U.S. patent application number 11/152642 was filed with the patent office on 2006-12-14 for two-component pharmaceutical composition for the treatment of pain.
This patent application is currently assigned to Applied Pharmacy Services, Inc.. Invention is credited to Alton Samuel II Kelly, James Gregory Sullivan.
Application Number | 20060281775 11/152642 |
Document ID | / |
Family ID | 37524878 |
Filed Date | 2006-12-14 |
United States Patent
Application |
20060281775 |
Kind Code |
A1 |
Kelly; Alton Samuel II ; et
al. |
December 14, 2006 |
Two-component pharmaceutical composition for the treatment of
pain
Abstract
The present invention is directed to a pharmaceutical
composition that includes a combination of about 2-5 milligrams of
a non-steroidal anti-inflammatory drug and from about 2-30
milligrams of an opioid analgesic in a single pharmaceutical dosage
unit that can provide effective pain management with the added
benefit of reduced side effects such as withdrawal and
gastrointestinal disorders. The non-steroidal anti-inflammatory
drug may be piroxicam and the opioid analgesic may be
buprenorphine. The present invention also provides for a method of
managing pain in a patient that includes administering the
pharmaceutical composition previously described. The pharmaceutical
composition previously described may be administered in a single or
multiple dosage regimen.
Inventors: |
Kelly; Alton Samuel II;
(Mobile, AL) ; Sullivan; James Gregory;
(Birmingham, AL) |
Correspondence
Address: |
FAEGRE & BENSON LLP;PATENT DOCKETING
2200 WELLS FARGO CENTER
90 SOUTH SEVENTH STREET
MINNEAPOLIS
MN
55402
US
|
Assignee: |
Applied Pharmacy Services,
Inc.
Montgomery
AL
|
Family ID: |
37524878 |
Appl. No.: |
11/152642 |
Filed: |
June 14, 2005 |
Current U.S.
Class: |
514/282 ;
514/569; 514/570 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/5415 20130101; A61K 31/485 20130101; A61P 29/00 20180101;
A61K 31/192 20130101; A61K 31/485 20130101 |
Class at
Publication: |
514/282 ;
514/569; 514/570 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 31/192 20060101 A61K031/192 |
Claims
1. A pharmaceutical dosage unit comprising about 2-5 milligrams of
a non-steroidal anti-inflammatory drug and about 2-30 milligrams of
an opioid analgesic.
2. The pharmaceutical dosage unit of claim 1, wherein the
non-steroidal anti-inflammatory drug is present in an amount of
about 2-3 milligrams.
3. The pharmaceutical dosage unit of claim 1, wherein the
non-steroidal anti-inflammatory drug is present in an amount of
about 2 milligrams.
4. The pharmaceutical dosage unit of claim 1, wherein the
non-steroidal anti-inflammatory drug is piroxicam.
5. The pharmaceutical dosage unit of claim 1, wherein the opioid
analgesic is present in an amount of about 2-15 milligrams.
6. The pharmaceutical dosage unit of claim 1, wherein the opioid
analgesic is present in an amount of about 2 milligrams.
7. The pharmaceutical dosage unit of claim 1, wherein the opioid
analgesic is buprenorphine.
8. The pharmaceutical dosage unit of claim 1, wherein the
pharmaceutical dosage unit is delivered by sublingual, mucosal,
parenteral, intravenous, intramuscular, transdermal administration
and combinations thereof.
9. The pharmaceutical dosage unit of claim 1, wherein the dosage
unit manages pain with reduced side effects.
10. The pharmaceutical dosage unit of claim 9, wherein the side
effect is gastrointestinal ulceration, abdominal pain, cramping,
nausea, gastritis, kidney disease, angiodema, pancreatitis,
gastrointestinal bleeding, liver toxicity, or combinations
thereof.
11. The pharmaceutical dosage unit of claim 9, wherein the side
effect is opioid withdrawal.
12. A pharmaceutical combination dosage unit comprising a low
effective amount of piroxicam and a high effective amount of
buprenorphine for management of pain with reduced side effects.
