine -- -- 201 Hydrocodone -- Promethazine --
-- Naltrexone -- 202 Hydrocodone -- Promethazine -- -- -- Niacin
203 Hydrocodone -- -- Butalbital Modafinil -- -- 204 Hydrocodone --
-- Butalbital Caffeine -- -- 205 Hydrocodone -- -- Butalbital --
Naltrexone -- 206 Hydrocodone -- -- Butalbital -- -- Niacin 207
Hydrocodone -- -- -- Modafinil Naltrexone -- 208 Hydrocodone -- --
-- Caffeine Naltrexone -- 209 Hydrocodone -- -- -- Modafinil --
Niacin 210 Hydrocodone -- -- -- Caffeine -- Niacin 211 Hydrocodone
-- -- -- -- Naltrexone Niacin 212 Hydrocodone Ibuprofen
Promethazine Butalbital -- -- -- 213 Hydrocodone Ibuprofen
Promethazine -- Modafinil -- -- 214 Hydrocodone Ibuprofen
Promethazine -- Caffeine -- -- 215 Hydrocodone Ibuprofen
Promethazine -- -- Naltrexone -- 216 Hydrocodone Ibuprofen
Promethazine -- -- -- Niacin 217 Hydrocodone Ibuprofen --
Butalbital Modafinil -- -- 218 Hydrocodone Ibuprofen -- Butalbital
Caffeine -- -- 219 Hydrocodone Ibuprofen -- Butalbital --
Naltrexone -- 220 Hydrocodone Ibuprofen -- Butalbital -- -- Niacin
221 Hydrocodone Ibuprofen -- -- Modafinil Naltrexone -- 222
Hydrocodone Ibuprofen -- -- Modafinil -- Niacin 223 Hydrocodone
Ibuprofen -- -- Caffeine Naltrexone -- 224 Hydrocodone Ibuprofen --
-- Caffeine -- Niacin 225 Hydrocodone Ibuprofen -- -- -- Naltrexone
Niacin 226 Hydrocodone -- Promethazine Butalbital Modafinil -- --
227 Hydrocodone -- Promethazine Butalbital Caffeine -- -- 228
Hydrocodone -- Promethazine Butalbital -- Naltrexone -- 229
Hydrocodone -- Promethazine Butalbital -- -- Niacin 230 Hydrocodone
-- Promethazine -- Modafinil Naltrexone -- 231 Hydrocodone --
Promethazine -- Caffeine Naltrexone -- 232 Hydrocodone --
Promethazine -- Modafinil -- Niacin 233 Hydrocodone -- Promethazine
-- Caffeine -- Niacin 234 Hydrocodone -- Promethazine -- --
Naltrexone Niacin 235 Hydrocodone -- -- Butalbital Modafinil
Naltrexone -- 236 Hydrocodone -- -- Butalbital Caffeine Naltrexone
-- 237 Hydrocodone -- -- Butalbital Modafinil -- Niacin
238 Hydrocodone -- -- Butalbital Caffeine -- Niacin 239 Hydrocodone
-- -- Butalbital -- Naltrexone Niacin 240 Hydrocodone -- -- --
Modafinil Naltrexone Niacin 241 Hydrocodone -- -- -- Caffeine
Naltrexone Niacin 242 Hydrocodone Ibuprofen Promethazine Butalbital
Modafinil -- -- 243 Hydrocodone Ibuprofen Promethazine Butalbital
Caffeine -- -- 244 Hydrocodone Ibuprofen Promethazine Butalbital --
Naltrexone -- 245 Hydrocodone Ibuprofen Promethazine Butalbital --
-- Niacin 246 Hydrocodone Ibuprofen Promethazine -- Modafinil
Naltrexone -- 247 Hydrocodone Ibuprofen Promethazine -- Caffeine
Naltrexone -- 248 Hydrocodone Ibuprofen Promethazine -- Modafinil
-- Niacin 249 Hydrocodone Ibuprofen Promethazine -- Caffeine --
Niacin 250 Hydrocodone Ibuprofen Promethazine -- -- Naltrexone
Niacin 251 Hydrocodone Ibuprofen -- Butalbital Modafinil Naltrexone
-- 252 Hydrocodone Ibuprofen -- Butalbital Caffeine Naltrexone --
253 Hydrocodone Ibuprofen -- Butalbital Modafinil -- Niacin 254
Hydrocodone Ibuprofen -- Butalbital Caffeine -- Niacin 255
Hydrocodone Ibuprofen -- Butalbital -- Naltrexone Niacin 256
Hydrocodone Ibuprofen -- -- Modafinil Naltrexone Niacin 257
Hydrocodone Ibuprofen -- -- Caffeine Naltrexone Niacin 258
Hydrocodone -- Promethazine Butalbital Modafinil Naltrexone -- 259
Hydrocodone -- Promethazine Butalbital Caffeine Naltrexone -- 260
Hydrocodone -- Promethazine Butalbital Modafinil -- Niacin 261
Hydrocodone -- Promethazine Butalbital Caffeine -- Niacin 262
Hydrocodone -- Promethazine Butalbital -- Naltrexone Niacin 263
Hydrocodone -- -- Butalbital Caffeine Naltrexone Niacin 264
Hydrocodone Ibuprofen Promethazine Butalbital Modafinil Naltrexone
-- 265 Hydrocodone Ibuprofen Promethazine Butalbital Caffeine
Naltrexone -- 266 Hydrocodone Ibuprofen Promethazine Butalbital
Modafinil -- Niacin 267 Hydrocodone Ibuprofen Promethazine
Butalbital Caffeine -- Niacin 268 Hydrocodone -- Promethazine
Butalbital Modafinil Naltrexone Niacin 269 Hydrocodone --
Promethazine Butalbital Caffeine Naltrexone Niacin 270 Hydrocodone
Ibuprofen -- Butalbital Modafinil Naltrexone Niacin 271 Hydrocodone
Ibuprofen -- Butalbital Caffeine Naltrexone Niacin 272 Hydrocodone
Ibuprofen Promethazine -- Modafinil Naltrexone Niacin 273
Hydrocodone Ibuprofen Promethazine -- Caffeine Naltrexone Niacin
274 Hydrocodone Ibuprofen Promethazine Butalbital -- Naltrexone
Niacin 275 Hydrocodone Ibuprofen Promethazine Butalbital Modafinil
Naltrexone Niacin 276 Hydrocodone Ibuprofen Promethazine Butalbital
Caffeine Naltrexone Niacin 277 Oxycodone Acetaminophen -- -- -- --
-- 278 Oxycodone -- Promethazine -- -- -- -- 279 Oxycodone -- --
Butalbital -- -- -- 280 Oxycodone -- -- -- Modafinil -- -- 281
Oxycodone -- -- -- Caffeine -- -- 282 Oxycodone -- -- -- --
Naltrexone -- 283 Oxycodone -- -- -- -- -- Niacin 284 Oxycodone
Acetaminophen Promethazine -- -- -- -- 285 Oxycodone Acetaminophen
-- Butalbital -- -- -- 286 Oxycodone Acetaminophen -- -- Modafinil
-- -- 287 Oxycodone Acetaminophen -- -- Caffeine -- -- 288
Oxycodone Acetaminophen -- -- -- Naltrexone -- 289 Oxycodone
Acetaminophen -- -- -- -- Niacin 290 Oxycodone -- Promethazine
Butalbital -- -- -- 291 Oxycodone -- Promethazine -- Modafinil --
-- 292 Oxycodone -- Promethazine -- Caffeine -- -- 293 Oxycodone --
Promethazine -- -- Naltrexone -- 294 Oxycodone -- Promethazine --
-- -- Niacin 295 Oxycodone -- -- Butalbital Modafinil -- -- 296
Oxycodone -- -- Butalbital Caffeine -- -- 297 Oxycodone -- --
Butalbital -- Naltrexone -- 298 Oxycodone -- -- Butalbital -- --
Niacin 299 Oxycodone -- -- -- Modafinil Naltrexone -- 300 Oxycodone
-- -- -- Caffeine Naltrexone -- 301 Oxycodone -- -- -- Modafinil --
Niacin 302 Oxycodone -- -- -- Caffeine -- Niacin 303 Oxycodone --
-- -- -- Naltrexone Niacin 304 Oxycodone Acetaminophen Promethazine
Butalbital -- -- -- 305 Oxycodone Acetaminophen Promethazine --
Modafinil -- -- 306 Oxycodone Acetaminophen Promethazine --
Caffeine -- -- 307 Oxycodone Acetaminophen Promethazine -- --
Naltrexone -- 308 Oxycodone Acetaminophen Promethazine -- -- --
Niacin 309 Oxycodone Acetaminophen -- Butalbital Modafinil -- --
