U.S. patent application number 14/644263 was filed with the patent office on 2015-07-02 for opioid-containing oral pharmaceutical compositions and methods.
The applicant listed for this patent is UPSHER-SMITH LABORATORIES, INC.. Invention is credited to Stephen M. BERGE, Kenneth L. EVENSTAD, James S. JENSEN, Victoria Ann O'NEILL, Christian F. WERTZ.
Application Number | 20150182462 14/644263 |
Document ID | / |
Family ID | 42260778 |
Filed Date | 2015-07-02 |
United States Patent
Application |
20150182462 |
Kind Code |
A1 |
EVENSTAD; Kenneth L. ; et
al. |
July 2, 2015 |
Opioid-Containing Oral Pharmaceutical Compositions and Methods
Abstract
The present invention provides sustained-release oral
pharmaceutical compositions and methods of use. The
sustained-release oral pharmaceutical compositions include an
opioid (including salts thereof) and a salt of a non-steroidal
anti-inflammatory drug (NSAID).
Inventors: |
EVENSTAD; Kenneth L.;
(Naples, FL) ; WERTZ; Christian F.; (St. Louis
Park, MN) ; JENSEN; James S.; (Edina, MN) ;
O'NEILL; Victoria Ann; (Wayzata, MN) ; BERGE; Stephen
M.; (Shoreview, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UPSHER-SMITH LABORATORIES, INC. |
Maple Grove |
MN |
US |
|
|
Family ID: |
42260778 |
Appl. No.: |
14/644263 |
Filed: |
March 11, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13715432 |
Dec 14, 2012 |
8987291 |
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14644263 |
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13142784 |
Jun 29, 2011 |
8362029 |
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PCT/US2009/069902 |
Dec 31, 2009 |
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13715432 |
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61141765 |
Dec 31, 2008 |
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Current U.S.
Class: |
514/282 ;
514/569 |
Current CPC
Class: |
A61K 31/135 20130101;
A61K 31/192 20130101; A61K 31/10 20130101; A61K 9/2054 20130101;
A61K 31/439 20130101; A61P 25/04 20180101; A61K 31/19 20130101;
A61K 31/19 20130101; A61K 31/485 20130101; A61K 31/485 20130101;
A61K 9/2013 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/192 20060101 A61K031/192; A61K 31/485 20060101
A61K031/485; A61K 31/135 20060101 A61K031/135 |
Claims
1. (canceled)
2. A method of preventing, alleviating, or ameliorating the level
of pain in a subject, the method comprising administering to a
subject a sustained-release oral pharmaceutical composition
comprising within a single dose: a hydrophilic matrix; a
therapeutically effective amount of an opioid or salt thereof; and
a salt of a non-steroidal anti-inflammatory drug (NSAID), wherein
the opioid and the salt of an NSAID are within the hydrophilic
matrix; and wherein the opioid or salt thereof is released as a
result of dissolution of the hydrophilic matrix.
3. The method of claim 2, wherein the composition exhibits a
release profile with respect to the opioid comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions.
4. The method of claim 2, wherein the composition further comprises
one or more pharmaceutically acceptable anionic surfactants,
wherein the one or more surfactants are in the hydrophilic matrix
in an amount effective to modify the rate of release of the opioid
from the hydrophilic matrix.
5. The method of claim 4, wherein the one or more anionic
surfactants are selected from the group consisting of sodium lauryl
sulfate, docusate sodium, docusate calcium, and combinations
thereof.
6. The method of claim 2, wherein the opioid comprises a tertiary
amine.
7. The method of claim 2, wherein the opioid is selected from the
group consisting of morphine, codeine, hydromorphone, hydrocodone,
oxycodone, oxymorphone, desomorphine, diacetylmorphine,
buprenorphine, dihydrocodeine, nicomorphine, benzylmorphine,
fentanyl, methadone, tramadol, propoxyphene, levorphanol, and
meperidine.
8. The method of claim 2, wherein the opioid is selected from the
group consisting of hydrocodone, tramadol, a salt of hydrocodone,
or a salt of tramadol.
9. The method of claim 2, wherein the NSAID salt is selected from
the group consisting of a salt of naproxen, a salt of diclofenac,
and a salt of ibuprofen.
10. The method of claim 2, wherein the NSAID salt is present in an
amount effective to provide zero-order release kinetics of the
opioid from the hydrophilic matrix under in vitro conditions.
11. The method of claim 2, wherein the hydrophilic matrix comprises
a methylcellulose, a hydroxypropyl methylcellulose, and
combinations thereof.
12. The method of claim 2, wherein the hydrophilic matrix comprises
a hydroxypropyl methylcellulose.
13. The method of claim 2 wherein the single dosage form is a
tablet form.
14. A method of suppressing cough in a subject, the method
comprising administering a sustained-release oral pharmaceutical
composition comprising within a single dose: a hydrophilic matrix;
a therapeutically effective amount of an opioid or salt thereof;
and a salt of a non-steroidal anti-inflammatory drug (NSAID),
wherein the opioid and the salt of an NSAID are within the
hydrophilic matrix; and wherein the opioid or salt thereof is
released as a result of dissolution of the hydrophilic matrix.
15. The method of claim 14, wherein the composition exhibits a
release profile with respect to the opioid comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions.
16. The method of claim 14, wherein the composition further
comprises one or more pharmaceutically acceptable anionic
surfactants, wherein the one or more surfactants are in the
hydrophilic matrix.
17. The method of claim 16, wherein the anionic surfactant is
present in the hydrophilic matrix in an amount effective to modify
the rate of release of the opioid from the hydrophilic matrix.
18. The method of claim 14, wherein the opioid is selected from the
group consisting of morphine, codeine, hydromorphone, hydrocodone,
oxycodone, oxymorphone, desomorphine, diacetylmorphine,
buprenorphine, dihydrocodeine, nicomorphine, benzylmorphine,
fentanyl, methadone, tramadol, propoxyphene, levorphanol, and
meperidine.
19. The method of claim 14, wherein the opioid is a salt comprising
a hydrochloride, a bitartrate, an acetate, a naphthylate, a
tosylate, a mesylate, a besylate, a succinate, a palmitate, a
stearate, an oleate, a pamoate, a laurate, a valerate, a
hydrobromide, a sulfate, a methane sulfonate, a tartrate, a
citrate, or a maleate.
20. The method of claim 14, wherein the NSAID salt is selected from
the group consisting of a salt of naproxen, a salt of diclofenac,
and a salt of ibuprofen.
21. The method of claim 14, wherein the NSAID salt is present in an
amount effective to provide zero-order release kinetics of the
opioid from the hydrophilic matrix under in vitro conditions.
Description
CONTINUING AND RELATED APPLICATION DATA
[0001] This application is a continuation of U.S. Ser. No.
13/715,432, filed on Dec. 14, 2012, issuing as U.S. Pat. No.
8,987,291 on Mar. 24, 2015, which is a continuation of U.S. Ser.
No. 13/142,784, issued as U.S. Pat. No. 8,362,029 on Jan. 29, 2013,
which is a U.S. National Stage application of International
Application No. PCT/US2009/069902, filed on Dec. 31, 2009,
published in the English language on Jul. 8, 2010 as International
Publication No. WO 2010/078486 A2, which claims the benefit of U.S.
Provisional Application Ser. No. 61/141,765, filed Dec. 31, 2008.
Attention is also directed to International Application No.
PCT/US2009/069912, filed Dec. 31, 2009, published in the English
language on Mar. 24, 2011 as International Publication No. WO
2011/034554 A1, which claims the benefit of U.S. Provisional
Application Ser. No. 61/243,391, filed Sep. 17, 2009. All of the
above are incorporated by reference herein.
BACKGROUND
[0002] Chronic pain is a major contributor to disability in the
industrialized world and is the cause of an untold amount of
suffering. The successful treatment of severe and chronic pain is a
primary goal of the physician, with opioid analgesics being the
current drugs of choice.
[0003] Opioid analgesics (i.e., opioids having analgesic
properties) are drugs that function in a manner similar to that of
morphine. These agents work by binding to opioid receptors, which
are found principally in the central nervous system and the
gastrointestinal tract. Although the term opiate is often used as a
synonym for opioid, it is more frequently used to refer to the
natural opium alkaloids and the semi-synthetics derived from
them.
[0004] An important goal of analgesic therapy is to achieve
continuous relief of chronic pain. Regular administration of an
analgesic is generally required to ensure that the next dose is
given before the effects of the previous dose have worn off.
Compliance with opioids increases as the required dosing frequency
decreases. Non-compliance results in suboptimal pain control and
poor quality-of-life outcomes. Scheduled rather than "as needed"
administration of opioids is currently recommended in guidelines
for their use in treating chronic non-malignant pain.
Unfortunately, evidence from prior clinical trials and clinical
experience suggests that the short duration of action of
immediate-release opioid formulations would necessitate 4-hourly
administrations in order to maintain optimal levels of analgesia in
patients with chronic pain. Moreover, immediate-release
formulations can exhibit low oral bioavailability. Thus, there is a
need for new opioid-containing oral pharmaceutical compositions
that provide sustained release, and ideally zero-order release
kinetics, and less frequent dosing.