13. The pharmaceutical combination dosage unit of claim 12, wherein
the side effect is gastrointestinal ulceration, abdominal pain,
cramping, nausea, gastritis, kidney disease, angiodema,
pancreatitis, gastrointestinal bleeding, liver toxicity, or
combinations thereof.
14. The pharmaceutical combination dosage unit of claim 12, wherein
the pharmaceutical combination dosage unit is delivered by
sublingual, mucosal, parenteral, intravenous, intramuscular,
transdermal administration and combinations thereof.
15. A method of treating pain in a patient comprising
administering, in a single or multiple dosage regimen, a
pharmaceutical dosage unit, the dosage unit including about 2-5
milligrams of piroxicam in combination with about 2-30 milligrams
of buprenorphine.
16. The method of claim 15, piroxicam is present in an amount of
about 2-3 milligrams and buprenorphine is present in an amount of
about 2-15 milligrams.
17. The method of claim 15, wherein piroxicam is present in an
amount of about 2.5 milligrams and buprenorphine is present in an
amount of about 2 milligrams.
18. The method of claim 15, wherein the pharmaceutical dosage unit
is delivered by sublingual, mucosal, parenteral, intravenous,
intramuscular, transdermal administration and combinations
thereof.
19. The method of claim 15, wherein the pharmaceutical dosage unit
manages pain with reduced side effects.
20. The method of claim 19, wherein the side effect is
gastrointestinal ulceration, abdominal pain, cramping, nausea,
gastritis, kidney disease, angiodema, pancreatitis,
gastrointestinal bleeding, liver toxicity, or combinations thereof.
Description
[0001] The invention relates generally to a pharmaceutical dosage
unit having a therapeutically effective amount of a non-steroidal
anti-inflammatory drug in combination with a therapeutically
effective amount of an opioid analgesic that can be used for the
treatment of pain with reduced side effects such as opioid
withdrawal and gastrointestinal irritation and damage. More
particularly, the pharmaceutical dosage unit includes piroxicam in
combination with buprenorphine for sublingual administration.
BACKGROUND OF THE INVENTION
[0002] Pain is prevalent. It is estimated that more than 50 million
Americans live with chronic pain caused by various diseases or
disorders, and each year nearly 25 million people suffer with acute
pain as a result of injury or surgery. Furthermore, chronic pain
has been said to be the most costly health problem in America.
Estimated annual costs, including direct medical expenses, lost
income, lost productivity, compensation payments, and legal charges
are currently about $90 billion. And the numbers are rising.
Estimates indicate that by 2030, 148 million people will have
chronic conditions, and associated annual direct costs will rise to
$798 billion. Thus, pain management has been identified as one of
the most difficult challenges for the health care industry.
[0003] Non-steroidal anti-inflammatory drug NSAIDs (also referred
to as non-narcotic analgesics) are administered for the treatment
of mild to severe pain and in some instances are prescribed for
continuous use in the treatment of acute or chronic inflammatory
states such as rheumatoid arthritis and osteoarthritis. NSAIDs are
well absorbed following oral administration but there is a high
potential for adverse side-effects such as ulcerations, abdominal
pain, cramping, nausea, gastritis, kidney disease, angiodema,
pancreatitis, and even serious gastrointestinal bleeding and liver
toxicity at the upper limits of their effective dose ranges. Thus,
the ability to use higher dosages of NSAIDs is generally limited.
Moreover, above each NSAIDs' upper limit or ceiling, administration
of additional NSAID or use of combinations of NSAIDs does not
usually increase the analgesic or anti-inflammatory effect.
[0004] Opioid analgesics (also referred to as narcotic analgesics)
such as buprenorphine are often used when pain control with NSAIDs
is ineffective. While narcotic analgesics vary considerably in
their chemical structures and pharmacological properties, almost
all suffer the disadvantages of tolerance and possible addiction
with continued usage.
[0005] Narcotic analgesics are classified generally as narcotic
agonists or narcotic antagonists. Drugs that activate receptors in
the brain are termed agonists. Hence, a drug that activates an
opioid receptor is termed an opioid agonist. The repeated
administration of opioid agonists results in dose-dependent
physical dependence and tolerance. Physical dependence manifests as
a characteristic set of withdrawal signs and symptoms upon
reduction, cessation, or loss of an active compound at an opioid
receptor. These withdrawal signs and symptoms can include sweating,
cramps, aches, lacrimation, diarrhea, rhinorrhea, piloerection, and
pupillary dilation. A drug that binds to a receptor in the brain to
block the receptor rather than activate it is termed an antagonist.