310 Oxycodone Acetaminophen -- Butalbital Caffeine -- -- 311
Oxycodone Acetaminophen -- Butalbital -- Naltrexone -- 312
Oxycodone Acetaminophen -- Butalbital -- -- Niacin 313 Oxycodone
Acetaminophen -- -- Modafinil Naltrexone -- 314 Oxycodone
Acetaminophen -- -- Modafinil -- Niacin 315 Oxycodone Acetaminophen
-- -- Caffeine Naltrexone -- 316 Oxycodone Acetaminophen -- --
Caffeine -- Niacin 317 Oxycodone Acetaminophen -- -- -- Naltrexone
Niacin 318 Oxycodone -- Promethazine Butalbital Modafinil -- -- 319
Oxycodone -- Promethazine Butalbital Caffeine -- -- 320 Oxycodone
-- Promethazine Butalbital -- Naltrexone -- 321 Oxycodone --
Promethazine Butalbital -- -- Niacin 322 Oxycodone -- Promethazine
-- Modafinil Naltrexone -- 323 Oxycodone -- Promethazine --
Caffeine Naltrexone -- 324 Oxycodone -- Promethazine -- Modafinil
-- Niacin 325 Oxycodone -- Promethazine -- Caffeine -- Niacin 326
Oxycodone -- Promethazine -- -- Naltrexone Niacin 327 Oxycodone --
-- Butalbital Modafinil Naltrexone -- 328 Oxycodone -- --
Butalbital Caffeine Naltrexone -- 329 Oxycodone -- -- Butalbital
Modafinil -- Niacin 330 Oxycodone -- -- Butalbital Caffeine --
Niacin 331 Oxycodone -- -- Butalbital -- Naltrexone Niacin 332
Oxycodone -- -- -- Modafinil Naltrexone Niacin 333 Oxycodone -- --
-- Caffeine Naltrexone Niacin 334 Oxycodone Acetaminophen
Promethazine Butalbital Modafinil -- -- 335 Oxycodone Acetaminophen
Promethazine Butalbital Caffeine -- -- 336 Oxycodone Acetaminophen
Promethazine Butalbital -- Naltrexone -- 337 Oxycodone
Acetaminophen Promethazine Butalbital -- -- Niacin 338 Oxycodone
Acetaminophen Promethazine -- Modafinil Naltrexone -- 339 Oxycodone
Acetaminophen Promethazine -- Caffeine Naltrexone -- 340 Oxycodone
Acetaminophen Promethazine -- Modafinil -- Niacin 341 Oxycodone
Acetaminophen Promethazine -- Caffeine -- Niacin 342 Oxycodone
Acetaminophen Promethazine -- -- Naltrexone Niacin 343 Oxycodone
Acetaminophen -- Butalbital Modafinil Naltrexone -- 344 Oxycodone
Acetaminophen -- Butalbital Caffeine Naltrexone -- 345 Oxycodone
Acetaminophen -- Butalbital Modafinil -- Niacin 346 Oxycodone
Acetaminophen -- Butalbital Caffeine -- Niacin 347 Oxycodone
Acetaminophen -- Butalbital -- Naltrexone Niacin 348 Oxycodone
Acetaminophen -- -- Modafinil Naltrexone Niacin 349 Oxycodone
Acetaminophen -- -- Caffeine Naltrexone Niacin 350 Oxycodone --
Promethazine Butalbital Modafinil Naltrexone -- 351 Oxycodone --
Promethazine Butalbital Caffeine Naltrexone -- 352 Oxycodone --
Promethazine Butalbital Modafinil -- Niacin 353 Oxycodone --
Promethazine Butalbital Caffeine -- Niacin 354 Oxycodone --
Promethazine Butalbital -- Naltrexone Niacin 355 Oxycodone -- --
Butalbital Caffeine Naltrexone Niacin 356 Oxycodone Acetaminophen
Promethazine Butalbital Modafinil Naltrexone -- 357 Oxycodone
Acetaminophen Promethazine Butalbital Caffeine Naltrexone -- 358
Oxycodone Acetaminophen Promethazine Butalbital Modafinil -- Niacin
359 Oxycodone Acetaminophen Promethazine Butalbital Caffeine --
Niacin 360 Oxycodone -- Promethazine Butalbital Modafinil
Naltrexone Niacin 361 Oxycodone -- Promethazine Butalbital Caffeine
Naltrexone Niacin 362 Oxycodone Acetaminophen -- Butalbital
Modafinil Naltrexone Niacin 363 Oxycodone Acetaminophen --
Butalbital Caffeine Naltrexone Niacin 364 Oxycodone Acetaminophen
Promethazine -- Modafinil Naltrexone Niacin 365 Oxycodone
Acetaminophen Promethazine -- Caffeine Naltrexone Niacin 366
Oxycodone Acetaminophen Promethazine Butalbital -- Naltrexone
Niacin 367 Oxycodone Acetaminophen Promethazine Butalbital
Modafinil Naltrexone Niacin 368 Oxycodone Acetaminophen
Promethazine Butalbital Caffeine Naltrexone Niacin 369 Oxycodone
Naproxen -- -- -- -- -- 370 Oxycodone -- Promethazine -- -- -- --
371 Oxycodone -- -- Butalbital -- -- -- 372 Oxycodone -- -- --
Modafinil -- -- 373 Oxycodone -- -- -- Caffeine -- -- 374 Oxycodone
-- -- -- -- Naltrexone -- 375 Oxycodone -- -- -- -- -- Niacin 376
Oxycodone Naproxen Promethazine -- -- -- -- 377 Oxycodone Naproxen
-- Butalbital -- -- -- 378 Oxycodone Naproxen -- -- Modafinil -- --
379 Oxycodone Naproxen -- -- Caffeine -- -- 380 Oxycodone Naproxen
-- -- -- Naltrexone -- 381 Oxycodone Naproxen -- -- -- -- Niacin
382 Oxycodone -- Promethazine Butalbital -- -- -- 383 Oxycodone --
Promethazine -- Modafinil -- -- 384 Oxycodone -- Promethazine --
Caffeine -- -- 385 Oxycodone -- Promethazine -- -- Naltrexone --
386 Oxycodone -- Promethazine -- -- -- Niacin 387 Oxycodone -- --
Butalbital Modafinil -- -- 388 Oxycodone -- -- Butalbital Caffeine
-- -- 389 Oxycodone -- -- Butalbital -- Naltrexone -- 390 Oxycodone
-- -- Butalbital -- -- Niacin 391 Oxycodone -- -- -- Modafinil
Naltrexone -- 392 Oxycodone -- -- -- Caffeine Naltrexone -- 393
Oxycodone -- -- -- Modafinil -- Niacin 394 Oxycodone -- -- --
Caffeine -- Niacin 395 Oxycodone -- -- -- -- Naltrexone Niacin 396
Oxycodone Naproxen Promethazine Butalbital -- -- -- 397 Oxycodone
Naproxen Promethazine -- Modafinil -- -- 398 Oxycodone Naproxen
Promethazine -- Caffeine -- -- 399 Oxycodone Naproxen Promethazine
-- -- Naltrexone -- 400 Oxycodone Naproxen Promethazine -- -- --
Niacin 401 Oxycodone Naproxen -- Butalbital Modafinil -- -- 402
Oxycodone Naproxen -- Butalbital Caffeine -- -- 403 Oxycodone
Naproxen -- Butalbital -- Naltrexone -- 404 Oxycodone Naproxen --
Butalbital -- -- Niacin 405 Oxycodone Naproxen -- -- Modafinil
Naltrexone -- 406 Oxycodone Naproxen -- -- Modafinil -- Niacin 407
Oxycodone Naproxen -- -- Caffeine Naltrexone -- 408 Oxycodone
Naproxen -- -- Caffeine -- Niacin 409 Oxycodone Naproxen -- -- --
Naltrexone Niacin 410 Oxycodone -- Promethazine Butalbital
Modafinil -- -- 411 Oxycodone -- Promethazine Butalbital Caffeine
-- -- 412 Oxycodone -- Promethazine Butalbital -- Naltrexone -- 413
Oxycodone -- Promethazine Butalbital -- -- Niacin 414 Oxycodone --
Promethazine -- Modafinil Naltrexone -- 415 Oxycodone --
Promethazine -- Caffeine Naltrexone -- 416 Oxycodone --
Promethazine -- Modafinil -- Niacin 417 Oxycodone -- Promethazine
-- Caffeine -- Niacin 418 Oxycodone -- Promethazine -- --
Naltrexone Niacin 419 Oxycodone -- -- Butalbital Modafinil