[0005] Opioids (particularly those with analgesic activity) are
sometimes the subject of abuse. Typically, a particular dose of an
opioid analgesic is more potent when administered parenterally as
compared to the same dose administered orally. Therefore, one
popular mode of abuse of oral opioid formulations involves the
extraction of the opioid from the dosage form, and the subsequent
injection of the opioid (using any "suitable" vehicle for
injection) in order to achieve a "high." Also, some formulations
can be tampered with in order to provide the opioid contained
therein better availability for illicit use. For example, an
opioid-containing tablet can be crushed in order to render the
opioid therein available for immediate release upon oral, nasal, or
intravenous administration. An opioid formulation can also be
abused by administration of more than the prescribed dose of the
drug. Thus, there is a need for new opioid-containing oral
pharmaceutical compositions that provide abuse deterrence in
addition to providing sustained-release, ideally zero-order release
kinetics, and less frequent dosing.
SUMMARY
[0006] The present invention provides sustained-release oral
pharmaceutical compositions and methods of use.
[0007] In one embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid (including salts thereof); and a salt
of a non-steroidal anti-inflammatory drug (NSAID); wherein the
opioid (including salts thereof) and the salt of an NSAID are
within the hydrophilic matrix; wherein the composition exhibits a
release profile comprising a substantial portion that is
representative of zero-order release kinetics (with respect to the
opioid) under in vitro conditions.
[0008] In another embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid (including salts thereof); a salt of
a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid
(including salts thereof), the salt of an NSAID, and the anionic
surfactant are within the hydrophilic matrix. Preferred such
compositions exhibit a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions.
[0009] In certain embodiments, the opioid comprises a tertiary
amine. In certain embodiments, the opioid comprises a ring nitrogen
that is a tertiary amine.
[0010] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; and
a salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; wherein the opioid (including
salts thereof) and the salt of an NSAID are within the hydrophilic
matrix; wherein the composition has a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions.
[0011] In another preferred embodiment, the present invention
provides a sustained-release oral pharmaceutical composition
comprising within a single dosage form: a hydrophilic matrix; a
therapeutically effective amount of an opioid selected from the
group consisting of hydrocodone, tramadol, salts thereof, and
combinations thereof; a salt of a non-steroidal anti-inflammatory
drug (NSAID) selected from the group consisting of a salt of
naproxen, diclofenac, ibuprofen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of sodium lauryl sulfate, docusate sodium,
docusate calcium, and combinations thereof; wherein the opioid
(including salts thereof), the salt of an NSAID, and the anionic
surfactant are within the hydrophilic matrix. Preferred such
compositions have a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions.
[0012] In preferred compositions, the opioid is an opioid that has
analgesic activity (i.e., an opioid analgesic). Thus, compositions
of the present invention are preferably used in methods of
preventing, alleviating, or ameliorating the level of pain in a
subject. Alternatively, compositions of the present invention can
be used in suppressing a cough.
[0013] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; and
a salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; wherein the opioid (including
salts thereof) and the salt of an NSAID are within the hydrophilic
matrix; wherein the composition exhibits a release profile
comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
[0014] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; and a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, and combinations thereof;
wherein the opioid (including salts thereof) and the salt of an
NSAID are within the hydrophilic matrix; wherein the composition
exhibits a release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions.
[0015] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of tramadol, a salt
thereof, and combinations thereof; and a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; wherein the opioid
(including salts thereof) and the salt of an NSAID are within the
hydrophilic matrix; wherein the composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
[0016] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix; a therapeutically
effective amount of an opioid selected from the group consisting of
hydrocodone, tramadol, salts thereof, and combinations thereof; a
salt of a non-steroidal anti-inflammatory drug (NSAID) selected
from the group consisting of a salt of naproxen, diclofenac,
ibuprofen, and combinations thereof; and a pharmaceutically
acceptable anionic surfactant selected from the group consisting of
sodium lauryl sulfate, docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
[0017] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of hydrocodone, a
salt thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
[0018] In a preferred embodiment, the present invention provides a
sustained-release oral pharmaceutical composition comprising within
a single dosage form: a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; a therapeutically effective amount
of an opioid selected from the group consisting of tramadol, a salt
thereof, and combinations thereof; a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; wherein the opioid (including salts thereof),
the salt of an NSAID, and the anionic surfactant are within the
hydrophilic matrix. Preferably, such composition exhibits a release
profile comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions.
[0019] In a preferred embodiment, the present invention provides a
method of preventing, alleviating, or ameliorating the level of
pain in a subject, the method administering to a subject a
composition comprising: a hydrophilic matrix; a pain-reducing
amount of an opioid analgesic (including salts thereof); and a salt
of a non-steroidal anti-inflammatory drug (NSAID) present in an
amount effective to provide zero-order release kinetics under in
vitro conditions; wherein the opioid analgesic (including salts
thereof) and salt of an NSAID are within the hydrophilic matrix;
wherein the composition has a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions.
[0020] In a preferred embodiment, the present invention provides a
method of preventing, alleviating, or ameliorating the level of
pain in a subject, the method administering to a subject a
composition comprising: a hydrophilic matrix; a therapeutically
effective amount of an opioid analgesic (including salts thereof);
a salt of a non-steroidal anti-inflammatory drug (NSAID); and a
pharmaceutically acceptable anionic surfactant; wherein the opioid
analgesic (including salts thereof), the salt of an NSAID, and the
anionic surfactant are within the hydrophilic matrix. Preferably,
such composition exhibits a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions.
[0021] In methods of the present invention, administering a
composition of the present invention comprises administering once
or twice per day, and often once per day.
[0022] The terms "comprises" and variations thereof do not have a
limiting meaning where these terms appear in the description and
claims.
[0023] The words "preferred" and "preferably" refer to embodiments
of the invention that may afford certain benefits, under certain
circumstances. However, other embodiments may also be preferred,
under the same or other circumstances. Furthermore, the recitation
of one or more preferred embodiments does not imply that other
embodiments are not useful, and is not intended to exclude other
embodiments from the scope of the invention.
[0024] As used herein, "a," "an," "the," "at least one," and "one
or more" are used interchangeably. Thus, for example, a composition
comprising "a" salt of a non-steroidal anti-inflammatory drug can
be interpreted to mean that the composition includes "one or more"
non-steroidal anti-inflammatory drugs. Similarly, a composition
comprising "a" pharmaceutically acceptable anionic surfactant can
be interpreted to mean that the composition includes "one or more"
pharmaceutically acceptable anionic surfactants.
[0025] As used herein, the term "or" is generally employed in its
sense including "and/or" unless the content clearly dictates
otherwise. The term "and/or" means one or all of the listed
elements or a combination of any two or more of the listed
elements.
[0026] Also herein, all numbers are assumed to be modified by the
term "about" and preferably by the term "exactly." Notwithstanding
that the numerical ranges and parameters setting forth the broad
scope of the invention are approximations, the numerical values set
forth in the specific examples are reported as precisely as
possible. All numerical values, however, inherently contain certain
errors necessarily resulting from the standard deviation found in
their respective testing measurements.
[0027] Also herein, the recitations of numerical ranges by
endpoints include all numbers subsumed within that range (e.g., 1
to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Where a range
of values is "up to" a particular value, that value is included
within the range.
[0028] The above summary of the present invention is not intended
to describe each disclosed embodiment or every implementation of
the present invention. The description that follows more
particularly exemplifies illustrative embodiments. In several
places throughout the application, guidance is provided through
lists of examples, which examples can be used in various
combinations. In each instance, the recited list serves only as a
representative group and should not be interpreted as an exclusive
list.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIGS. 1 and 2 show dissolution profiles in phosphate buffer
for certain tramadol hydrochloride (TMD) formulations in accordance
with embodiments of the present invention.
[0030] FIGS. 3 and 4 show dissolution profiles in phosphate buffer
for certain Hydrocodone Bitartrate (HCB) formulations in accordance
with embodiments of the present invention.
[0031] FIG. 5 shows dissolution profiles in acidic and
hydroalcoholic media for certain dextromethorphan (DXM)
formulations.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0032] The present invention provides sustained-release oral
pharmaceutical compositions and methods of use. Preferably, such
compositions are used for pain treatment, cough suppression, or
other indications typically requiring opioid administration. Such
compositions are in a single dosage form and include an opioid
(preferably an opioid analgesic) (including salts thereof), a salt
of a non-steroidal anti-inflammatory drug (NSAID), and a
hydrophilic matrix. Certain embodiments also include a
pharmaceutically acceptable anionic surfactant.
[0033] Herein, sustained-release compositions release the opioid
over a period of time greater than 60 minutes. Preferred
sustained-release formulations demonstrate at least 60%, and more
preferably at least 80%, release of the opioid over a desired
period (e.g., a period of 8 to 12 hours). If desired, however, the
formulations of the present invention could be tailored to release
the opioid over any period from 6 hours to 24 hours or longer.
[0034] Particularly preferred sustained-release compositions of the
present invention demonstrate a zero-order release profile with
respect to the opioid under in vitro conditions, such as when
tested in accordance with appropriate United States Pharmacopeia
test methods. Herein, "zero-order" with respect to the opioid
(including salts thereof) means a relatively constant rate of
release (i.e., exhibiting a substantially linear release profile
over a period of time, preferably at least a few hours). Although a
small portion (e.g., the initial 30-60 minutes) of the release
profile may not be zero-order (e.g., as in a formulation containing
an immediate-release coating, or a bilayer or multi-layer
formulation comprising an immediate-release layer), a substantial
portion (e.g., several hours), and preferably a major portion, of
the release profile is representative of zero-order release
kinetics.