Examples of opioid antagonists are naltrexone and naloxone. Partial
agonists are drugs that activate receptors in the brain but not to
the extent as full agonists. Buprenorphine is an example of a
partial agonist (also referred to as a partial opioid agonist or
opioid analgesic). It is the partial agonist properties of
buprenorphine that contribute to its effectiveness in pain
management and provide the added benefit of reduced dependence on
and/or addiction to opioids. Consistent with its agonist action at
opioid receptors, however, partial agonists such as buprenorphine
are still abusable, particularly by individuals who are not already
physically dependents on opioids.
[0006] Although NSAIDs and opioid analgesics are individually
limited in their ability to effectively manage pain without
inducing adverse side effects such as gastrointestinal disorders,
dependence and/or addiction to, and withdrawal upon cessation or
reduction, it has now been found that a pharmaceutical composition
for sublingual administration having relatively low effective
amounts of a NSAID such as piroxicam in combination with relatively
high effective amounts of an opioid analgesic such as buprenorphine
improves upon existing pain medications and provides the additional
benefit of reduced side effects.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a pharmaceutical
composition that includes a combination of a non-steroidal
anti-inflammatory drug such as piroxicam and an opioid analgesic
such as buprenorphine in a pharmaceutical dosage unit that provides
safe and effective pain management with the added benefit that side
effects such as gastrointestinal tract damage and withdrawal as a
result of physical dependence and/or addiction are reduced. In one
embodiment, the invention is a pharmaceutical combination of a low
effective amount of piroxicam and a high effective amount of
buprenorphine. In another embodiment, the pharmaceutical
composition is a combination of about 2-5 milligrams of a
non-steroidal anti-inflammatory drug such as piroxicam and about
2-30 milligrams of an opioid analgesic such as buprenorphine for
sublingual administration.
[0008] The present invention also provides for a method of managing
pain with reduced side effects in a patient that includes
administering to the patient, in a single or multiple dosage
regime, the pharmaceutical composition previously described.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
[0009] The present invention is a pharmaceutical composition for
managing pain that includes a combination of a non-steroidal
anti-inflammatory drug ("NSAID") and an opioid analgesic in a
single pharmaceutical dosage unit. As used herein, pain management
includes the pain treatment and pain control. The present invention
offers advantages over existing pain management compositions that
include opioid analgesics and NSAIDs by providing safe and
effective pain management with a reduction in side effects such as
gastrointestinal tract damage and withdrawal as a result of
physical dependence on and/or addiction to the opioid analgesic. In
one embodiment of the present invention, the pharmaceutical
composition is a combination of a NSAID such as piroxicam and an
opioid analgesic such as buprenorphine in a single pharmaceutical
dosage unit. In one embodiment, the pharmaceutical dosage unit may
be administered sublingually.
[0010] NSAIDs vary widely in their chemical structure and in their
biological profiles as analgesics, anti-inflammatory agents and
anti-pyretic agents. Aspirin, acetaminophen and phenacetin have
long been among the most commonly used NSAIDs. Other examples of
NSAIDs for use in the present invention include ibuprofen,
diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,
flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,
pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,
tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,
tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,
clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic
acid, niflumic acid tolfenamic acid, diflunisal, flufenisal,
piroxicam, meloxicam, sudoxicam or isoxicam, and mixtures thereof.
Among the newer NSAID compounds are diflunisal (DOLOBID), ibuprofen
(BRUFEN), naproxen (NAPROSYN), fenoprofen (FENOPRON), piroxicam
(FELDENE), flurbiprofen, mefenamic acid (PONSTAN) and sulindac
(CLINORIL). In one embodiment of the present invention, the NSAID
is indomethacin, meloxican, ketoprofen, piroxicam, or combinations
thereof. In a particular embodiment of the present invention the
NSAID is piroxicam.