Naltrexone -- 420 Oxycodone -- -- Butalbital Caffeine Naltrexone --
421 Oxycodone -- -- Butalbital Modafinil -- Niacin 422 Oxycodone --
-- Butalbital Caffeine -- Niacin 423 Oxycodone -- -- Butalbital --
Naltrexone Niacin 424 Oxycodone -- -- -- Modafinil Naltrexone
Niacin 425 Oxycodone -- -- -- Caffeine Naltrexone Niacin 426
Oxycodone Naproxen Promethazine Butalbital Modafinil -- -- 427
Oxycodone Naproxen Promethazine Butalbital Caffeine -- -- 428
Oxycodone Naproxen Promethazine Butalbital -- Naltrexone -- 429
Oxycodone Naproxen Promethazine Butalbital -- -- Niacin 430
Oxycodone Naproxen Promethazine -- Modafinil Naltrexone -- 431
Oxycodone Naproxen Promethazine -- Caffeine Naltrexone -- 432
Oxycodone Naproxen Promethazine -- Modafinil -- Niacin 433
Oxycodone Naproxen Promethazine -- Caffeine -- Niacin 434 Oxycodone
Naproxen Promethazine -- -- Naltrexone Niacin 435 Oxycodone
Naproxen -- Butalbital Modafinil Naltrexone -- 436 Oxycodone
Naproxen -- Butalbital Caffeine Naltrexone -- 437 Oxycodone
Naproxen -- Butalbital Modafinil -- Niacin 438 Oxycodone Naproxen
-- Butalbital Caffeine -- Niacin 439 Oxycodone Naproxen --
Butalbital -- Naltrexone Niacin 440 Oxycodone Naproxen -- --
Modafinil Naltrexone Niacin 441 Oxycodone Naproxen -- -- Caffeine
Naltrexone Niacin 442 Oxycodone -- Promethazine Butalbital
Modafinil Naltrexone -- 443 Oxycodone -- Promethazine Butalbital
Caffeine Naltrexone -- 444 Oxycodone -- Promethazine Butalbital
Modafinil -- Niacin 445 Oxycodone -- Promethazine Butalbital
Caffeine -- Niacin 446 Oxycodone -- Promethazine Butalbital --
Naltrexone Niacin 447 Oxycodone -- -- Butalbital Caffeine
Naltrexone Niacin 448 Oxycodone Naproxen Promethazine Butalbital
Modafinil Naltrexone -- 449 Oxycodone Naproxen Promethazine
Butalbital Caffeine Naltrexone -- 450 Oxycodone Naproxen
Promethazine Butalbital Modafinil -- Niacin 451 Oxycodone Naproxen
Promethazine Butalbital Caffeine -- Niacin 452 Oxycodone --
Promethazine Butalbital Modafinil Naltrexone Niacin 453 Oxycodone
-- Promethazine Butalbital Caffeine Naltrexone Niacin 454 Oxycodone
Naproxen -- Butalbital Modafinil Naltrexone Niacin 455 Oxycodone
Naproxen -- Butalbital Caffeine Naltrexone Niacin 456 Oxycodone
Naproxen Promethazine -- Modafinil Naltrexone Niacin 457 Oxycodone
Naproxen Promethazine -- Caffeine Naltrexone Niacin 458 Oxycodone
Naproxen Promethazine Butalbital -- Naltrexone Niacin 459 Oxycodone
Naproxen Promethazine Butalbital Modafinil Naltrexone Niacin 460
Oxycodone Naproxen Promethazine Butalbital Caffeine Naltrexone
Niacin 461 Oxycodone Ibuprofen -- -- -- -- -- 462 Oxycodone --
Promethazine -- -- -- -- 463 Oxycodone -- -- Butalbital -- -- --
464 Oxycodone -- -- -- Modafinil -- -- 465 Oxycodone -- -- --
Caffeine -- -- 466 Oxycodone -- -- -- -- Naltrexone -- 467
Oxycodone -- -- -- -- -- Niacin 468 Oxycodone Ibuprofen
Promethazine -- -- -- -- 469 Oxycodone Ibuprofen -- Butalbital --
-- -- 470 Oxycodone Ibuprofen -- -- Modafinil -- -- 471 Oxycodone
Ibuprofen -- -- Caffeine -- -- 472 Oxycodone Ibuprofen -- -- --
Naltrexone -- 473 Oxycodone Ibuprofen -- -- -- -- Niacin 474
Oxycodone -- Promethazine Butalbital -- -- -- 475 Oxycodone --
Promethazine -- Modafinil -- -- 476 Oxycodone -- Promethazine --
Caffeine -- -- 477 Oxycodone -- Promethazine -- -- Naltrexone --
478 Oxycodone -- Promethazine -- -- -- Niacin 479 Oxycodone -- --
Butalbital Modafinil -- -- 480 Oxycodone -- -- Butalbital Caffeine
-- -- 481 Oxycodone -- -- Butalbital -- Naltrexone --
482 Oxycodone -- -- Butalbital -- -- Niacin 483 Oxycodone -- -- --
Modafinil Naltrexone -- 484 Oxycodone -- -- -- Caffeine Naltrexone
-- 485 Oxycodone -- -- -- Modafinil -- Niacin 486 Oxycodone -- --
-- Caffeine -- Niacin 487 Oxycodone -- -- -- -- Naltrexone Niacin
488 Oxycodone Ibuprofen Promethazine Butalbital -- -- -- 489
Oxycodone Ibuprofen Promethazine -- Modafinil -- -- 490 Oxycodone
Ibuprofen Promethazine -- Caffeine -- -- 491 Oxycodone Ibuprofen
Promethazine -- -- Naltrexone -- 492 Oxycodone Ibuprofen
Promethazine -- -- -- Niacin 493 Oxycodone Ibuprofen -- Butalbital
Modafinil -- -- 494 Oxycodone Ibuprofen -- Butalbital Caffeine --
-- 495 Oxycodone Ibuprofen -- Butalbital -- Naltrexone -- 496
Oxycodone Ibuprofen -- Butalbital -- -- Niacin 497 Oxycodone
Ibuprofen -- -- Modafinil Naltrexone -- 498 Oxycodone Ibuprofen --
-- Modafinil -- Niacin 499 Oxycodone Ibuprofen -- -- Caffeine
Naltrexone -- 500 Oxycodone Ibuprofen -- -- Caffeine -- Niacin 501
Oxycodone Ibuprofen -- -- -- Naltrexone Niacin 502 Oxycodone --
Promethazine Butalbital Modafinil -- -- 503 Oxycodone --
Promethazine Butalbital Caffeine -- -- 504 Oxycodone --
Promethazine Butalbital -- Naltrexone -- 505 Oxycodone --
Promethazine Butalbital -- -- Niacin 506 Oxycodone -- Promethazine
-- Modafinil Naltrexone -- 507 Oxycodone -- Promethazine --
Caffeine Naltrexone -- 508 Oxycodone -- Promethazine -- Modafinil
-- Niacin 509 Oxycodone -- Promethazine -- Caffeine -- Niacin 510
Oxycodone -- Promethazine -- -- Naltrexone Niacin 511 Oxycodone --
-- Butalbital Modafinil Naltrexone -- 512 Oxycodone -- --
Butalbital Caffeine Naltrexone -- 513 Oxycodone -- -- Butalbital
Modafinil -- Niacin 514 Oxycodone -- -- Butalbital Caffeine --
Niacin 515 Oxycodone -- -- Butalbital -- Naltrexone Niacin 516
Oxycodone -- -- -- Modafinil Naltrexone Niacin 517 Oxycodone -- --
-- Caffeine Naltrexone Niacin 518 Oxycodone Ibuprofen Promethazine
Butalbital Modafinil -- -- 519 Oxycodone Ibuprofen Promethazine
Butalbital Caffeine -- -- 520 Oxycodone Ibuprofen Promethazine
Butalbital -- Naltrexone -- 521 Oxycodone Ibuprofen Promethazine
Butalbital -- -- Niacin 522 Oxycodone Ibuprofen Promethazine --
Modafinil Naltrexone -- 523 Oxycodone Ibuprofen Promethazine --
Caffeine Naltrexone -- 524 Oxycodone Ibuprofen Promethazine --
Modafinil -- Niacin 525 Oxycodone Ibuprofen Promethazine --
Caffeine -- Niacin 526 Oxycodone Ibuprofen Promethazine -- --
Naltrexone Niacin 527 Oxycodone Ibuprofen -- Butalbital Modafinil
Naltrexone -- 528 Oxycodone Ibuprofen -- Butalbital Caffeine
Naltrexone -- 529 Oxycodone Ibuprofen -- Butalbital Modafinil --