Opioids and Salts Thereof
[0035] An opioid is a chemical substance that works by binding to
opioid receptors, which are found principally in the central
nervous system and the gastrointestinal tract. The receptors in
these two organ systems mediate both the beneficial effects, and
the undesirable side effects. There are three principal classes of
opioid receptors, .mu., .kappa., .delta. (mu, kappa, and delta),
although up to seventeen have been reported, and include the
.epsilon., , .lamda., and .zeta. (Epsilon, Iota, Lambda and Zeta)
receptors. There are three subtypes of .mu., receptor: .mu..sub.1
and .mu..sub.2, and the newly discovered .mu..sub.3. Another
receptor of clinical importance is the opioid-receptor-like
receptor 1 (ORL1), which is involved in pain responses as well as
having a major role in the development of tolerance to .mu.-opioid
agonists used as analgesics. An opioid can have agonist
characteristics, antagonist characteristics, or both (e.g.,
pentazocine is a synthetic mixed agonist-antagonist opioid
analgesic of the benzomorphan class of opioids used to treat mild
to moderately severe pain). The main use for opioids is for pain
relief, although cough suppression is also a common use. For
example, hydromorphone is used to relieve moderate to severe pain
and severe, painful dry coughing. Hydrocodone is most commonly used
as an intermediate-strength analgesic and strong cough
suppressant.
[0036] There are a number of broad classes of opioids: natural
opiates, which are alkaloids contained in the resin of the opium
poppy, and include morphine and codeine; semi-synthetic opiates,
created from the natural opioids, such as hydromorphone (found in
Dilaudid), hydrocodone (found in Vicodin), oxycodone (found in
Oxycontin and Percocet), oxymorphone, desomorphine,
diacetylmorphine (Heroin), nicomorphine, buprenorphine,
dihydrocodeine, and benzylmorphine; and fully synthetic opioids,
such as fentanyl, methadone, tramadol, and propoxyphene (found in
Darvon and Darvocet N). Other examples of opioids include
levorphanol, meperidine (found in Demerol), pentazocine, tilidine,
and others disclosed, for example, at www.opioids.com.
[0037] Certain opioids have antagonist action. For example,
naloxone is a .mu.-opioid receptor competitive antagonist. Naloxone
is a drug used to counter the effects of opioid overdose, for
example heroin or morphine overdose. Naltrexone is an opioid
receptor antagonist used primarily in the management of alcohol
dependence and opioid dependence. N-methyl naltrexone is also an
opioid receptor antagonist.
[0038] Various combinations of such compounds can be used if
desired. Each of these compounds includes a tertiary amine as
shown, wherein the amine nitrogen may or may not be within a
ring:
##STR00001## ##STR00002## ##STR00003##
[0039] Preferred opioids are opioid analgesics, which have
morphine-like activity and produce bodily effects including pain
relief and sedation. For certain embodiments, the opioid,
particularly opioid analgesic, selected for use in compositions of
the present invention is one having a tertiary amine nitrogen. For
certain embodiments, the opioid, particularly opioid analgesic,
selected includes a ring nitrogen that is a tertiary amine.
[0040] The opioids can be used in a variety of salt forms including
"pharmaceutically acceptable salts." Preparation of such salts is
well-known to those skilled in pharmaceuticals. Examples of
suitable pharmaceutically acceptable salts include, but are not
limited to, hydrochlorides, bitartrates, acetates, naphthylates,
tosylates, mesylates, besylates, succinates, palmitates, stearates,
oleates, pamoates, laurates, valerates, hydrobromides, sulfates,
methane sulfonates, tartrates, citrates, maleates, and the like, or
combinations of any of the foregoing. Preferably, the opioid is
selected from the group consisting of hydrocodone (e.g.,
hydrocodone bitartrate), tramadol (e.g., tramadol hydrochloride),
and combinations thereof. For certain embodiments, the opioid is
hydrocodone (particularly hydrocodone bitartrate). For certain
embodiments, the opioid is tramadol (particularly tramadol
hydrochloride).
[0041] An opioid, particularly an opioid analgesic, is used herein
in a therapeutically effective amount. Determination of a
therapeutically effective amount will be determined by the
condition being treated (e.g., pain or cough) and on the target
dosing regimen (e.g., once per day, twice per day). Determination
of such an amount is well within the capability of those skilled in
the art, especially in light of the detailed disclosure provided
herein. For example, if the composition is used as a cough
suppressant, the amount of the opioid would be that which is
effective for suppressing a cough. If the composition is used to
treat pain, a therapeutically effective amount or an opioid is
referred to herein as a "pain-reducing amount." Herein, this means
an amount of compound effective to reduce or treat (i.e., prevent,
alleviate, or ameliorate) pain symptoms over the desired time
period. This amount can vary with each specific opioid depending on
the potency of each. For example, for hydrocodone, the amount per
single dosage form of the present invention may be 5 mg to 50
mg.
Salts of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
[0042] Compositions of the present invention include one or more
non-steroidal anti-inflammatory drugs, usually abbreviated to
NSAIDs or NAIDs. These are drugs with analgesic, antipyretic and,
in higher doses, anti-inflammatory effects.
[0043] NSAIDs are sometimes also referred to as non-steroidal
anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal
anti-inflammatory medicines (NSAIMs). All NSAIDs as used herein are
nonspecific COX inhibitors.
[0044] Surprisingly, in the practice of the present invention,
salts of NSAIDs (but not the free bases) provide compositions with
zero-order release kinetics with respect to the opioids (including
salts thereof).
[0045] There are roughly seven major classes of NSAIDs,
including:
[0046] (1) salicylate derivatives, such as acetylsalicylic acid
(aspirin), amoxiprin, benorylate/benorilate, choline magnesium
salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate,
magnesium salicylate, salicyl salicylate, and salicylamide; a few
structures of such compounds are as follows:
##STR00004##
[0047] (2) 2-aryl propionic acid derivatives, such as ibuprofen,
ketoprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen,
fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam,
ondoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen,
suprofen, and tiaprofenic acid; a few structures of such compounds
are as follows:
##STR00005##
[0048] (3) pyrazolidine derivatives, such as phenylbutazone,
ampyrone, azapropazone, clofezone, kebuzone, metamizole,
mofebutazone, oxyphenbutazone, phenazone, and sulfinpyrazone; a few
structures of such compounds are as follows:
##STR00006##
[0049] (4) N-arylanthranilic acid (or fenamate) derivatives, such
as mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic
acid, and esters thereof; a few structures of such compounds are as
follows:
##STR00007##
[0050] (5) oxicam derivatives, such as piroxicam, droxicam,
lornoxicam, meloxicam, and tenoxicam; a few structures of such
compounds are as follows:
##STR00008##
[0051] (6) arylalkanoic acids, such as diclofenac, aceclofenac,
acemethacin, alclofenac, bromfenac, etodolac, indomethacin,
nabumetone, oxametacin, proglumetacin, sulindac (prodrug), and
tolmetin; a few structures of such compounds are as follows:
##STR00009##
[0052] (7) indole derivatives, such as indomethacin, the structure
of which is as follows:
##STR00010##
[0053] Although acetaminophen (paracetamol) is an analgesic and it
is sometimes grouped with NSAIDs, it is not an NSAID (particularly
for the purposes of the present invention) because it does not have
any significant anti-inflammatory activity.
[0054] NSAIDs used in compositions of the present invention are
pharmaceutically acceptable salts thereof. Typically, such salts
include metal salts, such as sodium, calcium, or potassium salts.
Salts such as bismuth salts, magnesium salts, or zinc salts may
also be suitable. Various combinations of counterions and/or NSAID
salts can be used if desired.
[0055] Preferred NSAID salts include a terminal carboxylic acid or
terminal carboxylate group on the active moiety. In certain
embodiments, the NSAID salts include a terminal carboxylic acid
group on the active moiety. In certain embodiments, the NSAID salts
include a terminal carboxylate group on the active moiety.
Exemplary such NSAID salts are selected from the group consisting
of a salicylate derivative, a 2-aryl propionic acid derivative, an
N-arylanthranilic acid derivative, an aryl alkanoic acid, an indole
derivative, and combinations thereof. Preferred NSAID salts include
salts of 2-aryl propionic acid derivative (e.g., naproxen and
ibuprofen), aryl alkanoic acids, or combinations thereof.
Particularly preferred NSAID salts include naproxen sodium,
ibuprofen sodium, diclofenac sodium, and combinations thereof.
Structures of naproxen, diclofenac, and ibuprofen are as
follows:
##STR00011##
[0056] In preferred compositions, an NSAID salt is present in
compositions of the present invention in an amount to provide
zero-order release kinetics under in vitro conditions. Such amount
can be a sub-therapeutic amount or it can be a conventional
therapeutic amount. Determination of such an amount is well within
the capability of those skilled in the art, especially in light of
the detailed disclosure provided herein. For example, naproxen
sodium could be included in a single dosage form of the current
invention at an amount of 220 mg to 750 mg (for a twice per day
dosage form).
Pharmaceutically Acceptable Anionic Surfactants
[0057] Suitable pharmaceutically acceptable anionic surfactants
include, for example, monovalent alkyl carboxylates, acyl
lactylates, alkyl ether carboxylates, N-acyl sarcosinates,
polyvalent alkyl carbonates, N-acyl glutamates, fatty
acid-polypeptide condensates, sulfur-containing surfactants (e.g.,
sulfuric acid esters, alkyl sulfates such as sodium lauryl sulfate
(SLS), ethoxylated alkyl sulfates, ester linked sulfonates such as
docusate sodium or dioctyl sodium succinate (DSS), and alpha olefin
sulfonates), and phosphated ethoxylated alcohols. Preferred
surfactants are on the GRAS ("Generally Recognized as Safe") list.
Various combinations of pharmaceutically acceptable anionic
surfactants can be used if desired.
[0058] In certain embodiments, the pharmaceutically acceptable
anionic surfactant is a sulfur-containing surfactant, and
particularly an alkyl sulfate, an ester-linked sulfonate, and
combinations thereof. Preferred pharmaceutically acceptable anionic
surfactants include sodium lauryl sulfate, docusate (i.e., dioctyl
sulfosuccinate) sodium, docusate calcium, and combinations thereof.
A particularly preferred anionic surfactant is docusate sodium. The
structures of docusate sodium and sodium lauryl sulfate are as
follows:
##STR00012##
[0059] In preferred embodiments, a pharmaceutically acceptable
anionic surfactant is present in compositions of the present
invention in a release-modifying amount. A wide range of amounts
can be used to tailor the rate and extent of release. Determination
of such an amount is well within the capability of those skilled in
the art, especially in light of the detailed disclosure provided
herein.
[0060] In some embodiments, certain surfactants such as docusate
can function as a stool softener when used at a therapeutic level;
however, sub-therapeutic amounts can be used for release
modification.
[0061] Such surfactants can be used for their abuse deterrence
effects. For example, a surfactant could function as a nasal
irritant, which would make crushing and inhaling the compositions
undesirable. Also, a mixture of an opioid and a surfactant (e.g.,
docusate) in a hydrophilic matrix is difficult to extract and
separate into the individual components, and injection of the
mixture is undesirable and/or unsafe.
Hydrophilic Matrix and Other Excipients
[0062] Compositions of the present invention include a hydrophilic
matrix, wherein the opioid (including salts thereof), the salt of
an NSAID, and the optional anionic surfactant are within (e.g.,
mixed within) the hydrophilic matrix. Such matrix preferably
includes at least one hydrophilic polymeric compound. The
hydrophilic polymeric compound preferably forms a matrix that
releases the opioid, preferably opioid analgesic, or the
pharmaceutically acceptable salt thereof at a sustained rate upon
exposure to liquids. The rate of release of the opioid or the
pharmaceutically acceptable salt thereof from the hydrophilic
matrix typically depends, at least in part, on the opioid's
partition coefficient between the components of the hydrophilic
matrix and the aqueous phase within the gastrointestinal tract.
[0063] The sustained-release composition generally includes at
least one hydrophilic polymeric compound in an amount of 10% to 90%
by weight, preferably in an amount of 20% to 80% by weight, based
on the total weight of the composition.
[0064] The hydrophilic polymeric compound may be any known in the
art. Exemplary hydrophilic polymeric compounds include gums,
cellulose ethers, acrylic resins, polyvinyl pyrrolidone,
protein-derived compounds, and combinations thereof. Exemplary gums
include heteropolysaccharide gums and homopolysaccharide gums, such
as xanthan, tragacanth, pectins, acacia, karaya, alginates, agar,
guar, hydroxypropyl guar, carrageenan, locust bean gums, and gellan
gums. Exemplary cellulose ethers include hydroxyalkyl celluloses
and carboxyalkyl celluloses. Preferred cellulose ethers include
hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl
methylcelluloses, carboxy methylcelluloses, and mixtures thereof.
Exemplary acrylic resins include polymers and copolymers of acrylic
acid, methacrylic acid, methyl acrylate, and methyl methacrylate.
Various combinations of hydrophilic compounds can be used for
various effects.
[0065] In some embodiments, the hydrophilic compound is preferably
a cellulose ether. Exemplary cellulose ethers include those
commercially available under the trade designation METHOCEL Premium
from Dow Chemical Co. Such methylcellulose and hypromellose (i.e.,
hydroxypropyl methylcellulose) products are a broad range of
water-soluble cellulose ethers that enable pharmaceutical
developers to create formulas for tablet coatings, granulation,
sustained release, extrusion, and molding. For certain embodiments,
the cellulose ether comprises a hydroxypropyl methylcellulose.
[0066] Varying the types of cellulose ethers can impact the release
rate. For example, varying the types of METHOCEL cellulose ethers,
which have different viscosities of 2% solutions in water (METHOCEL
K4M Premium hypromellose 2208 (19-24% methoxy content; 7-12%
hydroxypropyl content; 3,000-5,600 cps of a 2% solution in water);
METHOCEL K15M Premium hypromellose 2208 (19-24% methoxy content;
7-12% hydroxypropyl content; 11,250-21,000 cps of a 2% solution in
water); and METHOCEL K100M Premium hypromellose 2208 (19-24%
methoxy content; 7-12% hydroxypropyl content; 80,000-120,000 cps of
a 2% solution in water)) can help tailor release rates.
[0067] Compositions of the present invention can also include one
or more excipients such as lubricants, glidants, flavorants,
coloring agents, stabilizers, binders, fillers, disintegrants,
diluents, suspending agents, viscosity enhancers, wetting agents,
buffering agents, control release agents, crosslinking agents,
preservatives, and the like. Such compounds are well known in the
art of drug release and can be used in various combinations.
[0068] One particularly useful excipient that can form at least a
portion of a composition of the present invention is a binder that
includes, for example, a cellulose such as microcrystalline
cellulose. An exemplary microcrystalline cellulose is that
available under the trade designation AVICEL PH (e.g., AVICEL
PH-101, AVICEL PH-102, AVICEL PH-301, AVICEL PH-302, and AVICEL
RC-591) from FMC BioPolymers. The sustained-release composition
generally includes at least one microcrystalline cellulose in an
amount of 3 wt-% to 50 wt-%, based on the total weight of the
composition.
[0069] Other additives can be incorporated into compositions of the
present invention to further modify the rate and extent of release.
For example, a non-pharmacologically active amine, such as
tromethamine, triethanolamine, betaine, benzathine, or erbumine
could be included in the compositions of the present invention to
further modify the release rate.
[0070] Compositions of the present invention can optionally include
compounds that function as abuse deterrents. For example, opioid
antagonists (e.g., naltrexone, N-methylnaltrexone, naloxone) can be
combined with opioid agonists to deter parenteral abuse of opioid
agonists. Such opioid agonist/antagonist combinations can be chosen
such that the opioid agonist and opioid antagonist are only
extractable from the dosage form together, and at least a two-step
extraction process is required to separate the opioid antagonist
from the opioid agonist. The amount of opioid antagonist is
sufficient to counteract opioid effects if extracted together and
administered parenterally and/or the amount of antagonist is
sufficient to cause the opioid agonist/antagonist combination to
provide an aversive effect in a physically dependent human subject
when the dosage form is orally administered. Typically, such
compositions are formulated in such a way that if the dosage form
is not tampered with, the antagonist passes through the GI tract
intact; however, upon crushing, chewing, dissolving, etc., the
euphoria-curbing antagonist is released.
[0071] In a similar fashion, compounds that cause nausea could be
added to the formulation to prevent abusers from taking more than
the intended dose. These components are added to the formulation at
sub-therapeutic levels, such that no adverse effects are realized
when the correct dose is taken.
[0072] Also, compositions of the present invention can include an
aversive agent such as a dye (e.g., one that stains the mucous
membrane of the nose and/or mouth) that is released when the dosage
form is tampered with and provides a noticeable color or dye which
makes the act of abuse visible to the abuser and to others such
that the abuser is less likely to inhale, inject, and/or swallow
the tampered dosage form. Examples of various dyes that can be
employed as the aversive agent, including for example, and without
limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C
Yellow No. 6, FD&C Blue No. 1, FD&C Blue No. 2, FD&C
Green No. 1, FD&C Green No. 3, FD&C Green No. 5, FD&C
Red No. 30, D&C Orange No. 5, D&C Red No. 8, D&C Red
No. 33, caramel, and ferric oxide, red, other FD&C dyes and
lakes, and natural coloring agents such as grape skin extract, beet
red powder, beta-carotene, annato, carmine, turmeric, paprika, and
combinations thereof.
[0073] The sustained-release compositions of the present invention
may also include one or more hydrophobic polymers. The hydrophobic
polymers may be used in an amount sufficient to slow the hydration
of the hydrophilic compound without disrupting it. For example, the
hydrophobic polymer may be present in an amount of 0.5% to 20% by
weight, based on the total weight of the composition.
[0074] Exemplary hydrophobic polymers include alkyl celluloses
(e.g., C.sub.1-6 alkyl celluloses, carboxymethylcellulose,
ethylcellulose), other hydrophobic cellulosic materials or
compounds (e.g., cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers
(e.g., polyvinyl acetate phthalate), polymers or copolymers derived
from acrylic and/or methacrylic acid esters, zein, waxes (e.g.,
carnauba wax), shellac, hydrogenated vegetable oils, and
combinations thereof.
Pharmaceutical Compositions
[0075] Pharmaceutical compositions of the present invention are
single dosage forms that can be in a form capable of providing
sustained release of the opioid. Herein, a "single dosage form"
refers to the components of the composition be included within one
physical unit (e.g., one tablet), whether it be in a uniform
matrix, a multilayered construction, or some other configuration.
Most commonly, this includes a tablet, which can include molded
tablets, compressed tablets, or freeze-dried tablets. Other
possible solid forms include pills, pellets, particulate forms
(e.g., beads, powders, granules), and capsules (e.g., with
particulate therein).
[0076] A single dosage form can be a coated dosage form with, for
example, an outer layer of an immediate-release (IR) material
(e.g., an opioid, an NSAID, or both, a release-modifying agent, a
film coating for taste masking or for ease of swallowing, or the
like), with a sustained-release (SR) core. Typically, such coated
formulations do not demonstrate zero-order release kinetics during
the initial immediate-release phase, but preferably demonstrate
zero-order release kinetics during the dissolution of the
sustained-release core.
[0077] A single dosage form can be incorporated into a
multi-layered dosage form (e.g., tablet). For example, a bilayer
tablet could be formulated to include a layer of a conventional
immediate-release matrix and a layer of a sustained-release
composition of the present invention. Optionally, a multi-layered
dosage form could be coated.
[0078] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in a conventional manner to
incorporate one or more physiologically acceptable carriers
comprising excipients and auxiliaries. Compositions of the
invention may be formulated as tablets, pills, capsules, and the
like, for oral ingestion by a patient to be treated.
[0079] Pharmaceutical compositions of the present invention may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, granulating, encapsulating, entrapping, or
tabletting processes.
[0080] Pharmaceutical compositions suitable for use in the present
invention include compositions where the ingredients are contained
in an amount effective to achieve its intended purpose. The exact
formulation, route of administration, and dosage for the
pharmaceutical compositions of the present invention can be chosen
by the individual physician in view of the patient's condition.
(See, e.g., Fingl et al. in "The Pharmacological Basis of
Therapeutics", Ch. 1, p. 1 (1975)). The exact dosage will be
determined on a drug-by-drug basis, in most cases. Dosage amount
and interval may be adjusted individually to provide plasma levels
of the active ingredients/moieties that are sufficient to maintain
the modulating effects, or minimal effective concentration (MEC).
The MEC will vary for each compound but can be estimated from in
vitro data. Dosages necessary to achieve the MEC will depend on
individual characteristics and route of administration. However,
HPLC assays or bioassays can be used to determine plasma
concentrations. The amount of composition administered will, of
course, be dependent on the subject being treated, on the subject's
weight, the severity of the pain, the manner of administration, and
the judgment of the prescribing physician.
[0081] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert.
[0082] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present invention. Therefore, it should be
clearly understood that the forms of the present invention are
illustrative only and are not intended to limit the scope of the
present invention.
Exemplary Embodiments of the Invention
[0083] 1. A sustained-release oral pharmaceutical composition
comprising within a single dosage form: [0084] a hydrophilic
matrix; [0085] a therapeutically effective amount of an opioid
(including salts thereof); and [0086] a salt of a non-steroidal
anti-inflammatory drug (NSAID); [0087] wherein the opioid and the
salt of an NSAID are within the hydrophilic matrix; and [0088]
wherein the composition exhibits a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions. [0089] 2. A sustained-release
oral pharmaceutical composition comprising within a single dosage
form: [0090] a hydrophilic matrix; [0091] a therapeutically
effective amount of an opioid (including salts thereof); [0092] a
salt of a non-steroidal anti-inflammatory drug (NSAID); and [0093]
a pharmaceutically acceptable anionic surfactant; [0094] wherein
the opioid, the salt of an NSAID, and the anionic surfactant are
within the hydrophilic matrix. [0095] 3. The composition of
embodiment 2 which exhibits a release profile comprising a
substantial portion that is representative of zero-order release
kinetics under in vitro conditions. [0096] 4. The composition of
any one of embodiments 1 through 3 wherein the opioid has analgesic
properties. [0097] 5. The composition of any one of embodiments 1
through 4 wherein the opioid comprises a tertiary amine [0098] 6.
The composition of embodiment 5 wherein the opioid comprises a ring
nitrogen that is a tertiary amine [0099] 7. The composition of any
one of embodiments 1 through 6 wherein the opioid is selected from
the group consisting of morphine, codeine, hydromorphone,
hydrocodone, oxycodone, oxymorphone, desomorphine,
diacetylmorphine, buprenorphine, dihydrocodeine, nicomorphine,
benzylmorphine, fentanyl, methadone, tramadol, propoxyphene,
levorphanol, meperidine, and combinations thereof [0100] 8. The
composition of any one of embodiments 1 through 7 wherein the
opioid is a salt comprising a hydrochloride, a bitartrate, an
acetate, a naphthylate, a tosylate, a mesylate, a besylate, a
succinate, a palmitate, a stearate, an oleate, a pamoate, a
laurate, a valerate, a hydrobromide, a sulfate, a methane
sulfonate, a tartrate, a citrate, a maleate, or a combination of
the foregoing. [0101] 9. The composition of embodiment 7 or
embodiment 8 wherein the opioid is selected from the group
consisting of hydrocodone, tramadol, salts thereof, and
combinations thereof [0102] 10. The composition of embodiment 9
wherein the opioid is selected from the group consisting of
hydrocodone bitartrate, tramadol hydrochloride, and combinations
thereof [0103] 11. The composition of any one of embodiments 7
through 9 wherein the opioid is selected from the group consisting
of hydrocodone, a salt thereof, and combinations thereof [0104] 12.
The composition of embodiment 11 wherein the opioid comprises
hydrocodone bitartrate. [0105] 13. The composition of any one of
embodiments 7 through 9 wherein the opioid is selected from the
group consisting of tramadol, a salt thereof, and combinations
thereof [0106] 14. The composition of embodiment 13 wherein the
opioid comprises tramadol hydrochloride. [0107] 15. The composition
of any one of the preceding embodiments wherein the NSAID salt is
selected from the group consisting of a salicylate derivative, a
2-aryl propionic acid derivative, a pyrazolidine derivative, an
N-arylanthranilic acid derivative, an oxicam derivative, an
arylalkanoic acid, an indole derivative, and combinations thereof
[0108] 16. The composition of embodiment 15 wherein the NSAID salt
comprises a terminal carboxylic acid group or terminal carboxylate
group. [0109] 17. The composition of embodiment 16 wherein the
NSAID salt is selected from the group consisting of a salicylate
derivative, a 2-aryl propionic acid derivative, an
N-arylanthranilic acid derivative, an aryl alkanoic acid, an indole
derivative, and combinations thereof [0110] 18. The composition of
embodiment 17 wherein the NSAID salt is a 2-aryl propionic acid
derivative, an aryl alkanoic acid, or combinations thereof [0111]
19. The composition of embodiment 18 wherein the NSAID salt is
selected from the group consisting of a salt of naproxen,
diclofenac, ibuprofen, and combinations thereof [0112] 20. The
composition of embodiment 19 wherein the NSAID salt is selected
from the group consisting of naproxen sodium, diclofenac sodium,
ibuprofen sodium, and combinations thereof [0113] 21. The
composition of any one of embodiments 2 through 20, as they depend
on embodiment 2, wherein the pharmaceutically acceptable anionic
surfactant is selected from the group consisting of monovalent
alkyl carboxylates, acyl lactylates, alkyl ether carboxylates,
N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl
glutamates, fatty acid-polypeptide condensates, sulfur-containing
surfactants, phosphated ethoxylated alcohols, and combinations
thereof [0114] 22. The composition of embodiment 21 wherein the
pharmaceutically acceptable anionic surfactant is a
sulfur-containing surfactant. [0115] 23. The composition of
embodiment 22 wherein the sulfur-containing surfactant is selected
from the group consisting of an alkyl sulfate, an ester-linked
sulfonate, and combinations thereof [0116] 24. The composition of
embodiment 23 wherein the pharmaceutically acceptable anionic
surfactant is selected from the group consisting of sodium lauryl
sulfate, docusate sodium, docusate calcium, and combinations
thereof [0117] 25. The composition of embodiment 24 wherein the
pharmaceutically acceptable anionic surfactant is docusate sodium.
[0118] 26. The composition of any one of the preceding embodiments
wherein the opioid is present in a pain-reducing amount. [0119] 27.
The composition of any one of the preceding embodiments wherein the
NSAID salt is present in an amount effective to provide zero-order
release kinetics under in vitro conditions. [0120] 28. The
composition of any one of the preceding embodiments wherein the
pharmaceutically acceptable anionic surfactant is present in a
release-modifying amount. [0121] 29. The composition of any one of
the preceding embodiments wherein the single dosage form is a
tablet form. [0122] 30. The composition of embodiment 29 wherein
the single dosage form tablet comprises a unitary matrix. [0123]
31. The composition of embodiment 29 wherein the single dosage form
tablet comprises a multilayer tablet. [0124] 32. The composition of
embodiment 31 wherein the single dosage form comprises an outer
layer of an immediate-release (IR) material and a sustained-release
(SR) core. [0125] 33. The composition of embodiment 32 wherein the
IR material comprises an opioid, an NSAID, or both. [0126] 34. The
composition of any one of the previous embodiments wherein the
hydrophilic matrix comprises at least one hydrophilic polymeric
compound selected from the group consisting of a gum, a cellulose
ether, an acrylic resin, a polyvinyl pyrrolidone, a protein-derived
compound, and combinations thereof [0127] 35. The composition of
embodiment 34 wherein the hydrophilic polymeric compound comprises
a cellulose ether. [0128] 36. The composition of embodiment 35
wherein the cellulose ether comprises a hydroxyalkyl cellulose, a
carboxyalkyl cellulose, and combinations thereof [0129] 37. The
composition of embodiment 35 wherein the cellulose ether comprises
a methylcellulose, a hydroxypropyl methylcellulose, and
combinations thereof [0130] 38. The composition of embodiment 37
wherein the cellulose ether comprises a hydroxypropyl
methylcellulose. [0131] 39. The composition of any one of the
previous embodiments further including one or more excipients.
[0132] 40. The composition of embodiment 39 wherein the excipients
comprise lubricants, glidants, flavorants, coloring agents,
stabilizers, binders, fillers, disintegrants, diluents, suspending
agents, viscosity enhancers, wetting agents, buffering agents,
control release agents, crosslinking agents, preservatives, and
combinations thereof [0133] 41. The composition of embodiment 40
comprising a binder. [0134] 42. The composition of embodiment 41
wherein the binder comprises a microcrystalline cellulose. [0135]
43. A sustained-release oral pharmaceutical composition comprising
within a single dosage form: [0136] a hydrophilic matrix; [0137] a
therapeutically effective amount of an opioid selected from the
group consisting of hydrocodone, tramadol, salts thereof, and
combinations thereof; and [0138] a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, diclofenac, ibuprofen, and combinations
thereof; [0139] wherein the opioid and the salt of an NSAID are
within the hydrophilic matrix; and [0140] wherein the composition
exhibits a release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. [0141] 44. The composition of embodiment 43 wherein the
opioid is selected from the group consisting of hydrocodone, a salt
thereof, and combinations thereof [0142] 45. The composition of
embodiment 44 wherein the opioid comprises hydrocodone bitartrate.
[0143] 46. The composition of embodiment 43 wherein the opioid is
selected from the group consisting of tramadol, a salt thereof, and
combinations thereof [0144] 47. The composition of embodiment 46
wherein the opioid comprises tramadol hydrochloride. [0145] 48. The
composition of any one of embodiments 43 through 47 wherein the
NSAID salt is selected from the group consisting of naproxen
sodium, diclofenac sodium, ibuprofen sodium, and combinations
thereof [0146] 49. The composition of any one of embodiments 43
through 48 wherein the hydrophilic polymeric compound comprises a
cellulose ether. [0147] 50. The composition of embodiment 49
wherein the cellulose ether comprises a hydroxyalkyl cellulose, a
carboxyalkyl cellulose, and combinations thereof [0148] 51. The
composition of embodiment 50 wherein the cellulose ether comprises
a methylcellulose, a hydroxypropyl methylcellulose, and
combinations thereof [0149] 52. The composition of embodiment 51
wherein the cellulose ether comprises a hydroxypropyl
methylcellulose. [0150] 53. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: [0151] a
hydrophilic matrix comprising a hydroxypropyl methylcellulose;
[0152] a therapeutically effective amount of an opioid selected
from the group consisting of hydrocodone, a salt thereof, and
combinations thereof; and [0153] a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; [0154] wherein the
opioid and the salt of an NSAID are within the hydrophilic matrix;
and [0155] wherein the composition exhibits a release profile
comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions. [0156] 54. A
sustained-release oral pharmaceutical composition comprising within
a single dosage form: [0157] a hydrophilic matrix comprising a
hydroxypropyl methylcellulose; [0158] a therapeutically effective
amount of an opioid selected from the group consisting of tramadol,
a salt thereof, and combinations thereof; and [0159] a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, and combinations thereof;
[0160] wherein the opioid and the salt of an NSAID are within the
hydrophilic matrix; and [0161] wherein the composition exhibits a
release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. [0162] 55. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: [0163] a
hydrophilic matrix; [0164] a therapeutically effective amount of an
opioid selected from the group consisting of hydrocodone, tramadol,
salts thereof, and combinations thereof; [0165] a salt of a
non-steroidal anti-inflammatory drug (NSAID) selected from the
group consisting of a salt of naproxen, diclofenac, ibuprofen, and
combinations thereof; and [0166] a pharmaceutically acceptable
anionic surfactant selected from the group consisting of sodium
lauryl sulfate, docusate sodium, docusate calcium, and combinations
thereof; [0167] wherein the opioid, the salt of an NSAID, and the
anionic surfactant are within the hydrophilic matrix. [0168] 56.
The composition of embodiment 55 which exhibits a release profile
comprising a substantial portion that is representative of
zero-order release kinetics under in vitro conditions. [0169] 57.
The composition of embodiment 55 or embodiment 56 wherein the
opioid is selected from the group consisting of hydrocodone, a salt
thereof, and combinations thereof [0170] 58. The composition of
embodiment 57 wherein the opioid comprises hydrocodone bitartrate.
[0171] 59. The composition of embodiment 55 or embodiment 56
wherein the opioid is selected from the group consisting of
tramadol, a salt thereof, and combinations thereof [0172] 60. The
composition of embodiment 59 wherein the opioid comprises tramadol
hydrochloride. [0173] 61. The composition of any one of embodiments
55 through 60 wherein the pharmaceutically acceptable anionic
surfactant is docusate sodium. [0174] 62. The composition of any
one of embodiments 55 through 61 wherein the hydrophilic polymeric
compound comprises a cellulose ether. [0175] 63. The composition of
embodiment 62 wherein the cellulose ether comprises a hydroxyalkyl
cellulose, a carboxyalkyl cellulose, and combinations thereof
[0176] 64. The composition of embodiment 63 wherein the cellulose
ether comprises a methylcellulose, a hydroxypropyl methylcellulose,
and combinations thereof [0177] 65. The composition of embodiment
64 wherein the cellulose ether comprises a hydroxypropyl
methylcellulose. [0178] 66. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: [0179] a
hydrophilic matrix comprising a hydroxypropyl methylcellulose;
[0180] a therapeutically effective amount of an opioid selected
from the group consisting of hydrocodone, a salt thereof, and
combinations thereof; [0181] a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and [0182] a
pharmaceutically acceptable anionic surfactant selected from the
group consisting of docusate sodium, docusate calcium, and
combinations thereof; [0183] wherein the opioid, the salt of an
NSAID, and the anionic surfactant are within the hydrophilic
matrix. [0184] 67. A sustained-release oral pharmaceutical
composition comprising within a single dosage form: [0185] a
hydrophilic matrix comprising a hydroxypropyl methylcellulose;
[0186] a therapeutically effective amount of an opioid selected
from the group consisting of tramadol, a salt thereof, and
combinations thereof; [0187] a salt of a non-steroidal
anti-inflammatory drug (NSAID) selected from the group consisting
of a salt of naproxen, and combinations thereof; and
[0188] a pharmaceutically acceptable anionic surfactant selected
from the group consisting of docusate sodium, docusate calcium, and
combinations thereof; [0189] wherein the opioid, the salt of an
NSAID, and the anionic surfactant are within the hydrophilic
matrix. [0190] 68. The composition of embodiment 66 or embodiment
67 which exhibits a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions. [0191] 69. A method of preventing,
alleviating, or ameliorating the level of pain in a subject, the
method comprising administering to a subject a composition of any
one of embodiments 1 through 68. [0192] 70. A method of suppressing
cough in a subject, the method comprising administering to a
subject a composition of any one of embodiments 1 through 68.
[0193] 71. A method of preventing, alleviating, or ameliorating the
level of pain in a subject, the method administering to a subject a
composition comprising: [0194] a hydrophilic matrix; [0195] a
pain-reducing amount of an opioid analgesic (including salts
thereof); and [0196] a salt of a non-steroidal anti-inflammatory
drug (NSAID) present in an amount effective to provide zero-order
release kinetics under in vitro conditions; [0197] wherein the
opioid analgesic and the salt of an NSAID are within the
hydrophilic matrix; and [0198] wherein the composition has a
release profile comprising a substantial portion that is
representative of zero-order release kinetics under in vitro
conditions. [0199] 72. A method of preventing, alleviating, or
ameliorating the level of pain in a subject, the method
administering to a subject a composition comprising: [0200] a
hydrophilic matrix; [0201] a therapeutically effective amount of an
opioid analgesic (including salts thereof); [0202] a salt of a
non-steroidal anti-inflammatory drug (NSAID); and [0203] a
pharmaceutically acceptable anionic surfactant; [0204] wherein the
opioid analgesic, the salt of an NSAID, and the anionic surfactant
are within the hydrophilic matrix. [0205] 73. The method of
embodiment 72 which has a release profile comprising a substantial
portion that is representative of zero-order release kinetics under
in vitro conditions. [0206] 74. The method of any one of
embodiments 69 through 73 wherein administering the composition
comprises administering once or twice per day. [0207] 75. The
method of embodiment 74 wherein administering the composition
comprises administering once per day.
EXAMPLES
[0208] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
Example 1
Preparation of Sustained-Release Hydrophilic Matrix Tablets
Containing Tramadol Hydrochloride (TMD), Naproxen Sodium (NAP), and
Docusate Sodium (DSS) at Benchtop Scale
[0209] Each hydrophilic matrix tablet lot was produced by
dry-blending the active substance(s) and excipients together
followed by direct compression. The TMD and NAP (when present) were
added together with all excipients in an HDPE bag. Blending was
accomplished by manually mixing the contents of the bag for five
minutes. Aliquots of the blend were massed out using an analytical
balance and were compressed using a Manesty DC16 press. Each tablet
aliquot was added to the die manually and compressed at a speed of
5 rpm. Lots without NAP were compressed using 0.3125-inch round,
concave Natoli tooling (HOB No. 91300), while lots containing NAP
were compressed using 0.3750-inch round, concave Natoli tooling
(HOB No. 91380). The compression force was varied until a tablet
breaking force of 14-16 kPa was consistently achieved.
TABLE-US-00001 TABLE 1 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Tramadol Granular Hydrochloride
Docusate (Spectrum Methocel Naproxen Sodium Total Chemical K4M
Avicel PH- Sodium (Cytec Tablet Manufacturing (Dow 302 (FMC
(Albemarle Industries, Mass Lot No. Corp. Chemical) Biopolymer)
Corp.) Inc.) (mg) Prototype 1 15.0 120.0 45.0 180.0 Prototype 2
15.0 120.0 45.0 17.6 197.6 Prototype 3 15.0 120.0 45.0 117.7 297.7
Prototype 4 15.0 120.0 45.0 220.0 400.0 Prototype 5 15.0 120.0 45.0
220.0 8.8 408.8 Prototype 6 15.0 120.0 45.0 220.0 17.6 417.6
Prototype 7 15.0 120.0 45.0 220.0 29.4 429.4 Prototype 8 15.0 120.0
45.0 220.0 117.7 517.7
[0210] USP Apparatus 2 was used for the dissolution testing of the
prototype tablets produced. The dissolution samples were assayed
for TMD using HPLC with UV detection at 280 nm. The system
parameters for both the chromatographic and dissolution analysis
are shown below. [0211] System: Hewlett Packard 1100 Series HPLC
System [0212] Column: Phenomenex Jupiter C18, 250.times.4.6 mm ID,
5.mu., 300 .ANG. Part No.: 00G-4053-EO [0213] Detector: UV
detector, 280 nm [0214] Mobile Phase A: 94.7/5.0/0.3 (v/v/v)
water/methanol/TFA [0215] Mobile Phase B: Pure methanol [0216]
Method Type: Gradient [0217] Flow Rate: 1.5 mL/min [0218] Injection
Volume: 30 .mu.L [0219] Run Time: 8.00 minutes (8.01-10.00 minutes
is reequilibration) [0220] Peakwidth: >0.1 min [0221] Column
Temp.: 35.degree. C. [0222] Autosampler Temp.: Ambient
TABLE-US-00002 [0222] TABLE 2 Gradient profile for HPLC mobile
phases A and B Initial 60% A 40% B 8.00 10% A 90% B 8.01 60% A 40%
B 10.00 60% A 40% B
TABLE-US-00003 TABLE 3 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 7.5 phosphate buffer (0.05M,
potassium phosphate monobasic 0.68%/NaOH 0.164%) Media Volume 900
mL Media Temperature 37.0 .+-. 0.5.degree. C. Sampling Time Points
1, 3, 6, 9 and 12 hours Sampling Volume 10 mL without media
replacement (Use 10 .mu.m Full-flow Filter)
[0223] FIG. 1 illustrates zero-order release kinetics over 12 hours
for TMD from the hydrophilic matrix containing naproxen sodium with
and without docusate sodium. Prototype 4 contains no DSS,
indicating that the surfactant is not critical to achieving linear
release kinetics. Prototypes 5-8 reveal that the addition of
surfactant into the hydrophilic matrix does impact the rate and
extent of release, with higher DSS levels showing a slower release
rate and a lower extent of release at 12 hours. Regardless of DSS
level, all dissolution profiles in the presence of naproxen sodium
are zero-order.
[0224] To further illustrate the importance of naproxen sodium and
DSS to the release kinetics of TMD from the hydrophilic matrix,
FIG. 2 shows dissolution profiles for several formulations in which
key components have been added or removed. Prototype 1 shows the
release of TMD from the hydrophilic matrix in the absence of
naproxen sodium and DSS. This formulation shows the largest extent
of release, however, the release profile is non-linear, indicating
that zero-order release is not achieved. Prototypes 2 and 3 show
the release profile of TMD at increasing levels of DSS (15 and 100
mg, respectively), revealing that surfactant level can also be used
to control the rate and extent of TMD release when the NSAID salt
is absent from the hydrophilic matrix. Prototypes 6 and 8 show TMD
release profiles at the same two DSS concentrations (15 and 100 mg,
respectively) in the presence of naproxen sodium. Here, the
addition of the NSAID salt to the matrix increases the rate and
extent of TMD release, while also causing the release rate to
become zero-order.
Example 2
Preparation of Sustained-Release Hydrophilic Matrix Tablets
Containing Hydrocodone Bitartrate (HCB), Naproxen Sodium (NAP), and
Docusate Sodium (DSS) at Benchtop Scale
[0225] Each hydrophilic matrix tablet lot was produced by
dry-blending the active substance(s) and excipients together
followed by direct compression. The blending process involved two
steps. The HCB and NAP (when present) were blended together with
all excipients except the Methocel K4M Premium which was later
added and blended during the second step. Blending was accomplished
by first dispensing the powdered components into a stainless steel
pan. The components were then mixed together using a stainless
steel spatula to affect homogenization of the blend. After
approximately 2-3 minutes of mixing, the powders were transferred
to a stainless steel 40 mesh screen where they were pushed through
using a plastic sieve scraper. The pass through was collected in a
separate stainless steel pan. The mixing and sieving processes were
then repeated. Each blending step required two mixing and two
sieving processes. After the final step, the dry blend was
transferred to a HDPE bag. Aliquots of the blend were massed out
using an analytical balance and were compressed using a GlobePharma
MTCM-1 hand tablet press. Lots without NAP were compressed using
0.3125-inch round, concave Natoli tooling (HOB No. 91300), while
lots containing NAP were compressed using 0.3750-inch round,
concave Natoli tooling (HOB No. 91380). The compression force was
varied until a tablet breaking force of 14-16 kPa was consistently
achieved.
TABLE-US-00004 TABLE 4 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Granular Docusate Methocel
Naproxen Sodium Total Hydrocodone K4M Avicel PH- Sodium (Cytec
Tablet Bitartrate (Dow 302 (FMC (Albemarle Industries, Mass Lot No.
(Mallinckrodt) Chemical) Biopolymer) Corp.) Inc.) (mg) Prototype 1
15.0 120.0 45.0 180.0 Prototype 2 15.0 120.0 45.0 17.6 197.6
Prototype 3 15.0 120.0 45.0 117.7 297.7 Prototype 4 15.0 120.0 45.0
220.0 400.0 Prototype 5 15.0 120.0 45.0 220.0 8.8 408.8 Prototype 6
15.0 120.0 45.0 220.0 17.6 417.6 Prototype 7 15.0 120.0 45.0 220.0
29.4 429.4 Prototype 8 15.0 120.0 45.0 220.0 117.7 517.7
[0226] USP Apparatus 2 was used for the dissolution testing of the
prototype tablets produced. The dissolution samples were assayed
for HCB using HPLC with UV detection at 280 nm. The system
parameters for both the chromatographic and dissolution analysis
are shown below. [0227] System: Waters Alliance 2487 HPLC System
[0228] Column: Phenomenex Jupiter C18, 250.times.4.6 mm ID, 5.mu.,
300 .ANG. Part No.: 00G-4053-EO [0229] Detector: UV detector, 280
nm [0230] Mobile Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA
[0231] Mobile Phase B: Pure methanol [0232] Method Type: Gradient
[0233] Flow Rate: 1.5 mL/min [0234] Injection Volume: 30 .mu.L
[0235] Run Time: 11 minutes (11.01-13.00 minutes is
reequilibration) [0236] Peakwidth: >0.1 min [0237] Column Temp.:
35.degree. C. [0238] Autosampler Temp.: Ambient
TABLE-US-00005 [0238] TABLE 5 Gradient profile for HPLC mobile
phases A and B Initial 90% A 10% B 10.00 10% A 90% B 11.00 10% A
90% B 11.01 90% A 10% B 13.00 90% A 10% B
TABLE-US-00006 TABLE 6 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 7.5 phosphate buffer (0.05M,
potassium phosphate monobasic 0.68%/NaOH 0.164%) Media Volume 900
mL Media Temperature 37.0 .+-. 0.5 C. Sampling Time Points 1, 3, 6,
9 and 12 hours Sampling Volume 3 mL without media replacement (Use
10 .mu.m Full-flow Filter)
[0239] FIG. 3 illustrates zero-order release kinetics over 12 hours
for HCB from the hydrophilic matrix containing naproxen sodium with
and without docusate sodium. Prototype 4 contains no DSS,
indicating that the surfactant is not critical to achieving linear
release kinetics. Prototypes 5-8 reveal that the addition of
surfactant into the hydrophilic matrix does impact the rate and
extent of release, however, the rate and extent of release do not
trend with surfactant level (as was observed for the TMD examples).
The HCB tablets were compressed using a single-station press,
making it difficult to control the dwell time. As a result, large
variations in tablet hardness were observed (10-18 kP) for
identical compression forces. It is hypothesized that this
variation in tablet hardness could impact water uptake and swelling
rates, resulting in the hysteresis observed in FIG. 3. Regardless
of DSS level, all dissolution profiles in the presence of naproxen
sodium are zero-order.
[0240] To further illustrate the importance of naproxen sodium and
DSS to the release kinetics of HCB from the hydrophilic matrix,
FIG. 4 shows dissolution profiles for several formulations in which
key components have been added or removed. Prototype 1 shows the
release of HCB from the hydrophilic matrix in the absence of
naproxen sodium and DSS. This formulation shows the largest extent
of release, however, the release profile is non-linear, indicating
that zero-order release is not achieved. Prototypes 2 and 3 show
the release profile of HCB at increasing levels of DSS (15 and 100
mg, respectively), revealing that surfactant level can also be used
to control the rate and extent of HCB release when the NSAID salt
is absent from the hydrophilic matrix. Prototypes 6 and 8 show HCB
release profiles at the same two DSS concentrations (15 and 100 mg,
respectively) in the presence of naproxen sodium. Here, the
addition of the NSAID salt to the matrix increases the rate and
extent of HCB release, while also causing the release rate to
become zero-order.
Example 3
Demonstration of the Abuse-Deterrent Features of Prototype
Formulations Containing Dextromethorphan Hydrobromide (DXM),
Naproxen Sodium (NAP) and Docusate Sodium (DSS)
Dose-Dumping
[0241] The abuse-deterrent characteristics of matrix tablets
containing dextromethorphan hydrobromide (DXM) (used herein as an
opioid surrogate), naproxen sodium (NAP), and docusate sodium (DSS)
was demonstrated by performing hydroalcoholic in vitro dissolution
and an independent small-volume extraction experiment.
[0242] DXM was chosen as an opioid surrogate due to its chemical,
physical, and structural similarities to the opioid analgesics
useful in the practice of the present invention.
##STR00013##
[0243] NAP and DSS were selected because these two compounds
represent a suitable NSAID salt and anionic surfactant,
respectively, in the practice of the present invention.
[0244] The hydroalcoholic "dose dumping" experiment investigates
the in vitro opioid (or opioid surrogate) release behavior in the
presence of alcohol. The experiment models ingestion of a tablet
with the concomitant use of alcoholic beverages (i.e.,
ethanol).
[0245] Each hydrophilic matrix tablet lot was produced by
dry-blending the active substance(s) and excipients together
followed by direct compression. The DXM and NAP were added together
with all excipients in an HDPE bag. Blending was accomplished by
manually mixing the contents of the bag for five minutes. Aliquots
of the blend were massed out using an analytical balance and were
compressed using a Manesty DC16 press. Each tablet aliquot was
added to the die manually and compressed at a speed of 5 rpm.
Prototypes 1, 2, and 3 were compressed using 0.3750 in. round,
concave Natoli tooling (HOB #91380). The compression force was
varied until a tablet breaking force of 14-16 kPa was consistently
achieved.
TABLE-US-00007 TABLE 7 Prototype formulation compositions
(mg/tablet) Formulation (mg/tablet) Granular Dextrome- Docusate
thorphan Methocel Naproxen Sodium Total Hydrobromide K4M Avicel PH-
Sodium (Cytec Tablet (Wockhardt (Dow 302 (FMC (Albemarle
Industries, Mass Lot No. Limited) Chemical) Biopolymer) Corp.)
Inc.) (mg) Prototype 1 15.0 120.0 45.0 220.0 17.6 417.6 Prototype 2
15.0 120.0 45.0 220.0 29.4 429.4 Prototype 3 15.0 120.0 45.0 220.0
58.8 458.8
[0246] In order to assess the potential for "dose dumping," the
dissolution method was modified by changing the media to 0.1N HCl
with varying levels of alcohol (ethanol). USP Apparatus 2 was used
for the dissolution testing of the prototype tablets. The
dissolution samples were assayed for DXM using HPLC with UV
detection at 280 nm. The system parameters for both the
chromatographic and dissolution analysis are shown below. [0247]
System: Agilent 1100 series HPLC system [0248] Column: Phenomenex
Jupiter C18, 250.times.4.6 mm ID, 5.mu., 300 .ANG. Part No.:
00G-4053-EO [0249] Detector: UV detector, 280 nm [0250] Mobile
Phase A: 94.7/5.0/0.3 (v/v/v) water/methanol/TFA [0251] Mobile
Phase B: Pure methanol [0252] Method Type: Gradient [0253] Flow
Rate: 1.5 mL/min [0254] Injection Volume: 30 .mu.L [0255] Run Time:
8.00 minutes (8.01-10.00 minutes is reequilibration) [0256]
Peakwidth: >0.1 min [0257] Column Temperature: 35.degree. C.
[0258] Autosampler temp: Ambient
TABLE-US-00008 [0258] TABLE 8 Gradient profile for HPLC mobile
phases A and B Initial 60% A 40% B 8.00 10% A 90% B 8.01 60% A 40%
B 10.00 60% A 40% B
TABLE-US-00009 TABLE 9 Dissolution parameters Parameters
Requirements Method Type USP Apparatus 2 (Paddle Method) Rotation
Speed 50 rpm Dissolution Media pH 1.2 USP buffer pH 1.2 USP buffer
(5% ethanol) pH 1.2 USP buffer (20% ethanol) Media Volume 900 mL
Media Temperature 37.0 .+-. 0.5 C. Sampling Time Points 1, 3, 6, 9
and 12 hours Sampling Volume 8 mL without media replacement (Use 10
.mu.m Full-flow Filter)
[0259] The purpose of this investigation was to measure the
integrity of the dosage formulation using acidic, hydroalcoholic
dissolution media. For this experiment, intact tablets were
evaluated. Prototype 1 was evaluated since this formulation is
expected to show significantly greater DXM release over 12 hours
compared to Prototypes 2 and 3 based on evaluation of previous
formulations of similar composition.
[0260] Dissolution profiles are provided in FIG. 5. The results
demonstrate that "dose dumping" does not occur, even with a 20%
ethanol level in the dissolution media. In addition, zero-order
release is maintained from 0-20% ethanol.
Opioid Extraction
[0261] The small-volume extraction experiment models the attempted
extraction of opioid that a substance abuser might undertake. In
this experiment, tablets were crushed and extracted with two common
solvents, water and 40% alcohol. A single tablet was crushed and
stirred with a small volume of solvent (50 mL). At time points of
30 minutes and 12 hours, aliquots were removed and assayed for both
DXM and docusate. Prior to HPLC analysis the aliquots were filtered
using a 10 .mu.m full-flow filter and subsequently centrifuged at
1000 rpm for 30 minutes. The supernatant from this procedure was
filled directly into HPLC vials for analysis. The HPLC assay for
DXM has been described previously. The following HPLC method was
developed to assay docusate: [0262] System: Agilent 1100 series
HPLC system [0263] Column: YMC-Pack CN, 250 mm.times.4.6 mm ID, 5
.mu.m, 120 .ANG. Part number: CN12S052546WT [0264] Detector: UV
detector, 225 nm [0265] Mobile Phase A: 0.02M tetrabutylammonium
hydrogen sulfate [0266] Mobile Phase B: Pure acetonitrile [0267]
Method Type: Isocratic 40% A/60% B [0268] Flow Rate: 1.5 mL/min
[0269] Injection Volume: 10 .mu.L [0270] Run Time: 5 minutes [0271]
Peakwidth: >0.1 min [0272] Column Temperature: 45.degree. C.
[0273] Autosampler temp: Ambient
TABLE-US-00010 [0273] TABLE 10 Simultaneous Release of
Dextromethorphan Hydrobromide and Docusate Sodium From Crushed
Tablets to Assess Abuse Potential DXM Docusate DXM Docusate
Released Released Released Released Extraction in 30 in 30 in in
Formulation Solvent minutes minutes 12 hours 12 hours Prototype 1
Water 58% 80% 47% 61% Prototype 1 Alcohol 93% 91% 100% 98% 40%
Prototype 2 Water 35% 47% 35% 47% Prototype 2 Alcohol 95% 93% 114%
108% 40% Prototype 3 Water 52% 48% 50% 43% Prototype 3 Alcohol 68%
67% 102% 95% 40%
[0274] The data (Table 10) demonstrates the simultaneous release of
DXM and docusate from formulations containing different levels of
docusate (Table 7). This data shows that extraction and separation
of DXM and docusate from these formulations would require advanced
chemical knowledge and substantial effort, and would likely be
time-consuming. The commingling of DXM and docusate would make
injection of extracted solutions unattractive to an abuser, and
potentially harmful. Additionally, drying the solution to create a
solid would be of no benefit to a drug abuser, as the solid would
be impure and contain irritating docusate. It is expected that
similar results would be obtained for formulations according to the
present invention that comprise an opioid analgesic.
[0275] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. Various
modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention. It should be understood that
this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein.
* * * * *
References