[0011] Piroxicam is
4-hydroxyl-2-methyl-N-2-pyridinal-2H-1,2-benzothiazine-3-carboximide
1,1-dioxide. Piroxicam occurs as a white crystalline solid that is
soluble in alcohol and aqueous solutions and sparingly soluble in
water, dilute acid and most organic solvents. Piroxicam exhibits a
weakly acidic 4-hydroxy proton (pKa 5.1) and weakly basic pyridyl
nitrogen (pKa 1.8). Piroxicam is available commercially as FELDENE
in 10 mg and 20 mg capsules from Pfizer Inc., distributed by Pfizer
Labs, New York, N.Y. Piroxicam has the molecular formula
C.sub.15H.sub.13N.sub.3O.sub.4S and the following structural
formula: ##STR1##
[0012] NSAIDs such as piroxicam generally possess
anti-inflammatory, antipyretic and analgesic activities. The exact
mechanism of action of NSAIDs and the relationship between chemical
structure and analgesic, anti-inflammatory and anti-pyretic effect
are not yet fully understood, but these properties may be mediated
through the inhibition of prostaglandin synthesis. More
specifically, NSAID compounds have been shown to be inhibitors of
either or both of cyclooxygenase I (COX I) or cyclooxygenase II
(COX II), which are involved in the synthesis of prostaglandins.
Induction of the synthesis of COX II is associated with
inflammatory processes and inhibition of COX II may result in the
antipyretic and anti-inflammatory properties of NSAID compounds.
Inhibition of constitutively-synthesized COX I may be associated
with undesirable side effects such as gastric ulcers. Accordingly,
selective inhibition of COX II rather than COX I may offer a
therapeutic advantage.
[0013] While piroxicam is available for oral administration as
FELDENE in 10 mg or 20 mg dosage units and is typically
administered in amounts of 20 mg daily, the present invention is
directed to relatively lower amounts (low effective amount) of
NSAIDs such as piroxicam compared to the dosage amounts typically
administered for pain management. Thus, as used herein, relatively
low amount includes dosage amounts at about or below 5 mg. In one
embodiment of the present invention, the NSAID is present in an
amount of about 2-5 mg. In another embodiment, the NSAID is present
in an amount of about 2-3 mg. In yet another embodiment of the
present invention, the NSAID is present in an amount of about 2.5
mg. In still another embodiment, the NSAID is present in an amount
of about 2 mg. Additionally, the NSAID of the present invention may
be administered sublingually for absorption through mucous
membranes in mouth. The low effective amount and sublingual
administration of the NSAID may decrease the risk of side effects
such as gastrointestinal disorders. In one embodiment, the side
effects are gastrointestinal ulceration, abdominal pain, cramping,
nausea, gastritis, kidney disease, angiodema, pancreatitis,
gastrointestinal bleeding, liver toxicity, or combinations
thereof.
[0014] Opioid analgesics also vary widely in their chemical
structure and in their biological profiles. Presently known opioid
analgesics include alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacyl morphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts thereof and
mixtures thereof. In a particular embodiment of the present
invention the opioid analgesic is buprenorphine.
[0015] Buprenorphine, a thebaine derivative that is legally
classified as a narcotic, is
17-(cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydr-
o-3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorphian-7-methanol.
Buprenorphine generally occurs as a white powder that is weakly
acidic with limited solubility in water. Buprenorphine HCl has the
molecular formula C.sub.29H.sub.41NO.sub.4 HCl and the following
structural formula: ##STR2##
[0016] Buprenorphine is available commercially for parenteral
administration under the name BUPRENEX (buprenorphine
hydrochloride) from Reckitt Benckiser, Richmond, Va., and
generically as buprenorphine from Abbott Laboratories.
Buprenorphine is also available in sublingual tablets SUBUTEX
(buprenorphine HCl) and SUBOXONE (buprenorphine HCl/naloxone HCl
dihydrate) both available from Reckitt Benckiser.