Niacin 530 Oxycodone Ibuprofen -- Butalbital Caffeine -- Niacin 531
Oxycodone Ibuprofen -- Butalbital -- Naltrexone Niacin 532
Oxycodone Ibuprofen -- -- Modafinil Naltrexone Niacin 533 Oxycodone
Ibuprofen -- -- Caffeine Naltrexone Niacin 534 Oxycodone --
Promethazine Butalbital Modafinil Naltrexone -- 535 Oxycodone --
Promethazine Butalbital Caffeine Naltrexone -- 536 Oxycodone --
Promethazine Butalbital Modafinil -- Niacin 537 Oxycodone --
Promethazine Butalbital Caffeine -- Niacin 538 Oxycodone --
Promethazine Butalbital -- Naltrexone Niacin 539 Oxycodone -- --
Butalbital Caffeine Naltrexone Niacin 540 Oxycodone Ibuprofen
Promethazine Butalbital Modafinil Naltrexone -- 541 Oxycodone
Ibuprofen Promethazine Butalbital Caffeine Naltrexone -- 542
Oxycodone Ibuprofen Promethazine Butalbital Modafinil -- Niacin 543
Oxycodone Ibuprofen Promethazine Butalbital Caffeine -- Niacin 544
Oxycodone -- Promethazine Butalbital Modafinil Naltrexone Niacin
545 Oxycodone -- Promethazine Butalbital Caffeine Naltrexone Niacin
546 Oxycodone Ibuprofen -- Butalbital Modafinil Naltrexone Niacin
547 Oxycodone Ibuprofen -- Butalbital Caffeine Naltrexone Niacin
548 Oxycodone Ibuprofen Promethazine -- Modafinil Naltrexone Niacin
549 Oxycodone Ibuprofen Promethazine -- Caffeine Naltrexone Niacin
550 Oxycodone Ibuprofen Promethazine Butalbital -- Naltrexone
Niacin 551 Oxycodone Ibuprofen Promethazine Butalbital Modafinil
Naltrexone Niacin 552 Oxycodone Ibuprofen Promethazine Butalbital
Caffeine Naltrexone Niacin 553 Propoxyphene Acetaminophen -- -- --
-- -- 554 Propoxyphene -- Promethazine -- -- -- -- 555 Propoxyphene
-- -- Butalbital -- -- -- 556 Propoxyphene -- -- -- Modafinil -- --
557 Propoxyphene -- -- -- Caffeine -- -- 558 Propoxyphene -- -- --
-- Naltrexone -- 559 Propoxyphene -- -- -- -- -- Niacin 560
Propoxyphene Acetaminophen Promethazine -- -- -- -- 561
Propoxyphene Acetaminophen -- Butalbital -- -- -- 562 Propoxyphene
Acetaminophen -- -- Modafinil -- -- 563 Propoxyphene Acetaminophen
-- -- Caffeine -- -- 564 Propoxyphene Acetaminophen -- -- --
Naltrexone -- 565 Propoxyphene Acetaminophen -- -- -- -- Niacin 566
Propoxyphene -- Promethazine Butalbital -- -- -- 567 Propoxyphene
-- Promethazine -- Modafinil -- -- 568 Propoxyphene -- Promethazine
-- Caffeine -- -- 569 Propoxyphene -- Promethazine -- -- Naltrexone
-- 570 Propoxyphene -- Promethazine -- -- -- Niacin 571
Propoxyphene -- -- Butalbital Modafinil -- -- 572 Propoxyphene --
-- Butalbital Caffeine -- -- 573 Propoxyphene -- -- Butalbital --
Naltrexone -- 574 Propoxyphene -- -- Butalbital -- -- Niacin 575
Propoxyphene -- -- -- Modafinil Naltrexone -- 576 Propoxyphene --
-- -- Caffeine Naltrexone -- 577 Propoxyphene -- -- -- Modafinil --
Niacin 578 Propoxyphene -- -- -- Caffeine -- Niacin 579
Propoxyphene -- -- -- -- Naltrexone Niacin 580 Propoxyphene
Acetaminophen Promethazine Butalbital -- -- -- 581 Propoxyphene
Acetaminophen Promethazine -- Modafinil -- -- 582 Propoxyphene
Acetaminophen Promethazine -- Caffeine -- -- 583 Propoxyphene
Acetaminophen Promethazine -- -- Naltrexone -- 584 Propoxyphene
Acetaminophen Promethazine -- -- -- Niacin 585 Propoxyphene
Acetaminophen -- Butalbital Modafinil -- -- 586 Propoxyphene
Acetaminophen -- Butalbital Caffeine -- -- 587 Propoxyphene
Acetaminophen -- Butalbital -- Naltrexone -- 588 Propoxyphene
Acetaminophen -- Butalbital -- -- Niacin 589 Propoxyphene
Acetaminophen -- -- Modafinil Naltrexone -- 590 Propoxyphene
Acetaminophen -- -- Modafinil -- Niacin 591 Propoxyphene
Acetaminophen -- -- Caffeine Naltrexone -- 592 Propoxyphene
Acetaminophen -- -- Caffeine -- Niacin 593 Propoxyphene
Acetaminophen -- -- -- Naltrexone Niacin 594 Propoxyphene --
Promethazine Butalbital Modafinil -- -- 595 Propoxyphene --
Promethazine Butalbital Caffeine -- -- 596 Propoxyphene --
Promethazine Butalbital -- Naltrexone -- 597 Propoxyphene --
Promethazine Butalbital -- -- Niacin 598 Propoxyphene --
Promethazine -- Modafinil Naltrexone -- 599 Propoxyphene --
Promethazine -- Caffeine Naltrexone -- 600 Propoxyphene --
Promethazine -- Modafinil -- Niacin 601 Propoxyphene --
Promethazine -- Caffeine -- Niacin 602 Propoxyphene -- Promethazine
-- -- Naltrexone Niacin 603 Propoxyphene -- -- Butalbital Modafinil
Naltrexone -- 604 Propoxyphene -- -- Butalbital Caffeine Naltrexone
-- 605 Propoxyphene -- -- Butalbital Modafinil -- Niacin 606
Propoxyphene -- -- Butalbital Caffeine -- Niacin 607 Propoxyphene
-- -- Butalbital -- Naltrexone Niacin 608 Propoxyphene -- -- --
Modafinil Naltrexone Niacin 609 Propoxyphene -- -- -- Caffeine
Naltrexone Niacin 610 Propoxyphene Acetaminophen Promethazine
Butalbital Modafinil -- -- 611 Propoxyphene Acetaminophen
Promethazine Butalbital Caffeine -- -- 612 Propoxyphene
Acetaminophen Promethazine Butalbital -- Naltrexone -- 613
Propoxyphene Acetaminophen Promethazine Butalbital -- -- Niacin 614
Propoxyphene Acetaminophen Promethazine -- Modafinil Naltrexone --
615 Propoxyphene Acetaminophen Promethazine -- Caffeine Naltrexone
-- 616 Propoxyphene Acetaminophen Promethazine -- Modafinil --
Niacin 617 Propoxyphene Acetaminophen Promethazine -- Caffeine --
Niacin 618 Propoxyphene Acetaminophen Promethazine -- -- Naltrexone
Niacin 619 Propoxyphene Acetaminophen -- Butalbital Modafinil
Naltrexone -- 620 Propoxyphene Acetaminophen -- Butalbital Caffeine
Naltrexone -- 621 Propoxyphene Acetaminophen -- Butalbital
Modafinil -- Niacin 622 Propoxyphene Acetaminophen -- Butalbital
Caffeine -- Niacin 623 Propoxyphene Acetaminophen -- Butalbital --
Naltrexone Niacin 624 Propoxyphene Acetaminophen -- -- Modafinil
Naltrexone Niacin 625 Propoxyphene Acetaminophen -- -- Caffeine
Naltrexone Niacin 626 Propoxyphene -- Promethazine Butalbital
Modafinil Naltrexone -- 627 Propoxyphene -- Promethazine Butalbital
Caffeine Naltrexone -- 628 Propoxyphene -- Promethazine Butalbital
Modafinil -- Niacin 629 Propoxyphene -- Promethazine Butalbital
Caffeine -- Niacin 630 Propoxyphene -- Promethazine Butalbital --
Naltrexone Niacin 631 Propoxyphene -- -- Butalbital Caffeine
Naltrexone Niacin 632 Propoxyphene Acetaminophen Promethazine