[0017] Buprenorphine has poor oral and/or gastrointestinal
bioavailability thus buprenorphine is usually given by injection,
via a sublingual tablet, or as a transdermal patch. Abuse of
buprenorphine has been reported to occur via the sublingual and
intranasal routes but primarily via diversion of sublingual tablets
to the injection route. Therefore, formulations of buprenorphine
for opioid addiction and dependency treatment are generally in the
form of sublingual tablets such as SUBUTEX and SUBOXONE.
[0018] The typical analgesic dose of buprenorphine is relatively
low at amounts of 0.3-0.6 mg when injected (intramuscular or
intravenous). Because the bioavailability of buprenorphine is less
when administered orally or sublingually as compared to injections
of buprenorphine, sublingual tablets are available in increased
dosages of 2 mg or 8 mg. The present invention, however, may
include a relatively high amount (high effective amount) of an
opioid analgesic such as buprenorphine in a pharmaceutical dosage
compared to dosages typically administered for pain management. In
one embodiment, relatively high amount includes dosage amounts
greater 0.6 mg of buprenorphine when injected or 8 mg of
buprenorphine when administered as a sublingual tablet. Thus, in
one embodiment of the present invention, an opioid analgesic such
as buprenorphine is present in an amount of about 2-30 mg. In
another embodiment, the opioid analgesic is present in an amount of
about 10-30 mg. In still another embodiment, the opioid analgesic
is present in an amount of about 10-15 mg.
[0019] Lower dosages of opioid analgesics such as buprenorphine are
also effective in the present invention, however, particularly when
administered in combination with a NSAID such as piroxicam. NSAIDs
such as piroxicam have a prolonged half-life (approximately 50
hours), which results in the maintenance of relatively stable
plasma concentrations throughout the day on once daily doses and to
significant accumulation upon multiple dosing. Opioid analgesics
such as buprenorphine also have an unusually long half-life
(approximately 36 hours). As such, these NSAIDs and opioid
analgesics may be combined in a single pharmaceutical dosage unit
as a pharmaceutical combination dosage unit to provide safe and
effective pain management with a reduction in side effects such as
gastrointestinal tract damage and withdrawal as a result of
physical dependence on and/or addiction to the opioid analgesic.
This pharmaceutical combination dosage unit may include a low
effective amount of a NSAID such as piroxicam and a high effective
amount of an opioid analgesic such as buprenorphine where low
effective amount of an NSAID is less than about 5 mg and high
effective amount of an opioid analgesic is about 2-30 mg. Thus, in
one embodiment, a NSAID such as piroxicam is present in an amount
of about 2-5 mg and an opioid analgesic such as buprenorphine is
present in an amount of about 2-30 mg. In another embodiment, the
NSAID is present in an amount of about 2-3 mg and the opioid
analgesic is present in an amount of about 2-15 mg. In still
another embodiment, the pharmaceutical dosage combination includes
about 2.5 mg of an NSAID and about 2 mg of an opioid analgesic.
[0020] The pharmaceutical dosage units of the present invention may
be formulated for various forms of administration, including, for
example, sublingual, mucosal, parenteral, intravenous,
intramuscular, and/or transdermal administration and combinations
thereof. Consistent with the various forms of administration, the
pharmaceutical dosage unit can generally be formulated, for
example, as a tablet, capsule, injection, and/or patch. In one
embodiment of the present invention, the NSAID and opioid analgesic
are combined in the same formulation of the pharmaceutical dosage
unit. In another embodiment of the present invention, the NSAID and
opioid analgesic are provided as individual formulations of the
pharmaceutical dosage unit but administered such that the active
ingredients are delivered to the patient simultaneously. In a
particular embodiment of the present invention, the NSAID and
opioid analgesic are combined in a sublingual tablet to be placed
within the mouth and/or under the tongue.
[0021] Sublingual tablets are designed to dissolve very rapidly.
Examples of such formulations include ergotamine tartrate,
isosorbide dinitrate, isoproterenol HCl. The necessary ingredients
for the pharmaceutical dosage unit may be processed in accordance
with known methods, using or incorporating familiar coatings and
additives as required. By way of example only, in addition to the
pharmaceutically active components, a dosage unit may contain
effective amounts of binders, fillers, disintegrants,
sustained-release agents, diluents, anti-adherents, glidants, flow
aids, plasticizers and lubricants, which are well known in the
field of pharmaceutical processing. For instance, the formulation
of these tablets may contain, in addition to the active agents, a
limited number of soluble excipients, including a binder such as
povidone or hydroxypropyl methylcellulose (HPMC), diluents such as
lactose, mannitol, starch or cellulose, a disintegrant such as
pregelatinized or modified starch, lubricants such as magnesium
stearate, stearic acid or hydrogenated vegetable oil, a sweetener
such as saccharin or sucrose and suitable flavoring and coloring
agents. The process of making sublingual tablets generally involves
moistening the blended powder components with an alcohol-water
solvent system containing approximately 60% alcohol and 40% water
and pressing this mixture into tablets.
[0022] A particular tablet-form formulation in accordance with the
above-described embodiment of the present invention includes the
following components:
Buprenorphine: 2 mg/tablet;
Piroxicam: 5 mg/tablet;
Sugar Base A: qs to desired tablet weight of approximately 215 mg;
and
Coloring: 20 mg per 150 tablets,
[0023] where Sugar Base A includes the following components given
by approximate wt.-% of Sugar Base A: DiPac (tableting sugar) 77
wt.-%, lactose 7 wt.-%, microcrystalline cellulose 5 wt.-%,
flavoring 5 wt.-%, CrosPovidone 5 wt.-%, and magnesium stearate 1
wt.-%.
[0024] In an alternative tablet-form formulation, Naloxone is added
to the formulation. Naloxone is an opioid antagonist that binds to
a receptor in the brain to block the receptor rather than activate
it. Thus, in some instances the inclusion of Naloxone may reduce
opiate tolerance or even partially reverse tolerance if it occurs.
Accordingly, Naloxone may be included to further reduce the abuse
potential of the pharmaceutical dosage unit and withdrawal as a
result of physical dependence and/or addiction. In this embodiment,
the following components are included:
Buprenorphine: 2 mg/tablet;
Piroxicam: 5 mg/tablet;
Naloxone: 0.2 mg/tablet
Sugar Base A: qs to desired tablet weight of approximately 215 mg;
and
Coloring: 20 mg per 150 tablets,
[0025] where Sugar Base A includes the following components given
by approximate wt.-% of Sugar Base A: DiPac (tableting sugar) 77
wt.-%, lactose 7 wt.-%, microcrystalline cellulose 5 wt.-%,
flavoring 5 wt.-%, CrosPovidone 5 wt.-%, and magnesium stearate 1
wt.-%.
[0026] The pharmaceutical dosage unit may be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. In one
embodiment, the pharmaceutical dosage unit may be formulated such
that a single sublingual tablet is administered twice daily. In one
embodiment, pharmaceutical dosage unit of the present invention
once in the morning, such as at 8:00 am, and then again six hours
later in the early afternoon or at approximately 2:00 pm.
[0027] Alternatively, the pharmaceutical dosage unit may formulated
so that the active ingredients (i.e. the NSAID and the opioid
analgesic) exhibit sustained-release characteristics upon
administration to the patient. For example, the active ingredients
may be delivered with an oral mucosal patch. Methods of making such
patches are well known to one of skill in the art. In one
embodiment the oral mucosal patch is prepared by homogeneously
mixing buprenorphine and piroxicam with appropriate amounts of
Carbopol 934, polyisobutylene, and polyisoprene using a two-roll
mill and then compressing the mixture to the appropriate thickness.
A membrane backing such as ethylcellulose is then applied to one
side of the compressed material and circular disks, having an area
of about 0.5 cm.sup.2 and thickness of about 0.6 mm for example,
may be punched from the material. The backing inhibits drug release
from one side of the disk and reduces adhesion to opposing side
tissues. The oral mucosal patches may be secured to mucosal buccal
surfaces such as the gums, lips, and cheeks, and worn for extended
periods. In one instance, the oral mucosal patches may be work for
about 12 hours.
[0028] In another sustained release embodiment, the active
ingredients may be delivered using a tablet-form dosage unit having
a partially hydrophilic matrix which exhibits sustained release of
at least one of the active components. In addition to the active
ingredients, the tablet is comprised of, for example,
ethylcellulose as a sustained-release agent and hydroxypropyl
methylcellulose (HPMC) as a film former. Further, bulking agents
such as microcrystalline cellulose and starch, a
polyvinylpyrrolidone binder, silicon dioxide as an anti-adherent,
dibutyl sebacate as a plasticizer, and magnesium stearate as a
lubricant may be included. Using conventional processes, the listed
ingredients, other than ethylcellulose, HPMC and dibutyl sebacate,
are combined and pressed into a tablet. The tablet is then coated
with the ethylcellulose, HPMC and dibutyl sebacate prior to
administration of the tablet. When this tablet encounters an
aqueous environment, such as the mucosal buccal surfaces, portions
of the tablet coating dissolve, leaving a non-continuous film of
water-insoluble ethylcellulose surrounding the remaining tablet
core. The rate of diffusion of the active ingredients from the
tablet core into the aqueous environment is determined by the
concentration of ethylcellulose, HPMC and dibutyl sebacate in the
coating.
[0029] As used in this specification and in the claims, the phrase
"sustained release" indicates that an active component is released
from the dosage unit over a period of time which is longer than its
ordinary in vivo half-life, thus extending the presence of the
component in a patient's system considerably beyond its ordinary
half-life. Under such circumstances, the active component is said
to "exhibit sustained-release characteristics." In contrast, the
phrase "immediate release" indicates that an active component is
released from the dosage unit within a short period of time (i.e.,
much shorter than its ordinary in vivo half-life); and decrease in
concentration of the active component over time will be
approximately described by its ordinary half-life. Under such
circumstances, the active component is said to "exhibit
immediate-release characteristics." In compositions of the present
invention having more than one active component that is intended to
exhibit sustained-release characteristics, an important
consideration is that the release rate of each active component
will need to be separately customized to produce the desired
release profile, since the components will have different in vivo
half-lives.
[0030] Another aspect of the present invention is a method of
managing pain, the method including administering a pharmaceutical
dosage unit having about 2-5 mg of a NSAID such as piroxicam in
combination with about 2-30 mg of an opioid analgesic such as
buprenorphine. The NSAID and opioid analgesic may be administered
sublingually as a single pharmaceutical dosage unit or
simultaneously in separate, sublingual pharmaceutical dosage units.
In one embodiment, the pharmaceutical dosage unit is a sublingual
tablet to be placed under the tongue.
[0031] The present invention also provides for a method of treating
pain with reduced side effects, the method including administering
a pharmaceutical dosage unit having about 2-5 mg of a NSAID such as
piroxicam in combination with about 2-30 mg of an opioid analgesic
such as buprenorphine. The NSAID and opioid analgesic may be
administered sublingually as a single pharmaceutical dosage unit or
simultaneously in separate, sublingual pharmaceutical dosage units.
In one embodiment the side effects may include opioid withdrawal.
Alternatively, the side effects may include, for example,
ulcerations, abdominal pain, nausea, liver toxicity,
gastrointestinal bleeding, kidney disease, or combinations
thereof.
[0032] The present invention further provides a method of treating
withdrawal, the method including administering a pharmaceutical
dosage unit having about 2-5 mg of a NSAID such as piroxicam in
combination with about 2-30 mg of an opioid analgesic such as
buprenorphine. The NSAID and opioid analgesic may be administered
sublingually as a single pharmaceutical dosage unit or
simultaneously in separate, sublingual pharmaceutical dosage units.
In one embodiment, the pharmaceutical dosage unit is a sublingual
tablet to be placed under the tongue.
[0033] The appropriate dosages for administration to a patient for
any of the compositions or methods of the present invention should
be determined in accordance with accepted guidelines, such as those
given by the Physician's Desk Reference. The patient's response to
the pharmaceutical composition of the present invention may be
monitored and the dosage adjusted as necessary.
[0034] The present invention is also directed to a method of
treating pain in a human patient that includes administering to the
human patient, in a single or multiple dosage regimen, a
pharmaceutical dosage unit, where the dosage unit includes about
2-5 mg of a NSAID such as piroxicam in combination with about 2-30
milligrams of an opioid analgesic such as buprenorphine. The NSAID
and opioid analgesic may be administered sublingually as a single
pharmaceutical dosage unit or simultaneously in separate,
sublingual pharmaceutical dosage units. In one embodiment, the
pharmaceutical dosage unit is a sublingual tablet to be placed
under the tongue. The method may additionally include monitoring
the human patient to determine if the dosage regime is appropriate
and either increasing or decreasing the dosage regimen as
necessary.
[0035] The present invention offers significant advantages to
patients already using high dosages of opioids, to patients seeking
pain management methods to treat chronic pain without side effects
or long term effects, and to patients seeking opioid addiction
treatment. The present invention also provides physicians and
patients an ability to switch from the present invention to a
different pain management prescription without withdrawal
issues.
[0036] Further objects and advantages of the invention will become
apparent from a consideration of the examples and ensuing
description which illustrate embodiments of the invention, it being
understood that the foregoing statements of the objects of the
invention are intended to generally explain the same without
limiting it in any manner.
EXAMPLES
Example 1
[0037] Patients taking 15-80 mg/day of hydrocodone or 40-320 mg/day
of oxycontin were switched to a pharmaceutical dosage unit
including 2.5 mg piroxicam and 2 mg buprenorphine in a sublingual
tablet. The sublingual tablets were administered to each patient
twice daily. The patients perceived pain was measured using a
visual analog scale (VAS).
[0038] Patients formerly taking 15-80 mg/day of hydrocodone
experienced a 21% decrease in perceived pain scores after
conversion. The perceived pain scores also remained stable when 1/2
dose reduction was attempted after a 22 day stabilization
phase.
[0039] Patients that had been taking 40-320 mg/day of oxycontin
experienced a 27% reduction in perceived pain 72 hours after
conversion. No withdrawal or parasympathetic symptoms were noted in
the oxycontin patients. The perceived pain scores remained stable
when dose reduction was attempted after a 40-day stabilization
phase.
[0040] The patients also generally reported feelings of being more
in control of their lives, thinking clearer, sleeping better and
being less lethargic than when they were taking hydrocodone or
oxycontin.
Example 2
[0041] Patients taking 20-140 mg/day of methadone were also
switched to a pharmaceutical dosage unit including 2.5 mg piroxicam
and 2 mg buprenorphine in a sublingual tablet. These patients took
an average of 6 days to convert before withdrawal was completely
eliminated.
[0042] Patients taking 20-50 mg/day of methadone converted without
ill effects, but did not take methadone the first day.
[0043] Patients taking 50-140 mg/day of methadone were first
titrated down with Ultram (2-3 tablets every 4 hrs) for four days.
Following this period, patients were given injections containing
0.03 mg buprenorphine and 60 mg torodol to see if further time was
needed before the sublingual tablets containing buprenorphine and
piroxicam could be started without risk of precipitating
withdrawal. Significant withdrawal was observed in 18% of the
patients on the first day the sublingual tablets were administered.
Stomach tightness, nausea, and restless legs were the most common
complaints from these patients. None of the patients experienced
withdrawal on the second day the sublingual tablet was
administered.
[0044] Pain scores using a VAS did not improve until week 2 with
the methadone patients. By week 4, the methadone patients were
willing to titrate down and by week 6 there was significant
improvement in the VAS and no difference was noted with methadone
and other opiate tolerant groups after the 6th week.
Example 3
[0045] Patients that had been taking piroxicam were also switched
to a pharmaceutical dosage unit including 2.5 mg piroxicam and 2 mg
buprenorphine in a sublingual tablet. The patients reported a 50%
reduction in GI upset compared to when they were taking piroxicam
orally.
[0046] The particular embodiments disclosed above are illustrative
only, as the invention may be modified and practiced in different
but equivalent manners apparent to those skilled in the art having
the benefit of the teachings herein. Furthermore, no limitations
are intended to the details of construction or design herein shown,
other than as described in the claims below. It is therefore
evident that the particular embodiments disclosed above may be
altered or modified and all such variations are considered within
the scope and spirit of the invention. Accordingly, the protection
sought herein is as set forth in the claims below.
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