Butalbital Modafinil Naltrexone -- 633 Propoxyphene Acetaminophen
Promethazine Butalbital Caffeine Naltrexone -- 634 Propoxyphene
Acetaminophen Promethazine Butalbital Modafinil -- Niacin 635
Propoxyphene Acetaminophen Promethazine Butalbital Caffeine --
Niacin 636 Propoxyphene -- Promethazine Butalbital Modafinil
Naltrexone Niacin 637 Propoxyphene -- Promethazine Butalbital
Caffeine Naltrexone Niacin 638 Propoxyphene Acetaminophen --
Butalbital Modafinil Naltrexone Niacin 639 Propoxyphene
Acetaminophen -- Butalbital Caffeine Naltrexone Niacin 640
Propoxyphene Acetaminophen Promethazine -- Modafinil Naltrexone
Niacin 641 Propoxyphene Acetaminophen Promethazine -- Caffeine
Naltrexone Niacin 642 Propoxyphene Acetaminophen Promethazine
Butalbital -- Naltrexone Niacin 643 Propoxyphene Acetaminophen
Promethazine Butalbital Modafinil Naltrexone Niacin 644
Propoxyphene Acetaminophen Promethazine Butalbital Caffeine
Naltrexone Niacin 645 Propoxyphene Naproxen -- -- -- -- -- 646
Propoxyphene -- Promethazine -- -- -- -- 647 Propoxyphene -- --
Butalbital -- -- -- 648 Propoxyphene -- -- -- Modafinil -- -- 649
Propoxyphene -- -- -- Caffeine -- -- 650 Propoxyphene -- -- -- --
Naltrexone -- 651 Propoxyphene -- -- -- -- -- Niacin 652
Propoxyphene Naproxen Promethazine -- -- -- -- 653 Propoxyphene
Naproxen -- Butalbital -- -- -- 654 Propoxyphene Naproxen -- --
Modafinil -- -- 655 Propoxyphene Naproxen -- -- Caffeine -- -- 656
Propoxyphene Naproxen -- -- -- Naltrexone -- 657 Propoxyphene
Naproxen -- -- -- -- Niacin 658 Propoxyphene -- Promethazine
Butalbital -- -- -- 659 Propoxyphene -- Promethazine -- Modafinil
-- -- 660 Propoxyphene -- Promethazine -- Caffeine -- -- 661
Propoxyphene -- Promethazine -- -- Naltrexone -- 662 Propoxyphene
-- Promethazine -- -- -- Niacin 663 Propoxyphene -- -- Butalbital
Modafinil -- -- 664 Propoxyphene -- -- Butalbital Caffeine -- --
665 Propoxyphene -- -- Butalbital -- Naltrexone -- 666 Propoxyphene
-- -- Butalbital -- -- Niacin 667 Propoxyphene -- -- -- Modafinil
Naltrexone -- 668 Propoxyphene -- -- -- Caffeine Naltrexone -- 669
Propoxyphene -- -- -- Modafinil -- Niacin 670 Propoxyphene -- -- --
Caffeine -- Niacin 671 Propoxyphene -- -- -- -- Naltrexone Niacin
672 Propoxyphene Naproxen Promethazine Butalbital -- -- -- 673
Propoxyphene Naproxen Promethazine -- Modafinil -- -- 674
Propoxyphene Naproxen Promethazine -- Caffeine -- -- 675
Propoxyphene Naproxen Promethazine -- -- Naltrexone -- 676
Propoxyphene Naproxen Promethazine -- -- -- Niacin 677 Propoxyphene
Naproxen -- Butalbital Modafinil -- -- 678 Propoxyphene Naproxen --
Butalbital Caffeine -- -- 679 Propoxyphene Naproxen -- Butalbital
-- Naltrexone -- 680 Propoxyphene Naproxen -- Butalbital -- --
Niacin 681 Propoxyphene Naproxen -- -- Modafinil Naltrexone -- 682
Propoxyphene Naproxen -- -- Modafinil -- Niacin 683 Propoxyphene
Naproxen -- -- Caffeine Naltrexone -- 684 Propoxyphene Naproxen --
-- Caffeine -- Niacin 685 Propoxyphene Naproxen -- -- -- Naltrexone
Niacin 686 Propoxyphene -- Promethazine Butalbital Modafinil -- --
687 Propoxyphene -- Promethazine Butalbital Caffeine -- -- 688
Propoxyphene -- Promethazine Butalbital -- Naltrexone -- 689
Propoxyphene -- Promethazine Butalbital -- -- Niacin 690
Propoxyphene -- Promethazine -- Modafinil Naltrexone -- 691
Propoxyphene -- Promethazine -- Caffeine Naltrexone -- 692
Propoxyphene -- Promethazine -- Modafinil -- Niacin 693
Propoxyphene -- Promethazine -- Caffeine -- Niacin 694 Propoxyphene
-- Promethazine -- -- Naltrexone Niacin 695 Propoxyphene -- --
Butalbital Modafinil Naltrexone -- 696 Propoxyphene -- --
Butalbital Caffeine Naltrexone -- 697 Propoxyphene -- -- Butalbital
Modafinil -- Niacin 698 Propoxyphene -- -- Butalbital Caffeine --
Niacin 699 Propoxyphene -- -- Butalbital -- Naltrexone Niacin 700
Propoxyphene -- -- -- Modafinil Naltrexone Niacin 701 Propoxyphene
-- -- -- Caffeine Naltrexone Niacin 702 Propoxyphene Naproxen
Promethazine Butalbital Modafinil -- -- 703 Propoxyphene Naproxen
Promethazine Butalbital Caffeine -- -- 704 Propoxyphene Naproxen
Promethazine Butalbital -- Naltrexone -- 705 Propoxyphene Naproxen
Promethazine Butalbital -- -- Niacin 706 Propoxyphene Naproxen
Promethazine -- Modafinil Naltrexone -- 707 Propoxyphene Naproxen
Promethazine -- Caffeine Naltrexone -- 708 Propoxyphene Naproxen
Promethazine -- Modafinil -- Niacin 709 Propoxyphene Naproxen
Promethazine -- Caffeine -- Niacin 710 Propoxyphene Naproxen
Promethazine -- -- Naltrexone Niacin 711 Propoxyphene Naproxen --
Butalbital Modafinil Naltrexone -- 712 Propoxyphene Naproxen --
Butalbital Caffeine Naltrexone -- 713 Propoxyphene Naproxen --
Butalbital Modafinil -- Niacin 714 Propoxyphene Naproxen --
Butalbital Caffeine -- Niacin 715 Propoxyphene Naproxen --
Butalbital -- Naltrexone Niacin 716 Propoxyphene Naproxen -- --
Modafinil Naltrexone Niacin 717 Propoxyphene Naproxen -- --
Caffeine Naltrexone Niacin 718 Propoxyphene -- Promethazine
Butalbital Modafinil Naltrexone -- 719 Propoxyphene -- Promethazine
Butalbital Caffeine Naltrexone -- 720 Propoxyphene -- Promethazine
Butalbital Modafinil -- Niacin 721 Propoxyphene -- Promethazine
Butalbital Caffeine -- Niacin 722 Propoxyphene -- Promethazine
Butalbital -- Naltrexone Niacin 723 Propoxyphene -- -- Butalbital
Caffeine Naltrexone Niacin
724 Propoxyphene Naproxen Promethazine Butalbital Modafinil
Naltrexone -- 725 Propoxyphene Naproxen Promethazine Butalbital
Caffeine Naltrexone -- 726 Propoxyphene Naproxen Promethazine
Butalbital Modafinil -- Niacin 727 Propoxyphene Naproxen
Promethazine Butalbital Caffeine -- Niacin 728 Propoxyphene --
Promethazine Butalbital Modafinil Naltrexone Niacin 729
Propoxyphene -- Promethazine Butalbital Caffeine Naltrexone Niacin
730 Propoxyphene Naproxen -- Butalbital Modafinil Naltrexone Niacin
731 Propoxyphene Naproxen -- Butalbital Caffeine Naltrexone Niacin
732 Propoxyphene Naproxen Promethazine -- Modafinil Naltrexone
Niacin 733 Propoxyphene Naproxen Promethazine -- Caffeine
Naltrexone Niacin 734 Propoxyphene Naproxen Promethazine Butalbital
-- Naltrexone Niacin 735 Propoxyphene Naproxen Promethazine
Butalbital Modafinil Naltrexone Niacin 736 Propoxyphene Naproxen
Promethazine Butalbital Caffeine Naltrexone Niacin 737 Propoxyphene
Ibuprofen -- -- -- -- -- 738 Propoxyphene -- Promethazine -- -- --
-- 739 Propoxyphene -- -- Butalbital -- -- -- 740 Propoxyphene --
-- -- Modafinil -- -- 741 Propoxyphene -- -- -- Caffeine -- -- 742
Propoxyphene -- -- -- -- Naltrexone -- 743 Propoxyphene -- -- -- --
-- Niacin 744 Propoxyphene Ibuprofen Promethazine -- -- -- -- 745
Propoxyphene Ibuprofen -- Butalbital -- -- -- 746 Propoxyphene
Ibuprofen -- -- Modafinil -- -- 747 Propoxyphene Ibuprofen -- --
Caffeine -- -- 748 Propoxyphene Ibuprofen -- -- -- Naltrexone --
749 Propoxyphene Ibuprofen -- -- -- -- Niacin 750 Propoxyphene --
Promethazine Butalbital -- -- -- 751 Propoxyphene -- Promethazine
-- Modafinil -- -- 752 Propoxyphene -- Promethazine -- Caffeine --
-- 753 Propoxyphene -- Promethazine -- -- Naltrexone -- 754
Propoxyphene -- Promethazine -- -- -- Niacin 755 Propoxyphene -- --
Butalbital Modafinil -- -- 756 Propoxyphene -- -- Butalbital
Caffeine -- -- 757 Propoxyphene -- -- Butalbital -- Naltrexone --
758 Propoxyphene -- -- Butalbital -- -- Niacin 759 Propoxyphene --
-- -- Modafinil Naltrexone -- 760 Propoxyphene -- -- -- Caffeine
Naltrexone -- 761 Propoxyphene -- -- -- Modafinil -- Niacin 762
Propoxyphene -- -- -- Caffeine -- Niacin 763 Propoxyphene -- -- --
-- Naltrexone Niacin 764 Propoxyphene Ibuprofen Promethazine
Butalbital -- -- -- 765 Propoxyphene Ibuprofen Promethazine --
Modafinil -- -- 766 Propoxyphene Ibuprofen Promethazine -- Caffeine
-- -- 767 Propoxyphene Ibuprofen Promethazine --- --- Naltrexone
--- 768 Propoxyphene Ibuprofen Promethazine -- -- -- Niacin 769
Propoxyphene Ibuprofen -- Butalbital Modafinil -- -- 770
Propoxyphene Ibuprofen -- Butalbital Caffeine -- -- 771
Propoxyphene Ibuprofen -- Butalbital -- Naltrexone -- 772
Propoxyphene Ibuprofen -- Butalbital -- -- Niacin 773 Propoxyphene
Ibuprofen -- -- Modafinil Naltrexone -- 774 Propoxyphene Ibuprofen
-- -- Modafinil -- Niacin 775 Propoxyphene Ibuprofen -- -- Caffeine
Naltrexone -- 776 Propoxyphene Ibuprofen -- -- Caffeine -- Niacin
777 Propoxyphene Ibuprofen -- -- -- Naltrexone Niacin 778
Propoxyphene -- Promethazine Butalbital Modafinil -- -- 779
Propoxyphene -- Promethazine Butalbital Caffeine -- -- 780
Propoxyphene -- Promethazine Butalbital -- Naltrexone -- 781
Propoxyphene -- Promethazine Butalbital -- -- Niacin 782
Propoxyphene -- Promethazine -- Modafinil Naltrexone -- 783
Propoxyphene -- Promethazine -- Caffeine Naltrexone -- 784
Propoxyphene -- Promethazine -- Modafinil -- Niacin 785
Propoxyphene -- Promethazine -- Caffeine -- Niacin 786 Propoxyphene
-- Promethazine -- -- Naltrexone Niacin 787 Propoxyphene -- --
Butalbital Modafinil Naltrexone -- 788 Propoxyphene -- --
Butalbital Caffeine Naltrexone -- 789 Propoxyphene -- -- Butalbital
Modafinil -- Niacin 790 Propoxyphene -- -- Butalbital Caffeine --
Niacin 791 Propoxyphene -- -- Butalbital -- Naltrexone Niacin 792
Propoxyphene -- -- -- Modafinil Naltrexone Niacin 793 Propoxyphene
-- -- -- Caffeine Naltrexone Niacin 794 Propoxyphene Ibuprofen
Promethazine Butalbital Modafinil -- -- 795 Propoxyphene Ibuprofen
Promethazine Butalbital Caffeine -- -- 796 Propoxyphene Ibuprofen
Promethazine Butalbital -- Naltrexone -- 797 Propoxyphene Ibuprofen
Promethazine Butalbital -- -- Niacin 798 Propoxyphene Ibuprofen
Promethazine -- Modafinil Naltrexone -- 799 Propoxyphene Ibuprofen
Promethazine -- Caffeine Naltrexone -- 800 Propoxyphene Ibuprofen
Promethazine -- Modafinil -- Niacin 801 Propoxyphene Ibuprofen
Promethazine -- Caffeine -- Niacin 802 Propoxyphene Ibuprofen
Promethazine -- -- Naltrexone Niacin 803 Propoxyphene Ibuprofen --
Butalbital Modafinil Naltrexone -- 804 Propoxyphene Ibuprofen --
Butalbital Caffeine Naltrexone -- 805 Propoxyphene Ibuprofen --
Butalbital Modafinil -- Niacin 806 Propoxyphene Ibuprofen --
Butalbital Caffeine -- Niacin 807 Propoxyphene Ibuprofen --
Butalbital -- Naltrexone Niacin 808 Propoxyphene Ibuprofen -- --
Modafinil Naltrexone Niacin 809 Propoxyphene Ibuprofen -- --
Caffeine Naltrexone Niacin 810 Propoxyphene -- Promethazine
Butalbital Modafinil Naltrexone -- 811 Propoxyphene -- Promethazine
Butalbital Caffeine Naltrexone -- 812 Propoxyphene -- Promethazine
Butalbital Modafinil -- Niacin 813 Propoxyphene -- Promethazine
Butalbital Caffeine -- Niacin 814 Propoxyphene -- Promethazine
Butalbital -- Naltrexone Niacin 815 Propoxyphene -- -- Butalbital
Caffeine Naltrexone Niacin 816 Propoxyphene Ibuprofen Promethazine
Butalbital Modafinil Naltrexone -- 817 Propoxyphene Ibuprofen
Promethazine Butalbital Caffeine Naltrexone -- 818 Propoxyphene
Ibuprofen Promethazine Butalbital Modafinil -- Niacin 819
Propoxyphene Ibuprofen Promethazine Butalbital Caffeine -- Niacin
820 Propoxyphene -- Promethazine Butalbital Modafinil Naltrexone
Niacin 821 Propoxyphene -- Promethazine Butalbital Caffeine
Naltrexone Niacin 822 Propoxyphene Ibuprofen -- Butalbital
Modafinil Naltrexone Niacin 823 Propoxyphene Ibuprofen --
Butalbital Caffeine Naltrexone Niacin 824 Propoxyphene Ibuprofen
Promethazine -- Modafinil Naltrexone Niacin 825 Propoxyphene
Ibuprofen Promethazine -- Caffeine Naltrexone Niacin 826
Propoxyphene Ibuprofen Promethazine Butalbital -- Naltrexone Niacin
827 Propoxyphene Ibuprofen Promethazine Butalbital Modafinil
Naltrexone Niacin 828 Propoxyphene Ibuprofen Promethazine
Butalbital Caffeine Naltrexone Niacin 829 Propoxyphene Ibuprofen --
-- -- -- -- 830 -- Acetaminophen -- -- Modafinil -- -- 831 --
Acetaminophen -- -- Caffeine -- -- 832 -- Ibuprofen -- -- Modafinil
-- -- 833 -- Ibuprofen -- -- Caffeine -- -- 834 -- Naproxen -- --
Modafinil -- -- 835 -- Naproxen -- -- Caffeine -- -- 836 --
Acetaminophen -- Butalbital Modafinil -- -- 837 -- Acetaminophen --
Butalbital Caffeine -- -- 838 -- Ibuprofen -- Butalbital Modafinil
-- -- 839 -- Ibuprofen -- Butalbital Caffeine -- -- 840 -- Naproxen
-- Butalbital Modafinil -- -- 841 -- Naproxen -- Butalbital
Caffeine -- -- Note: -- indicates that the respective agent is
absent from a particular composition.
TABLE-US-00008 TABLE 2 Multi-drug Compositions Composition No.
Triptan Antiemetic agent 842 naratriptan promethazine 843
naratriptan aprepitant 844 naratriptan dronabinol 845 naratriptan
perphenazine 846 naratriptan palonosetron 847 naratriptan
trimethyobenzamide 848 naratriptan metoclopromide 849 naratriptan
domperidone 850 naratriptan prochlorperazine 851 naratriptan
promethazine 852 naratriptan chlorpromazine 853 naratriptan
trimethobenzamide 854 naratriptan ondansetron 855 naratriptan
granisetron 856 naratriptan hydroxyzine 857 naratriptan
acetylleucine 858 naratriptan monoethanolamine 859 naratriptan
alizapride 860 naratriptan azasetron 861 naratriptan benzquinamide
862 naratriptan bietanautine 863 naratriptan bromopride 864
naratriptan buclizine 865 naratriptan clebopride 866 naratriptan
cyclizine 867 naratriptan dimenhydrinate 868 naratriptan diphenidol
869 naratriptan dolasetron 870 naratriptan meclizine 871
naratriptan methallatal 872 naratriptan metopimazine 873
naratriptan nabilone 874 naratriptan oxyperndyl 875 naratriptan
pipamazine 876 naratriptan scopolamine 877 naratriptan sulpiride
878 naratriptan tetrahydrocannabinol 879 naratriptan
thiethylperazine 880 naratriptan thioproperazine 881 naratriptan
tropisetron 882 naratriptan droperidol 883 naratriptan haloperidol
884 naratriptan prochloperazine 885 naratriptan metoclopramide 886
naratriptan diphenhydramine 887 naratriptan cannabis 888
naratriptan midazolam 889 naratriptan lorazepam 890 naratriptan
hyoscine 891 naratriptan dexamethasone 892 naratriptan emetrol 893
naratriptan propofol 894 almotriptan promethazine 895 almotriptan
aprepitant 896 almotriptan dronabinol 897 almotriptan perphenazine
898 almotriptan palonosetron 899 almotriptan trimethyobenzamide 900
almotriptan metoclopromide 901 almotriptan domperidone 902
almotriptan prochlorperazine 903 almotriptan promethazine 904
almotriptan chlorpromazine 905 almotriptan trimethobenzamide 906
almotriptan ondansetron 907 almotriptan granisetron 908 almotriptan
hydroxyzine 909 almotriptan acetylleucine 910 almotriptan
monoethanolamine 911 almotriptan alizapride 912 almotriptan
azasetron 913 almotriptan benzquinamide 914 almotriptan
bietanautine 915 almotriptan bromopride 916 almotriptan buclizine
917 almotriptan clebopride 918 almotriptan cyclizine 919
almotriptan dimenhydrinate 920 almotriptan diphenidol 921
almotriptan dolasetron 922 almotriptan meclizine 923 almotriptan
methallatal 924 almotriptan metopimazine 925 almotriptan nabilone
926 almotriptan oxyperndyl 927 almotriptan pipamazine 928
almotriptan scopolamine 929 almotriptan sulpiride 930 almotriptan
tetrahydrocannabinol 931 almotriptan thiethylperazine 932
almotriptan thioproperazine 933 almotriptan tropisetron 934
almotriptan droperidol 935 almotriptan haloperidol 936 almotriptan
prochloperazine 937 almotriptan metoclopramide 938 almotriptan
diphenhydramine 939 almotriptan cannabis 940 almotriptan midazolam
941 almotriptan lorazepam 942 almotriptan hyoscine 943 almotriptan
dexamethasone 944 almotriptan emetrol 945 almotriptan propofol 946
sumatriptan promethazine 947 sumatriptan aprepitant 948 sumatriptan
dronabinol 949 sumatriptan perphenazine 950 sumatriptan
palonosetron 951 sumatriptan trimethyobenzamide 952 sumatriptan
metoclopromide 953 sumatriptan domperidone 954 sumatriptan
prochlorperazine 955 sumatriptan promethazine 956 sumatriptan
chlorpromazine 957 sumatriptan trimethobenzamide 958 sumatriptan
ondansetron 959 sumatriptan granisetron 960 sumatriptan hydroxyzine
961 sumatriptan acetylleucine 962 sumatriptan monoethanolamine 963
sumatriptan alizapride 964 sumatriptan azasetron 965 sumatriptan
benzquinamide 966 sumatriptan bietanautine 967 sumatriptan
bromopride 968 sumatriptan buclizine 969 sumatriptan clebopride 970
sumatriptan cyclizine 971 sumatriptan dimenhydrinate 972
sumatriptan diphenidol 973 sumatriptan dolasetron 974 sumatriptan
meclizine 975 sumatriptan methallatal 976 sumatriptan metopimazine
977 sumatriptan nabilone 978 sumatriptan oxyperndyl 979 sumatriptan
pipamazine 980 sumatriptan scopolamine 981 sumatriptan sulpiride
982 sumatriptan tetrahydrocannabinol 983 sumatriptan
thiethylperazine 984 sumatriptan thioproperazine 985 sumatriptan
tropisetron 986 sumatriptan droperidol 987 sumatriptan haloperidol
988 sumatriptan prochloperazine 989 sumatriptan metoclopramide 990
sumatriptan diphenhydramine 991 sumatriptan cannabis 992
sumatriptan midazolam 993 sumatriptan lorazepam 994 sumatriptan
hyoscine 995 sumatriptan dexamethasone 996 sumatriptan emetrol 997
sumatriptan propofol 998 zolmitriptan promethazine 999 zolmitriptan
aprepitant 1000 zolmitriptan dronabinol 1001 zolmitriptan
perphenazine 1002 zolmitriptan palonosetron 1003 zolmitriptan
trimethyobenzamide 1004 zolmitriptan metoclopromide 1005
zolmitriptan domperidone 1006 zolmitriptan prochlorperazine 1007
zolmitriptan promethazine 1008 zolmitriptan chlorpromazine 1009
zolmitriptan trimethobenzamide 1010 zolmitriptan ondansetron 1011
zolmitriptan granisetron 1012 zolmitriptan hydroxyzine 1013
zolmitriptan acetylleucine 1014 zolmitriptan monoethanolamine 1015
zolmitriptan alizapride 1016 zolmitriptan azasetron 1017
zolmitriptan benzquinamide 1018 zolmitriptan bietanautine 1019
zolmitriptan bromopride 1020 zolmitriptan buclizine 1021
zolmitriptan clebopride 1022 zolmitriptan cyclizine 1023
zolmitriptan dimenhydrinate 1024 zolmitriptan diphenidol 1025
zolmitriptan dolasetron 1026 zolmitriptan meclizine 1027
zolmitriptan methallatal 1028 zolmitriptan metopimazine 1029
zolmitriptan nabilone 1030 zolmitriptan oxyperndyl 1031
zolmitriptan pipamazine 1032 zolmitriptan scopolamine 1033
zolmitriptan sulpiride 1034 zolmitriptan tetrahydrocannabinol 1035
zolmitriptan thiethylperazine 1036 zolmitriptan thioproperazine
1037 zolmitriptan tropisetron 1038 zolmitriptan droperidol 1039
zolmitriptan haloperidol 1040 zolmitriptan prochloperazine 1041
zolmitriptan metoclopramide 1042 zolmitriptan diphenhydramine 1043
zolmitriptan cannabis 1044 zolmitriptan midazolam 1045 zolmitriptan
lorazepam 1046 zolmitriptan hyoscine 1047 zolmitriptan
dexamethasone 1048 zolmitriptan emetrol 1049 zolmitriptan propofol
1050 eletriptan promethazine 1051 eletriptan aprepitant 1052
eletriptan dronabinol 1053 eletriptan perphenazine 1054 eletriptan
palonosetron 1055 eletriptan trimethyobenzamide 1056 eletriptan
metoclopromide 1057 eletriptan domperidone 1058 eletriptan
prochlorperazine 1059 eletriptan promethazine 1060 eletriptan
chlorpromazine 1061 eletriptan trimethobenzamide 1062 eletriptan
ondansetron 1063 eletriptan granisetron 1064 eletriptan hydroxyzine
1065 eletriptan acetylleucine 1066 eletriptan monoethanolamine 1067
eletriptan alizapride 1068 eletriptan azasetron 1069 eletriptan
benzquinamide 1070 eletriptan bietanautine 1071 eletriptan
bromopride 1072 eletriptan buclizine 1073 eletriptan clebopride
1074 eletriptan cyclizine 1075 eletriptan dimenhydrinate 1076
eletriptan diphenidol 1077 eletriptan dolasetron 1078 eletriptan
meclizine 1079 eletriptan methallatal 1080 eletriptan metopimazine
1081 eletriptan nabilone 1082 eletriptan oxyperndyl 1083 eletriptan
pipamazine 1084 eletriptan scopolamine 1085 eletriptan
sulpiride
1086 eletriptan tetrahydrocannabinol 1087 eletriptan
thiethylperazine 1088 eletriptan thioproperazine 1089 eletriptan
tropisetron 1090 eletriptan droperidol 1091 eletriptan haloperidol
1092 eletriptan prochloperazine 1093 eletriptan metoclopramide 1094
eletriptan diphenhydramine 1095 eletriptan cannabis 1096 eletriptan
midazolam 1097 eletriptan lorazepam 1098 eletriptan hyoscine 1099
eletriptan dexamethasone 1100 eletriptan emetrol 1101 eletriptan
propofol 1102 frovatriptan promethazine 1103 frovatriptan
aprepitant 1104 frovatriptan dronabinol 1105 frovatriptan
perphenazine 1106 frovatriptan palonosetron 1107 frovatriptan
trimethyobenzamide 1108 frovatriptan metoclopromide 1109
frovatriptan domperidone 1110 frovatriptan prochlorperazine 1111
frovatriptan promethazine 1112 frovatriptan chlorpromazine 1113
frovatriptan trimethobenzamide 1114 frovatriptan ondansetron 1115
frovatriptan granisetron 1116 frovatriptan hydroxyzine 1117
frovatriptan acetylleucine 1118 frovatriptan monoethanolamine 1119
frovatriptan alizapride 1120 frovatriptan azasetron 1121
frovatriptan benzquinamide 1122 frovatriptan bietanautine 1123
frovatriptan bromopride 1124 frovatriptan buclizine 1125
frovatriptan clebopride 1126 frovatriptan cyclizine 1127
frovatriptan dimenhydrinate 1128 frovatriptan diphenidol 1129
frovatriptan dolasetron 1130 frovatriptan meclizine 1131
frovatriptan methallatal 1132 frovatriptan metopimazine 1133
frovatriptan nabilone 1134 frovatriptan oxyperndyl 1135
frovatriptan pipamazine 1136 frovatriptan scopolamine 1137
frovatriptan sulpiride 1138 frovatriptan tetrahydrocannabinol 1139
frovatriptan thiethylperazine 1140 frovatriptan thioproperazine
1141 frovatriptan tropisetron 1142 frovatriptan droperidol 1143
frovatriptan haloperidol 1144 frovatriptan prochloperazine 1145
frovatriptan metoclopramide 1146 frovatriptan diphenhydramine 1147
frovatriptan cannabis 1148 frovatriptan midazolam 1149 frovatriptan
lorazepam 1150 frovatriptan hyoscine 1151 frovatriptan
dexamethasone 1152 frovatriptan emetrol 1153 frovatriptan propofol
1154 rizatriptan promethazine 1155 rizatriptan aprepitant 1156
rizatriptan dronabinol 1157 rizatriptan perphenazine 1158
rizatriptan palonosetron 1159 rizatriptan trimethyobenzamide 1160
rizatriptan metoclopromide 1161 rizatriptan domperidone 1162
rizatriptan prochlorperazine 1163 rizatriptan promethazine 1164
rizatriptan chlorpromazine 1165 rizatriptan trimethobenzamide 1166
rizatriptan ondansetron 1167 rizatriptan granisetron 1168
rizatriptan hydroxyzine 1169 rizatriptan acetylleucine 1170
rizatriptan monoethanolamine 1171 rizatriptan alizapride 1172
rizatriptan azasetron 1173 rizatriptan benzquinamide 1174
rizatriptan bietanautine 1175 rizatriptan bromopride 1176
rizatriptan buclizine 1177 rizatriptan clebopride 1178 rizatriptan
cyclizine 1179 rizatriptan dimenhydrinate 1180 rizatriptan
diphenidol 1181 rizatriptan dolasetron 1182 rizatriptan meclizine
1183 rizatriptan methallatal 1184 rizatriptan metopimazine 1185
rizatriptan nabilone 1186 rizatriptan oxyperndyl 1187 rizatriptan
pipamazine 1188 rizatriptan scopolamine 1189 rizatriptan sulpiride
1190 rizatriptan tetrahydrocannabinol 1191 rizatriptan
thiethylperazine 1192 rizatriptan thioproperazine 1193 rizatriptan
tropisetron 1194 rizatriptan droperidol 1195 rizatriptan
haloperidol 1196 rizatriptan prochloperazine 1197 rizatriptan
metoclopramide 1198 rizatriptan diphenhydramine 1199 rizatriptan
cannabis 1200 rizatriptan midazolam 1201 rizatriptan lorazepam 1202
rizatriptan hyoscine 1203 rizatriptan dexamethasone 1204
rizatriptan emetrol 1205 rizatriptan propofol
[0396] As to any pharmaceutically active agent disclosed in the
foregoing Table 1 or Table 2, it should be noted that any
pharmaceutically acceptable salt of the pharmaceutically active
agent is within the various embodiments of the present invention.
Furthermore, non-limiting examples of such pharmaceutically
acceptable salts are disclosed herein.
[0397] While particular embodiments described herein have been
shown and described herein, such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *