U.S. patent application number 14/704955 was filed with the patent office on 2016-04-07 for abuse-resistant mucoadhesive devices for delivery of buprenorphine.
The applicant listed for this patent is BioDelivery Sciences International, Inc.. Invention is credited to Andrew Finn, Niraj Vasisht.
Application Number | 20160095821 14/704955 |
Document ID | / |
Family ID | 47712819 |
Filed Date | 2016-04-07 |
United States Patent
Application |
20160095821 |
Kind Code |
A1 |
Finn; Andrew ; et
al. |
April 7, 2016 |
ABUSE-RESISTANT MUCOADHESIVE DEVICES FOR DELIVERY OF
BUPRENORPHINE
Abstract
The present invention provides abuse deterrent mucoadhesive
devices for delivery of buprenorphine. Each device comprises a
mucoadhesive layer and a backing layer, and the pH in each layer is
selected, such that absorption of buprenorphine is maximized.
Inventors: |
Finn; Andrew; (Raleigh,
NC) ; Vasisht; Niraj; (Cary, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioDelivery Sciences International, Inc. |
Raleigh |
NC |
US |
|
|
Family ID: |
47712819 |
Appl. No.: |
14/704955 |
Filed: |
May 5, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14499651 |
Sep 29, 2014 |
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14704955 |
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14176036 |
Feb 7, 2014 |
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14499651 |
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13590094 |
Aug 20, 2012 |
8703177 |
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14176036 |
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61525094 |
Aug 18, 2011 |
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Current U.S.
Class: |
424/443 ;
514/279; 514/282 |
Current CPC
Class: |
A61P 25/04 20180101;
A61K 47/22 20130101; A61P 25/36 20180101; A61K 47/14 20130101; A61P
1/00 20180101; A61P 39/02 20180101; A61K 9/006 20130101; A61K 47/10
20130101; A61K 31/485 20130101; A61K 31/46 20130101; A61K 9/7007
20130101; A61K 31/4748 20130101; A61K 47/38 20130101; A61P 29/00
20180101; A61P 25/00 20180101; A61P 43/00 20180101; A61K 47/12
20130101; A61K 47/32 20130101; A61K 47/02 20130101; A61K 31/485
20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/485 20060101 A61K031/485; A61K 31/4748 20060101
A61K031/4748 |
Claims
1. An abuse deterrent mucoadhesive device for use in managing pain
or opioid dependence, the device comprising: a mucoadhesive layer
comprising an effective amount of buprenorphine buffered to a pH of
between about 4.0 and about 6.0; and a backing layer buffered to a
pH between about 4.0 and about 4.8.
2. The device according to claim 1, wherein the backing layer
comprises an effective amount of naloxone and wherein the w/w ratio
of buprenorphine to naloxone present in the device is between 1:1
and 10:1.
3. The device according to claim 2, wherein the w/w ratio of
buprenorphine to naloxone present in the device is 6:1.
4. The device according to claim 3, wherein the mucoadhesive layer
is buffered to a pH of between about 4.50 and about 5.50 and the
wherein the backing layer is buffered to a pH of between about 4.10
and about 4.4.
5. The device according to claim 4, wherein the mucoadhesive layer
is buffered to a pH of about 4.75 and the backing layer is buffered
to a pH of about 4.25.
6. The device according to claim 1 comprising about 0.075-12 mg
buprenorphine.
7. The device according to claim 2 comprising about 0.0125-2 mg of
naloxone.
8. The device according to claim 1 wherein the bioavailability of
buprenorphine absorbed from the device is greater than 40%.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/499,651, filed Sep. 29, 2014; which is a
continuation application of U.S. patent application Ser. No.
14/176,036, filed on Feb. 7, 2014; which is a continuation of U.S.
patent application Ser. No. 13/590,094, filed on Aug. 20, 2012, now
U.S. Pat. No. 8,703,177, issued on Apr. 22, 2014; which claims
priority to U.S. Provisional Application No. 61/525,094, filed on
Aug. 18, 2011. This application is also related to U.S. patent
application Ser. No. 08/734,519, filed on Oct. 18, 1996, now U.S.
Pat. No. 5,800,832, issued on Sep. 1, 1998; U.S. patent application
Ser. No. 11/639,408, filed on Dec. 13, 2006; U.S. patent
application Ser. No. 11/817,915, filed on Sep. 6, 2007; and U.S.
patent application Ser. No. 13/184,306, filed on Jul. 15, 2011, now
U.S. Pat. No. 8,147,866, issued on Apr. 3, 2012. The entire
contents of each of the foregoing applications are incorporated
herein by reference.
BACKGROUND
[0002] Buprenorphine is a partial .mu.-opiate receptor agonist, an
ORL1/nociceptin receptor agonist with high affinity, and slow
association and dissociation from the receptors, and a
.kappa.-opiate receptor antagonist. Transmucosal bioavailability of
buprenorphine is greater than its oral bioavailability, and, as a
result, buprenorphine has been initially developed and marketed as
a sublingual dosage form. Buprenorphine has been generally
available as Temgesic.RTM. 0.2 mg sublingual tablets and as
Buprenex.RTM. in a 0.3 mg/ml parenteral formulation, both indicated
for the treatment of moderate to severe pain.
[0003] Because there is some risk of abuse with buprenorphine,
particularly in the doses used for opioid dependence, a combination
product with naloxone, an opioid antagonist, has been developed.
The addition of naloxone to buprenorphine decreases the parenteral
abuse potential of buprenorphine in opioid dependent subjects, as
injected naloxone precipitates withdrawal by displacing the
non-buprenorphine opioid from the receptor sites and blocking those
sites from buprenorphine occupancy. Human laboratory studies have
been conducted to test different dosage ratios of buprenorphine and
naloxone (Fudala P. J. et al., Effects of buprenorphine and
naloxone in morphine-stabilized opioid addicts, (1998) Drug Alcohol
Depend., 50(1):1-8; Mendelson J. et al., Buprenorphine and naloxone
combinations: the effects of three dose ratios in
morphine-stabilized, opiate-dependent volunteers, (1999)
Psychopharmacology 141:37-46) and have led to the conclusion that a
formulation comprising buprenorphine and naloxone at the dose ratio
of w/w 2:1 or 4:1 should be optimal for providing deterrence for
opiate abusers. Suboxone.RTM. a sublingual pill preparation of
buprenorphine that contains buprenorphine and naloxone at a 4:1 w/w
dose ratio, and has been approved by the FDA for treating opioid
dependence.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIG. 1 is a schematic representation of exemplary
embodiments of the present invention.
[0005] FIG. 2 is a graph showing assessment of dose-proportionality
of buprenorphine C.sub.max after administration of the devices of
the invention containing 0.875/0.15 mg, 3.5/0.6 mg and 5.25/0.9 mg
of buprenorphine/naloxone as described in Example 4.
[0006] FIG. 3 is a graph showing assessment of dose-proportionality
of buprenorphine AUC.sub.inf after administration of the devices of
the invention containing 0.875/0.15 mg, 3.5/0.6 mg and 5.25/0.9 mg
of buprenorphine/naloxone as described in Example 4.
[0007] FIG. 4 is a graph showing COWS total scores recorded within
1 hour of subjects receiving study medication as a part of Naloxone
Withdrawal Study as described in Example 5.
[0008] FIG. 5 is a graph showing changes in blood pressure, heart
rate and oxygen saturation in subjects receiving study medication
as a part of Naloxone Withdrawal Study as described in Example
5.
SUMMARY OF THE INVENTION
[0009] The present invention is based, at least in part, on the
discovery that bioavailability of an opioid agonist, e.g.,
buprenorphine, disposed in the mucoadhesive layer of a two-layered,
abuse-resistant transmucosal drug delivery device is not only
affected by the pH of the mucoadhesive layer, but is also affected
by the pH of the backing layer that resides on the lingual side of
the bi-layer film. This layer may or may not contain an opioid
antagonist, however in the preferred embodiment of the composition
of the backing layer, it does include an opioid antagonist such as
naloxone. Accordingly, both the pH of the mucoadhesive layer and
the pH of the backing layer may be chosen such that the absorption
of buprenorphine from the mucoadhesive layer is similar or higher
than absorption from the mucoadhesive layer of a device with an
unbuffered backing layer, while the absorption of naloxone, if
present in the backing layer, is impeded.
[0010] The present invention is also based, at least in part, on
the surprising discovery, that the mucoadhesive devices with
buffered backing layer may comprise smaller doses of naloxone,
while still providing abuse deterrence. The dose of naloxone is
lowered, such that the w/w buprenorphine to naloxone ratio is
higher than the ratio of 4:1, accepted in the art as being
effective for providing abuse deterrence. In some embodiments, the
w/w buprenorphine to naloxone ratio present in the mucoadhesive
device of the invention is between 4:1 and 10:1. In a specific
embodiment, the w/w buprenorphine to naloxone ratio is 6:1. Such a
device is advantageous because it can provide effective abuse
deterrence at a lower naloxone dose.
[0011] This invention does not purport the need for naloxone in the
backing layer. In some embodiments, the amount of naloxone required
to precipitate withdrawal is as low as 0.1 mg when abused by
injection. In some embodiments, the maximum ratio of buprenorphine
dose to naloxone is 10:1 and can be as low at 1:1. In some
embodiments, the ratio of buprenorphine dose to naloxone is 10:1 to
4:1. In a specific embodiment, the ratio is 6:1.
[0012] In some embodiments, the present invention provides an abuse
deterrent mucoadhesive device for use in managing pain or opioid
dependence, the device comprising: [0013] a mucoadhesive layer
comprising buprenorphine buffered to a pH of between about 4.0 and
about 6.0; and [0014] a backing layer buffered to a pH between
about 4.0 and about 4.8.
[0015] In some embodiments, the absorption of buprenorphine through
the oral mucosal membrane is optimized and a therapeutically
effective dose of buprenorphine is provided. In some embodiments,
the backing layer comprises naloxone. In some embodiments, the w/w
ratio of buprenorphine to naloxone present in the device is between
1:1 and 10:1. In some embodiments, the ratio is between about 4:1
and 10:1. In a preferred embodiment, the w/w ratio of buprenorphine
to naloxone present in the device is 6:1.
[0016] In some embodiments, the present invention provides an abuse
deterrent mucoadhesive device for use in managing pain or opioid
dependence, the device comprising: [0017] a mucoadhesive layer
comprising buprenorphine buffered to a pH of between about 4.0 and
about 6.0; [0018] and a backing layer buffered to a pH between
about 4.0 and about 4.8;
[0019] wherein bioavailability of buprenorphine absorbed from the
device is greater than 40%. In some embodiments, the
bioavailability is about 60%. In some embodiments, the
bioavailability is about 65%. In some embodiments, the
bioavailability is about 75%.
[0020] In some embodiments, the mucoadhesive layer is buffered to a
pH of between about 4.50 and about 5.50 and the backing layer is
buffered to a pH of between about 4.10 and about 4.4. In a
preferred embodiment, the mucoadhesive layer is buffered to a pH of
about 4.75 and the backing layer is buffered to a pH of about
4.25.
[0021] In some embodiments, the device comprises about 0.075-12 mg
of buprenorphine. In some embodiments, the amount of buprenorphine
is 0.15-12 mg of buprenorphine. In some embodiments, the device
also comprises about 0.0125-2 mg of naloxone. In some embodiments,
the amount of naloxone is about 0.1-2 mg. In some embodiments, the
bioavailability of buprenorphine absorbed from the device is
greater than 40%.
[0022] In some embodiments, the present invention provides an abuse
deterrent mucoadhesive device for use in managing pain or opioid
dependence, the device comprising: [0023] a mucoadhesive layer
comprising buprenorphine and buffered to a first pH; [0024] a
backing layer buffered to a second pH; [0025] the second pH
selected such that the transmucosal delivery of buprenorphine is
not impeded, such that the bioavailability of buprenophine is
greater than 40%. In some embodiments, the backing layer comprises
naloxone, and the delivery of naloxone is impeded.
[0026] In some embodiments, the invention also provides an abuse
deterrent mucoadhesive device for use in managing pain or opioid
dependence, the device comprising: [0027] a mucoadhesive layer
comprising buprenorphine and buffered to a first pH, [0028] a
backing layer buffered to a second pH, [0029] the first pH and the
second pH selected such that the unidirectional delivery gradient
of buprenorphine toward the mucosa is not impeded, such that the
total bioavailability of buprenophine provided by the device is
similar to the total bioavailability of buprenorphine provided by
the same device wherein the pH of the backing layer is not
adjusted. In one embodiment, the backing layer comprises naloxone,
and the delivery of naloxone is impeded.
[0030] In some embodiments, an abuse deterrent mucoadhesive device
for use in managing pain or opioid dependence comprises: [0031] a
mucoadhesive layer comprising buprenorphine and buffered to a first
pH and a backing layer buffered to a second pH; [0032] wherein the
first pH is between about 4.0 and about 6.0; [0033] wherein the
second pH is between about 4.0 and about 4.8.
[0034] In some embodiments, the backing layer comprises naloxone.
In some embodiments, buprenorphine and naloxone disposed in the
device are present in w/w ratio of about 4:1 to about 10:1 of
buprenorphine:naloxone. In one embodiment, the ratio is about
6:1.
[0035] In some embodiments, the first pH is between about 4.50 and
about 5.50 and the second pH is between about 4.10 and about 4.4.
In a specific embodiment, the first pH is about 4.75 and the second
pH is about 4.25. In some embodiments, the device comprises about
0.075 to 12 mg of buprenorphine and about 0.0125-2 mg of
naloxone.
[0036] In some embodiments, an abuse deterrent mucoadhesive device
for use in managing pain or opioid dependence comprises: [0037] a
mucoadhesive layer comprising buprenorphine and buffered to a first
pH and a backing layer buffered to a second pH; [0038] wherein the
first pH is between about 4.0 and about 6.0; [0039] wherein the
second pH is between about 4.0 and about 4.8; and [0040] wherein
bioavailability of buprenorphine absorbed from the device is
greater than 40%. In some embodiments, the backing layer comprises
naloxone.
[0041] In some embodiments, the first pH is between about 4.50 and
about 5.50 and the second pH is between about 4.10 and about 4.4.
In a specific embodiment, the first pH is about 4.75 and the second
pH is about 4.25. In some embodiments, the device comprises about
0.075 to 12 mg of buprenorphine and about 0.0125-2 mg of
naloxone.
[0042] In a preferred embodiment, the abuse deterrent mucoadhesive
device for use in managing pain or opioid dependence comprises:
[0043] a mucoadhesive layer comprising buprenorphine and buffered
to a first pH and a backing layer comprising naloxone and buffered
to a second pH; [0044] wherein the first pH is about 4.75; [0045]
wherein the second pH is about 4.25; and [0046] wherein
buprenorphine and naloxone disposed in the device are present in
w/w ratio of about 6:1 of buprenorphine:naloxone.
[0047] In some embodiments, methods of treating pain or managing
opioid dependence in a subject are also provided. The methods
generally comprise administering to a subject in need thereof an
abuse deterrent mucoadhesive device of the invention, such that
pain is treated or opioid dependence is managed in a subject.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0048] The following definitions are provided as guidance as to the
meaning of certain terms used herein.
[0049] As used herein, the articles "a" and "an" mean "one or more"
or "at least one," unless otherwise indicated. That is, reference
to any element of the present invention by the indefinite article
"a" or "an" does not exclude the possibility that more than one of
the element is present.
[0050] As used herein, the term "absorption" refers to the process
of a substance, such as a drug, entering the bloodstream.
Absorption can be measured by pharmacokinetic parameters, such as
AUC.sub.inf and C.sub.max.
[0051] As used herein, the term "acute pain" refers to pain
characterized by a short duration, e.g., three to six months. Acute
pain is typically associated with tissue damage, and manifests in
ways that can be easily described and observed. It can, for
example, cause sweating or increased heart rate. Acute pain can
also increase over time, and/or occur intermittently.
[0052] As used herein, the term "bioavailability" is as defined in
21 CFR Section 320.1 and refers to the rate and extent to which the
active ingredient or active moiety is absorbed from a drug product
and becomes available at the site of action. The term
"bioavailable," "absolute bioavailability" or "total
bioavailability" refers to the total bioavailability including
amounts that are transmitted via the mucosal membrane (i.e.,
transmucosally) and through the GI tract. The term "absolute
bioavailability" refers to a fraction of a drug absorbed through
non-intravenous administration (i.e., transmucosal, oral, rectal,
transdermal, subcutaneous, or sublingual administration) compared
with the bioavailability of the same drug following intravenous
administration. The comparison is dose normalized, i.e., accounts
for different doses consequently, the amount absorbed is corrected
by dividing the corresponding dose administered. In some
embodiments, the mucoadhesive devices of the present invention
provide absolute bioavailability of the opioid agonist
buprenorphine that is equal to or greater than 40%, e.g., 40%, 41%,
42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%,
55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,
68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,
81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, 99% or 100%.
[0053] As used herein, the term "bioequivalence" or "bioequivalent"
is as defined in 21 CFR Section 320.1, and means the absence of a
significant difference in the rate and extent of absorption of an
active ingredient or active moiety in one pharmaceutical product
and another. For bioequivalence, the pharmacokinetic parameters
C.sub.max and AUC for bioequivalent actives fall within the
80%-125% range of each other. In some embodiments, the devices of
the present invention may be bioequivalent to Suboxone.RTM.
sublingual tablet. Pharmacokinetic parameters, e.g., C.sub.max and
AUC.sub.inf, for Suboxone.RTM. sublingual tablets comprising
2.0/0.5 mg and 8.0/2.0 mg of buprenorphine/naloxone is contained in
the product label for Suboxone.RTM., which is incorporated herein
by reference in its entirety.
[0054] As used herein, the term "chronic pain" refers to pain which
persists beyond the usual recovery period for an injury or illness.
Chronic pain can be constant or intermittent. Common causes of
chronic pain include, but are not limited to, arthritis, cancer,
Reflex Sympathetic Dystrophy Syndrome (RSDS), repetitive stress
injuries, shingles, headaches, fibromyalgia, and diabetic
neuropathy, lower back pain, neck and shoulder pain, moderate to
severe osteoarthritis, and patients with severe migraine.
[0055] As used herein, unless indicated otherwise, the term
"buprenorphine", includes any pharmaceutically acceptable form of
buprenorphine, including, but not limited to, salts, esters, and
prodrugs thereof. In one embodiment, the term "buprenorphine"
refers to buprenorphine hydrochloride. As used herein, the term
"buprenorphine derivative" refers to compounds having similar
structure and function to buprenorphine. In some embodiments,
buprenorphine derivatives include those of the following
formula:
##STR00001##
or pharmaceutically acceptable salts or esters thereof, wherein
##STR00002##
is a double or single bond; R.sub.3 is selected from a --C.sub.1-4
alkyl group or a cycloalkyl-substituted-C.sub.1-4 alkyl group;
R.sub.4 is selected from a --C.sub.1-4 alkyl; R.sub.5 is --OH, or
taken together, R.sub.4 and R.sub.5 form a .dbd.O group; and
R.sub.6 is selected from --H or a --C.sub.1-4 alkyl group.
[0056] Buprenorphine derivatives include, but are not limited to,
etorphine and diprenorphine. General buprenorphine derivatives are
described in WO 2008/011194, which is hereby incorporated by
reference.
[0057] As used herein, unless indicated otherwise, the term
"naloxone" includes any pharmaceutically acceptable form of
naloxone, including, but not limited to, salts, esters, and
prodrugs thereof. In one embodiment, the term "naloxone" refers to
naloxone hydrochloride. In some embodiments, naloxone is
represented by the following chemical structure:
##STR00003##
[0058] As used herein, the term "mucoadhesive layer" or "polymeric
diffusion environment" refers to an environment capable of allowing
flux of a medicament to a mucosal surface upon creation of a
gradient by adhesion of the polymeric diffusion environment to a
mucosal surface. The flux of a transported medicament is
proportionally related to the diffusivity of the environment which
can be manipulated by, e.g., adjusting the pH, taking into account
the ionic nature of the medicament and/or the ionic nature of the
polymer or polymers included in the environment.
[0059] As used herein, the term "backing layer" or "non-adhesive
polymeric environment" refers to an environment in the form of,
e.g., a layer or coating or barrier layer, capable of slowing,
reducing or stopping flux of a medicament in its direction and does
not adhere to surfaces in the oral cavity. In some embodiments, the
pH of the backing layer is adjusted, such as it stops flux of a
medicament contained therein and in the mucoadhesive layer, except
in the direction of the mucosa. In some embodiments, the
non-adhesive polymeric environment significantly slows flux of a
medicament, e.g., enough so that little or no medicament is washed
away by saliva. In some embodiments, the non-adhesive polymeric
environment slows or stops flux of a medicament, while allowing
hydration of the polymeric diffusion environment e.g., by
saliva.
[0060] As used herein, the term "unidirectional gradient" refers to
a gradient which allows for the flux of a medicament (e.g.,
buprenorphine) through the device, e.g., through a polymeric
diffusion environment, in substantially one direction, e.g., to the
mucosa of a subject. For example, the polymeric diffusion
environment may be a mucoadhesive polymeric diffusion environment
in the form of a layer or film disposed adjacent to a backing layer
or film. Upon mucosal administration, a gradient is created between
the mucoadhesive polymeric diffusion environment and the mucosa,
and the medicament flows from the mucoadhesive polymeric diffusion
environment, substantially in one direction towards the mucosa. In
some embodiments, some flux of the medicament is not entirely
unidirectional across the gradient; however, there is typically not
free flux of the medicament in all directions.
[0061] As used herein, "treating" or "treatment" of a subject
includes the administration of a drug to a subject with the purpose
of preventing, curing, healing, alleviating, relieving, altering,
remedying, ameliorating, improving, stabilizing or affecting a
disease or disorder, or a symptom of a disease or disorder (e.g.,
to alleviate pain).
[0062] The term "subject" refers to living organisms such as
humans, dogs, cats, and other mammals. Administration of the
medicaments included in the devices of the present invention can be
carried out at dosages and for periods of time effective for
treatment of a subject. In some embodiments, the subject is a
human. In some embodiments, the pharmacokinetic profiles of the
devices of the present invention are similar for male and female
subjects.
[0063] An "effective amount" of a drug necessary to achieve a
therapeutic effect may vary according to factors such as the age,
sex, and weight of the subject. Dosage regimens can be adjusted to
provide the optimum therapeutic response. For example, several
divided doses may be administered daily or the dose may be
proportionally reduced as indicated by the exigencies of the
therapeutic situation.
[0064] The term "transmucosal," as used herein, refers to any route
of administration via a mucosal membrane. Examples include, but are
not limited to, buccal, sublingual, nasal, vaginal, and rectal. In
one embodiment, the administration is buccal. In one embodiment,
the administration is sublingual. As used herein, the term "direct
transmucosal" refers to mucosal administration via the oral mucosa,
e.g., buccal and/or sublingual.
[0065] As used herein, the term "water erodable" or "at least
partially water erodable" refers to a substance that exhibits a
water erodability ranging from negligible to completely water
erodable. The substance may readily dissolve in water or may only
partially dissolve in water with difficulty over a long period of
time. Furthermore, the substance may exhibit a differing
erodability in body fluids compared with water because of the more
complex nature of body fluids. For example, a substance that is
negligibly erodable in water may show an erodability in body fluids
that is slight to moderate. However, in other instances, the
erodability in water and body fluid may be approximately the
same.
[0066] The term "impeded" when used to describe the absorption or
the delivery of the opioid antagonist from the abuse-resistant
device refers to the absorption and/or delivery of said opioid
antagonist that is insufficient to inhibit the effects of the
opioid agonist comprised in the same device.
[0067] As used herein, "addiction therapy" as related to a subject
includes the administration of a drug to a subject with the purpose
of reducing the cravings for the addictive substance.
[0068] As used herein, the term "abusive" or "abusive manner"
refers to uses of the devices beyond transmucosal administration
such as by injecting or snorting.
[0069] As used herein, the term "disposed" refers to the uniform or
non-uniform distribution of an element within another.
Maintenance Treatment of Opioid Dependence
[0070] Certain aspects of the present invention include methods for
providing maintenance treatment for a subject addicted to opioids.
Presently, buprenorphine maintenance is one of the most promising
courses of action for addicted subjects in terms of long-term
abstinence.
Pain Management
[0071] Certain aspects of the present invention include methods for
providing pain management and/or relief to a subject in need
thereof. The pain can be any pain known in the art, caused by any
disease, disorder, condition and/or circumstance and can be chronic
pain or acute pain.
Transmucosal Mucoadhesive Pharmaceutical Delivery Device
[0072] In certain aspects of the present invention, abuse-resistant
transmucosal delivery devices are provided. Accordingly, in one
embodiment, the present invention is directed to abuse-resistant
mucoadhesive delivery devices suitable for administration of an
effective amount of an opioid drug to a subject, for the management
of pain and/or opioid dependence. The device is capable of
delivering the opioid agonist by means of a unidirectional gradient
(i.e. flux that flows toward the mucosa) that is created upon
application of the device to a mucosal surface.
[0073] The devices of the present invention can include any
combination or sub-combination of ingredients, layers and/or
compositions of, e.g., the devices described in U.S. Pat. No.
6,159,498, U.S. Pat. No. 5,800,832, U.S. Pat. No. 6,585,997, U.S.
Pat. No. 6,200,604, U.S. Pat. No. 6,759,059 and/or PCT Publication
No. WO 05/06321. The contents of these patent and publications are
incorporated herein by reference in their entireties.
i. Mucoadhesive Layer
[0074] In some embodiments, the mucoadhesive layer is a bioerodable
or water-erodable mucoadhesive layer. In some embodiments, the
devices of the present invention include a bioerodable mucoadhesive
layer which comprises a mucoadhesive polymeric diffusion
environment. The device adheres to a mucosal surface of the subject
within about 5 seconds following application.
[0075] In some embodiments, the mucoadhesive polymeric diffusion
environment comprises an opioid agonist. In some embodiments, the
opioid agonist is buprenorphine. In some embodiments related to the
treatment of opioid dependence, the dose of buprenorphine that can
be incorporated into the device of the present invention depends on
the desired treatment dosage to be administered and can range from
about 10 .mu.g to about 20 mg of buprenorphine. In other
embodiments related to the treatment of pain, the dose of
buprenorphine can range from about 60 .mu.g to about 6 mg. In some
embodiments, the low dose of buprenorphine comprised in the
mucoadhesive device of the invention is between about 0.075 and 12
mg of buprenorphine, e.g., 0.075 mg, 0.080 mg, 0.085 mg, 0.090 mg,
0.095 mg, 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg,
0.40 mg, 0.45 mg, 0.50 mg, 0.44 mg, 0.60 mg, 0.65 mg, 0.70 mg, 0.75
mg, 0.80 mg, 0.85 mg, 0.90 mg, 0.95 mg, 1.00 mg, 1.5 mg, 1.75 mg,
2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.25 mg,
5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5
mg, 10.0 mg, 10.5 mg, 11.0 mg, 11.5 mg or 12.0 mg or buprenorphine.
In one embodiment, the dose is 0.875 mg of buprenorphine. In
another embodiment, the dose is 1.75 mg of buprenorphine. In
another embodiment, the dose is 3.5 mg of buprenorphine. In yet
another embodiment, the dose is 5.25 mg of buprenorphine.
[0076] In some embodiments, the mucoadhesive polymeric diffusion
environment can include the drug, at least one pharmacologically
acceptable polymer capable of bioadhesion (the "bioadhesive
polymer"), and can optionally include at least one film-forming
bioerodable or water-erodable polymer (the "film-forming polymer").
Alternatively, the mucoadhesive polymeric diffusion environment can
be formed of a single polymer that acts as both the bioadhesive
polymer and the first film-forming polymer. Additionally or
alternatively, the mucoadhesive polymeric diffusion environment can
include other film-forming water-erodable polymers and/or
water-erodable plasticizers, such as glycerin and/or polyethylene
glycol (PEG).
[0077] In some embodiments, the bioadhesive polymer of the
mucoadhesive polymeric diffusion environment can include any water
erodable substituted cellulosic polymer or substituted olefinic
polymer wherein the substituents may be ionic or hydrogen bonding,
such as carboxylic acid groups, hydroxyl alkyl groups, amine groups
and amide groups. For hydroxyl containing cellulosic polymers, a
combination of alkyl and hydroxyalkyl groups will be preferred for
provision of the bioadhesive character and the ratio of these two
groups will have an effect upon water swellability and
dispersability. Examples include polyacrylic acid (PAA), which can
optionally be partially cross-linked, sodium carboxymethyl
cellulose (NaCMC), moderately to highly substituted
hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP3
which can optionally be partially cross-linked), moderately to
highly substituted hydroxyethylmethyl cellulose (HEMC) or
combinations thereof. In one embodiment, HEMC can be used as the
bioadhesive polymer and the first film forming polymer as described
above for a mucoadhesive polymeric diffusion environment formed of
one polymer. These bioadhesive polymers are preferred because they
have good and instantaneous mucoadhesive properties in a dry,
system state.
[0078] In some embodiments, the mucoadhesive polymeric diffusion
environment, e.g., a bioerodable mucoadhesive layer, is generally
comprised of water-erodable polymers which include, but are not
limited to, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl
cellulose (HEMC), polyacrylic acid (PAA) which may or may not be
partially cross-linked, sodium carboxymethyl cellulose (NaCMC), and
polyvinylpyrrolidone (PVP), or combinations thereof. Other
mucoadhesive water-erodable polymers may also be used in the
present invention. The term "polyacrylic acid" includes both
uncross-linked and partially cross-linked forms, e.g.,
polycarbophil.
[0079] Similar film-forming water-erodable polymers can also be
used. The film-forming water-erodable polymers can optionally be
cross-linked and/or plasticized in order to alter its dissolution
kinetics.
[0080] In some embodiments, the properties of the mucoadhesive
polymeric diffusion environment are influenced by its pH. In some
embodiments, e.g., when mucoadhesive polymeric diffusion
environment comprises buprenorphine, its pH is between about 4.0
and about 7.5. In one embodiment, the pH is between 4.0 and 6.0,
more specifically, between 4.5 and 5.5, and even more specifically,
between 4.75 and 5.25. In a specific embodiment, the pH is 4.75. It
is to be understood that all values and ranges between these values
and ranges are meant to be encompassed by the present
invention.
[0081] The pH of the mucoadhesive polymeric diffusion environment
can be adjusted and/or maintained by methods including, but not
limited to, the use of buffering agents, or by adjusting the
composition of the device of the present invention.
[0082] Buffering agents suitable for use with the present invention
include, for example, phosphates, such as sodium phosphate;
phosphates monobasic, such as sodium dihydrogen phosphate and
potassium dihydrogen phosphate; phosphates dibasic, such as
disodium hydrogen phosphate and dipotassium hydrogen phosphate;
phosphates tribasic, such as trisodium phosphate; citrates, such as
sodium citrate (anhydrous or dehydrate) and triethyl citrate;
bicarbonates, such as sodium bicarbonate and potassium bicarbonate;
acetates, such as sodium acetate, may be used. In one embodiment, a
single buffering agent, e.g., a dibasic buffering agent is used. In
another embodiment, a combination of buffering agents is employed,
e.g., a combination of a tri-basic buffering agent and a monobasic
buffering agent. In some embodiments, the amount of buffering agent
is present in a composition used to make the mucoadhesive layer is
about 1 to 20% of the amount of the agonist drug, e.g.,
buprenorphine.
ii. Backing Layer
[0083] The device further comprises at least one additional
non-adhesive polymeric environment, e.g., a backing layer. This
layer is disposed adjacent to the mucoadhesive polymeric diffusion
environment, e.g., a backing layer, functions to facilitate the
delivery of the opioid agonist, such as buprenorphine, to the
mucosa. This additional layer may comprise the same or a different
combination of polymers as the mucoadhesive polymeric diffusion
environment or the non-adhesive polymeric diffusion
environment.
[0084] In some embodiments, the backing layer includes an
additional medicament, such as an opioid antagonist, to render the
device of the invention abuse-resistant. In some embodiments, the
opioid antagonist is naloxone. The dose of naloxone that can be
incorporated into the device of the present invention depends on
the desired treatment dosage to be administered and can range from
about 100 .mu.g to 5 mg of naloxone for the treatment of
dependence, and from 60 .mu.g to 1.5 mg naloxone for the pain
indication. In some embodiments, the dose of naloxone is between
about 0.0125 mg to about 2.0 mg of naloxone, e.g., 0.0125 mg,
0.0130 mg, 0.0135 mg, 0.0140 mg, 0.0145 mg, 0.0150 mg, 0.0155 mg,
0.0160 mg, 0.0165 mg, 0.0170 mg, 0.0175 mg, 0.0180 mg, 0.0185 mg,
0.0190 mg, 0.0195 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg,
0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.145 mg, 0.2 mg, 0.29 mg, 0.3
mg, 0.4 mg, 0.5 mg, 0.58 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.87 mg, 0.9
mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg,
1.8 mg, 1.9 mg or 2.0 mg of naloxone. In one embodiment, the dose
is 0.145 mg of naloxone. In another embodiment, the dose is 290
.mu.g of naloxone. In another embodiment, the dose is 580 .mu.g of
naloxone. In yet another embodiment, the dose is 870 .mu.g of
naloxone. In some embodiments, the amount of buprenorphine and the
amount of naloxone disposed in the device are present in a ratio
chosen such that the effect of buprenorphine is negated by naloxone
if the mixture is injected or snorted. In such embodiment,
buprenorphine and naloxone disposed in the device are present in a
w/w ratio that ranges between 1:4 and 1:10. In a preferred
embodiment, the w/w ratio of buprenorphine to naloxone is 1:4 to
1:6, wherein 1:6 is the most preferred embodiment.
[0085] In some embodiments, the backing layer (i.e., the
non-adhesive polymeric embodiment) functions as a barrier to
facilitate a unidirectional flux of the medicament, e.g.,
buprenorphine, disposed in the mucoadhesive layer. Upon application
to a mucosal surface, a diffusional gradient of a medicament is
created towards the mucosa. In another embodiment the backing
layer, can serve an erodible polymer that facilitate absorption of
buprenorphine in the orophyrangeal tissue. In some embodiments,
prevents diffusion away from the mucosal surface. In such
instances, a majority of the medicament, i.e., at least 50% flows
towards the mucosa. In other embodiments, as depicted in FIG. 1,
the non-adhesive polymeric environment may circumscribe the
boundaries of the mucoadhesive polymeric diffusion environment
thereby ensuring that medicament flows toward the mucosa.
[0086] The backing layer (e.g., a water-erodable non-adhesive
backing layer) can further include at least one water erodable,
film-forming polymer. This layer may optinally include a drug. The
polymer or polymers can include polyethers and polyalcohols as well
as hydrogen bonding cellulosic polymers having either hydroxyalkyl
group substitution or hydroxyalkyl group and alkyl group
substitution preferably with a moderate to high ratio of
hydroxyalkyl to alkyl group. Examples include, but are not limited
to, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (HPMC), hydroxyethylmethyl cellulose
(HEMC), polyvinyl alcohol (PVA), polyethylene glycol (PEG),
polyethylene oxide (PEO), ethylene oxide-propylene oxide co
polymers, ethylene oxide-propylene oxide co-polymers, and
combinations thereof. The water-erodable non-adhesive backing layer
component can optionally be cross-linked.
[0087] In certain embodiments, the non-adhesive backing layer is
free of cross-linked polymers. In a preferred embodiment of the
device, the non-adhesive backing layer is free of polyacrylic acid.
While not wishing to be bound by any specific theory, it is
estimated that the residence time is reduced by the absence of said
polyacrylic acid. For example, in certain embodiments, the
residence time is between 15 and 30 minutes. In a preferred
embodiment, the water erodable non-adhesive backing layer includes
hydroxyethyl cellulose and hydroxypropyl cellulose.
[0088] The devices of the present invention can include ingredients
that are employed to, at least in part, provide a desired residence
time. In some embodiments, this is a result of the selection of the
appropriate backing layer formulation, providing a slower rate of
erosion of the backing layer. Thus, the non-adhesive backing layer
is further modified to render controlled erodability which can be
accomplished by coating the backing layer film with a more
hydrophobic polymer selected from a group of FDA approved
Eudragit.TM. polymers, ethyl cellulose, cellulose acetate
phthalate, and hydroxyl propyl methyl cellulose phthalate, that are
approved for use in other pharmaceutical dosage forms. Other
hydrophobic polymers may be used, alone or in combination with
other hydrophobic or hydrophilic polymers, provided that the layer
derived from these polymers or combination of polymers erodes in a
moist environment. Dissolution characteristics may be adjusted to
modify the residence time and the release profile of a drug when
included in the backing layer.
[0089] In some embodiments, any of the layers in the devices of the
present invention may also contain a plasticizing agent, such as
propylene glycol, polyethylene glycol, or glycerin in a small
amount, 0 to 15% by weight, in order to improve the "flexibility"
of this layer in the mouth and to adjust the erosion rate of the
device. In addition, humectants such as hyaluronic acid, glycolic
acid, and other alpha hydroxyl acids can also be added to improve
the "softness" and "feel" of the device. Finally, colors and
opacifiers may be added to help distinguish the resulting
non-adhesive backing layer from the mucoadhesive polymeric
diffusion environment. Some opacifers include titanium dioxide,
zinc oxide, zirconium silicate, etc.
[0090] The device can also optionally include a pharmaceutically
acceptable dissolution-rate-modifying agent, a pharmaceutically
acceptable disintegration aid (e.g., polyethylene glycol, dextran,
polycarbophil, carboxymethyl cellulose, or poloxamers), a
pharmaceutically acceptable plasticizer, a pharmaceutically
acceptable coloring agent (e.g., FD&C Blue #1), a
pharmaceutically acceptable opacifier (e.g., titanium dioxide),
pharmaceutically acceptable anti-oxidant (e.g., tocopherol
acetate), a pharmaceutically acceptable system forming enhancer
(e.g., polyvinyl alcohol or polyvinyl pyrrolidone), a
pharmaceutically acceptable preservative, flavorants (e.g.,
saccharin and peppermint), neutralizing agents (e.g., sodium
hydroxide), buffering agents (e.g., monobasic, or tribasic sodium
phosphate), or combinations thereof. Preferably, these components
are individually present at no more than about 1% of the final
weight of the device, but the amount may vary depending on the
other components of the device.
[0091] In some embodiments, the non-adhesive polymeric diffusion
environment, e.g., the backing layer, is a buffered environment. In
some embodiments the pH of the backing layer is between 4.0 and
6.0, more specifically, between 4.2 and 4.7, and even more
specifically, between 4.2 and 4.4. In one embodiment, the pH of the
backing layer is 4.25. It is to be understood that all values and
ranges between these values and ranges are meant to be encompassed
by the present invention.
[0092] The pH of the backing layer can be adjusted and/or
maintained by methods including, but not limited to, the use of
buffering agents, or by adjusting the composition of the device of
the present invention. In some embodiments, the properties of the
polymeric diffusion environment are influenced by its buffering
capacity. In some embodiments, buffering agents are included in the
mucoadhesive polymeric diffusion environment. Buffering agents
suitable for use with the present invention include, for example,
phosphates, such as sodium phosphate; phosphates monobasic, such as
sodium dihydrogen phosphate and potassium dihydrogen phosphate;
phosphates dibasic, such as disodium hydrogen phosphate and
dipotassium hydrogen phosphate; phosphates tribasic, such as
trisodium phosphate; citrates, such as sodium citrate (anhydrous or
dehydrate) and triethyl citrate; bicarbonates, such as sodium
bicarbonate and potassium bicarbonate; acetates, such as sodium
acetate, may be used. In one embodiment, a single buffering agent,
e.g., a dibasic buffering agent is used. In another embodiment, a
combination of buffering agents is employed, e.g., a combination of
a tri-basic buffering agent and a monobasic buffering agent. In
some embodiments, the backing layer comprises the opioid
antagonist. In another embodiment, the backing layer comprises an
opioid antagonist that is present as a microencapsulated particle
with polymers. These polymers include, but are not limited to
alginates, polyethylene oxide, poly ethylene glycols, polylactide,
polyglycolide, lactide-glycolide copolymers,
poly-epsilon-caprolactone, polyorthoesters, polyanhydrides and
derivatives, methyl cellulose, ethyl cellulose, hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,
hydroxypropylmethyl cellulose, polyacrylic acid, and sodium
carboxymethyl cellulose, poly vinyl acetate, poly vinyl alcohols,
polyethylene glycol, polyethylene oxide, ethylene oxide-propylene
oxide co-polymers, collagen and derivatives, gelatin, albumin,
polyaminoacids and derivatives, polyphosphazenes, polysaccharides
and derivatives, chitin, chitosan bioadhesive polymers, polyacrylic
acid, polyvinyl pyrrolidone, sodium carboxymethyl cellulose and
combinations thereof.
EXEMPLIFICATION OF THE INVENTION
[0093] The invention will be further understood by the following
examples. However, those skilled in the art will readily appreciate
that the specific experimental details are only illustrative and
are not meant to limit the invention as described herein, which is
defined by the claims which follow thereafter.
Example 1
Preparation of the Devices of the Invention
[0094] Several formulations were prepared comprising different
doses of buprenorphine and naloxone, with the backing layers
adjusted to different pHs, as described in the Table 1 below:
TABLE-US-00001 TABLE 1 Formulations of the invention pH pH Ratio of
Formu- back- muco- buprenorphine lation ing adhesive Buprenorphine
Naloxone to naloxone No. layer layer (mg) (mg) (w/w) 1 2.8 4.75
0.75 0.1875 4:1 2 2.8 4.75 3.0 0.75 4:1 3 4.25 4.75 0.75 0.1875 4:1
4 4.25 4.75 3.0 0.75 4:1 5 4.25 4.75 0.875 0.15 6:1 6 4.25 4.75 3.5
0.6 6:1 7 4.25 4.75 5.25 0.875 6:1
[0095] The ingredients used to prepare the mucoadhesive layer for
Formulations 2, 4 and 6 are summarized in the Table 2 below:
TABLE-US-00002 TABLE 2 Ingredients for preparing the mucoadhesive
layer at pH 4.75 Amount (mg) Formulation 2 Formulation 4
Formulation 6 Ingredient 3.11 cm.sup.2 film 3.11 cm.sup.2 film 3.58
cm.sup.2 film Purified Water Constitutes Constitutes Constitutes
88.911% w/w of 88.911% w/w of 88.911% w/w of the wet blend the wet
blend the wet blend Propylene 0.704 0.704 0.822 Glycol Sodium 0.082
0.082 0.095 Benzoate Methylparaben 0.137 0.137 0.160 Propylparaben
0.038 0.038 0.045 Yellow Ferric 0.082 0.082 0.095 Oxide Citric
Acid, 0.082 0.082 0.096 Anhydrous Vitamin E 0.008 0.008 0.010
Acetate Monobasic 0.521 0.520 0.607 Sodium Phosphate, Anhydrous
Buprenorphine 3.234 3.234 3.773 HCl Polycarbophil 0.980 0.979 1.143
Hydroxypropyl 1.051 1.051 1.226 Cellulose Hydroxyethyl 3.144 3.143
3.668 Cellulose Carboxy- 8.399 8.398 9.799 methyl- cellulose Sodium
Sodium 0.043 0.043 0.051 Hydroxide
[0096] The mucoadhesive layer for Formulations 1 and 3 is prepared
using the same ingredients as for formulations 2 and 4,
respectively, except that the amounts of all ingredients are
adjusted in direct proportion to the amount of buprenorphine and
the film size of 0.78 cm.sup.2. Similarly, the mucoadhesive layer
for Formulations 5 and 7 are prepared using the same ingredients as
for Formulation 6, except that the amounts of all ingredients are
adjusted in direct proportion to the amount of buprenorphine and
film size of 0.9 cm.sup.2 for formulation 5 and 5.37 cm.sup.2 for
Formulation 7.
[0097] The ingredients used to prepare the backing layer in
Formulation 2 are summarized in the Table 3 below:
TABLE-US-00003 TABLE 3 Ingredients for preparing the backing layer
at pH 2.8 and 4.25 Amount (mg) Formulation 2 Formulation 4
Formulation 6 Ingredient 3.11 cm.sup.2 film 3.11 cm.sup.2 film 3.58
cm.sup.2 film Purified Water Constitutes Constitutes Constitutes
88.911% w/w of 88.911% w/w of 88.911% w/w of the wet blend the wet
blend the wet blend Hydroxypropyl -- 46.337 56.164 Cellulose
Hydroxyethyl 65.182 22.920 27.740 Cellulose Sodium 0.296 0.371
0.449 Benzoate Methylparaben 0.296 0.337 0.408 Propylparaben 0.074
0.067 0.082 Dibasic -- 0.167 0.203 Sodium Phosphate Citric acid,
2.955 0.412 0.498 anhydrous Vitamin E 0.030 0.034 0.041 acetate
Saccharin 1.786 1.416 0.054 Sodium Yellow Ferric 0.057 0.044 1.751
Oxide Triethyl Citrate 3.774 -- -- Citrus Flavor -- 1.989 2.409
Peppermint Oil 0.608 -- -- Naloxone HCl 0.916 0.916 0.733
[0098] The backing layer for Formulations 1 and 3 is prepared using
the same ingredients as for Formulations 2 and 4, respectively,
except that the amounts of all ingredients are adjusted in direct
proportion to the amount of naloxone and the film size of 0.78
cm.sup.2. Similarly, the backing layer for Formulations 5 and 7 is
prepared using the same ingredients as for Formulation 6, except
that the amounts of all ingredients are adjusted in direct
proportion to the amount of buprenorphine and film size of 0.9
cm.sup.2 for Formulation 5 and 5.37 cm.sup.2 for Formulation 7.
Example 2
Absorption Profiles for Formulations 1 and 2
[0099] This was an open label, active controlled study in healthy
subjects in order to compare pharmacokinetic parameters of
buprenorphine and naxolone from formulations 1 and 2 with
Suboxone.RTM. sublingual tablets. Blood samples for analysis were
collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 16
hours post-dose and analyzed using the established procedures
utilizing liquid chromatography and mass spectrometry (LC/MS). The
selected pharmacokinetic parameters for buprenorphine and total
naloxone are shown in Tables 4 and 5.
TABLE-US-00004 TABLE 4 Selected Pharmacokinetic Parameters for
Buprenorphine and Total Naloxone for low dose formulations.
Formulation 1 (0.75 mg Suboxone .RTM. (2.0 mg buprenorphine/0.1875
mg naloxone, buprenorphine/0.5 mg backing layer at pH 2.8)
naloxone) Pharmacokinetic Total Total Parameter Buprenorphine
Naloxone Buprenorphine Naloxone Mean T.sub.max (hr) 2.29 1.29 1.75
0.92 Mean C.sub.max (ng/mL) 0.564 2.24 1.28 5.88 Mean AUC.sub.last
(hr*ng/mL) 3.379 4.021 9.177 12.38 Mean AUC.sub.inf (hr*ng/mL)
3.868 4.585 10.92 13.26 Mean T.sub.1/2 10.72 2.58 23.72 4.15
Absolute Bioavailability 46% -- 25% .sup.1 -- .sup.1 Roy, S. D. et
al., Transdermal delivery of buprenorphine through cadaver skin
(1994), J. Pharm. Sci., 83: 126-130.
TABLE-US-00005 TABLE 5 Selected Pharmacokinetic Parameters for
Buprenorphine and Total Naloxone for high dose formulations
Formulation 2 (3.0 mg Suboxone .RTM. (8.0 mg buprenorphine/0.75 mg
naloxone, buprenorphine/2.0 mg backing layer at pH 2.8) naloxone)
Pharmacokinetic Total Total Parameter Buprenorphine Naloxone
Buprenorphine Naloxone Mean T.sub.max (hr) 2.29 1.29 1.75 0.92 Mean
C.sub.max (ng/mL) 0.564 2.24 1.28 5.88 Mean AUC.sub.last (hr*ng/mL)
3.379 4.021 9.177 12.38 Mean AUC.sub.inf (hr*ng/mL) 3.868 4.585
10.92 13.26 Mean T.sub.1/2 10.72 2.58 23.72 4.15 Absolute
Bioavailability 50% -- 25% --
[0100] The results indicate that C.sub.max and AUC.sub.inf values
for buprenorphine and total naloxone from Formulations 1 and 2 are
less than the values observed from the control Suboxone.RTM.
tablets.
Example 3
Absorption Profiles for Formulations 3 and 4
[0101] This study was designed to compare the plasma
pharmacokinetic parameters of buprenorphine and naxolone from
formulations 3 and 4 with Suboxone.RTM. sublingual tablets. This
was a single dose, 2-period, crossover design with 24 subjects
randomized to one of two, 12-subject groups. Each group received
the device of the invention and Suboxone.RTM. tablets in random
sequence, each separated by at least 5 days. Group 1 subjects
received a single low dose Suboxone.RTM. tablet (containing 2.0 mg
of buprenorphine and 0.5 mg of naloxone) and a single dose of
formulation 3. Group 2 subjects received a single high dose
Suboxone.RTM. tablet (containing 8.0 mg of buprenorphine and 2.0 mg
of naloxone) and a single dose of formulation 4. Naltrexone was
co-administered approximately 12 hours and 30 minutes prior to and
approximately 12 and 24 hours after the single study drug doses.
Serial blood samples for pharmacokinetic analyses were collected
pre-dose and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180,
210, 240, 270, 300, 330 and 360 minutes post-dose and at 8, 10, 12,
24 and 48 hours post-dose. Blood samples were analyzed using the
established procedures utilizing liquid chromatography and mass
spectrometry (LC/MS). The selected pharmacokinetic parameters for
buprenorphine and free naloxone are shown in Tables 6 and 7.
TABLE-US-00006 TABLE 6 Selected Pharmacokinetic Parameters for
Buprenorphine and Free Naloxone for low dose formulations
Formulation 3 (0.75 mg Suboxone .RTM. (2.0 mg buprenorphine/0.1875
mg naloxone, buprenorphine/0.5 mg backing layer at pH 4.25)
naloxone) Pharmacokinetic Free Free Parameter Buprenorphine
Naloxone Buprenorphine Naloxone Mean T.sub.max (hr) 2.11 1.17 1.8
0.85 Mean C.sub.max (ng/mL) 1.10 0.0528 0.853 0.0441 Mean
AUC.sub.last (hr*ng/mL) 5.325 0.1297 6.321 0.1151 Mean AUC.sub.inf
(hr*ng/mL) 5.938 0.1346 7.339 0.1208 Mean T.sub.1/2 10.10 1.22
20.33 2.06 Absolute Bioavailability 75% -- 25% --
TABLE-US-00007 TABLE 7 Selected Pharmacokinetic Parameters for
Buprenorphine and Free Naloxone for high dose formulations
Formulation 4 (3.0 mg Suboxone .RTM. (8.0 mg buprenorphine/0.75 mg
naloxone, buprenorphine/2.0 mg backing layer at pH 4.25) naloxone)
Pharmacokinetic Free Free Parameter Buprenorphine Naloxone
Buprenorphine Naloxone Mean T.sub.max (hr) 2.17 1.05 1.70 0.92 Mean
C.sub.max (ng/mL) 3.44 0.233 3.21 0.152 Mean AUC.sub.last
(hr*ng/mL) 19.46 0.5815 23.05 0.4529 Mean AUC.sub.inf (hr*ng/mL)
21.50 0.5884 29.76 0.471 Mean T.sub.1/2 18.82 2.80 29.21 6.33
Absolute Bioavailability 65% -- 25% --
[0102] The results indicate that, unexpectedly, the absorption of
buprenorphine from Formulations 3 and 4 are increased, as compared
to control. This increase in buprenorphine absorption is
particularly surprising in view of the results of Example 2 and is
caused by the change of pH of the backing layer from 2.8 in
Formulations 1 and 2 to 4.25 in Formulations 3 and 4.
[0103] The results also indicate that C.sub.max values for
buprenorphine from Formulations 3 and 4 are comparable to values
from the control Suboxone.RTM. tablets and that the AUC.sub.inf
values for buprenorphine from the devices of the invention are
slightly less than the values from the corresponding Suboxone.RTM.
tablets. Further, the C.sub.max and AUC.sub.inf values for free
(unconjugated) naloxone are greater than the values from the
corresponding Suboxone.RTM. tablets.
Example 4
Absorption Profiles for Formulations 5, 6 and 7
[0104] This study was designed to assess the plasma pharmacokinetic
parameters for buprenorphine and naloxone exposure following
administration of Formulations 5, 6 and 7 comprising buprenorphine
and naloxone present at the w/w ratio of 6:1 of buprenorphine to
naloxone and with the backing layer formulated at pH of 4.25. This
study was also designed to demonstrate the linearity of
buprenorphine exposure across the range of doses. In addition,
pharmacokinetic profiles following administration of four devices
prepared according to formulation 5 (4.times.0.875/0.15 mg
buprenorphine/naloxone) was compared with those from a single
device prepared according to formulation 6 that contained an
equivalent dose of actives (3.5/0.6 mg buprenorphine/naloxone).
[0105] This was an open label, single dose, 4-period crossover
study in 20 healthy subjects. Each subject received 4 doses of
buprenorphine in the devices of the invention in a random sequence,
each dose separated by at least 7 days. The doses administered were
0.875/0.15 mg, 3.5/0.6 mg, 5.25/0.9 mg and 4.times.0.875/0.15 mg
buprenorphine/naloxone in the devices prepared according to
Formulations 5, 6, 7 and 5, respectively. Naltrexone was
co-administered approximately 12 hours and 30 minutes prior to and
approximately 12 and 24 hours after the single study drug doses.
Serial blood samples for pharmacokinetic analyses were collected
pre-dose and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180,
210, 240, 270, 300, 330 and 360 minutes post-dose and at 8, 10, 12,
24 and 48 hours post-dose. Blood samples were analyzed using the
established procedures utilizing liquid chromatography and mass
spectrometry (LC/MS). The selected pharmacokinetic parameters for
buprenorphine and free naloxone are shown in Tables 8 and 9.
TABLE-US-00008 TABLE 8 Selected Pharmacokinetic Parameters for
Buprenorphine and Free Naloxone for formulations 5 and 7
Formulation 5 (0.875 mg Formulation 7 (5.25 mg buprenorphine/0.15
mg naloxone, buprenorphine/0.875 mg naloxone, backing layer at pH
4.25) backing layer at pH 4.25) Pharmacokinetic Free Free Parameter
Buprenorphine Naloxone Buprenorphine Naloxone Mean T.sub.max (hr)
2.84 1.13 2.71 1.38 Mean C.sub.max (ng/mL) 1.15 0.0443 5.13 0.182
Mean AUC.sub.last (hr*ng/mL) 7.372 0.1166 33.28 0.4892 Mean
AUC.sub.inf (hr*ng/mL) 8.380 0.1202 36.19 0.5233 Absolute
Bioavailability ~60% -- ~60% --
TABLE-US-00009 TABLE 9 Selected Pharmacokinetic Parameters for
Buprenorphine and Free Naloxone for formulation 6 and formulation 5
administered as 4 doses Formulation 6 (3.5 mg 4 x Formulation 5
(0.875 mg buprenorphine/0.6 mg naloxone, buprenorphine/0.15 mg
naloxone, backing layer at pH 4.25) backing layer at pH 4.25)
Pharmacokinetic Free Free Parameter Buprenorphine Naloxone
Buprenorphine Naloxone Mean T.sub.max (hr) 2.78 1.48 2.75 1.38 Mean
C.sub.max (ng/mL) 4.03 0.179 3.89 0.182 Mean AUC.sub.last
(hr*ng/mL) 24.77 0.4801 25.33 0.4892 Mean AUC.sub.inf (hr*ng/mL)
27.32 0.4883 27.29 0.5233 Absolute Bioavailability ~60% -- --
--
[0106] The results of the study indicate that changing the w/w
ratio of buprenorphine to naloxone from 4:1 to 6:1 results in
decreased naloxone exposure that I s more in line with the exposure
needed to precipitate withdrawal if abused but not so much as to
precipitate the withdrawal if used as indicated. The results also
indicate that C.sub.max and AUC.sub.inf of buprenorphine from
formulations 5, 6 and 7 is dose proportional. Dose proportionality
of buprenorphine C.sub.max and AUC.sub.inf are also illustrated by
the graphs shown in FIGS. 2 and 3, respectively.
Example 5
Naloxone Withdrawal Study
[0107] The transmucosal devices of the invention that are prepared
according to Formulations 1, 3 and 5 comprise relatively small
doses of buprenorphine and naloxone (0.75 mg/0.19 mg and 0.875/0.15
mg buprenorphine/naloxone, as compared to 2 mg/0.5 mg
buprenorphine/naloxone contained in the equivalent Suboxone.RTM.
tablet). While the lower dose of the naloxone may be beneficial for
the patient using the product correctly, it may not produce the
expected aversive reaction experienced by those who are dependent
on full-agonist opioids. Accordingly, the objective of the study
was to determine the minimum effective dose of naloxone that will
produce a withdrawal response when administered with a 0.75 mg dose
of buprenorphine in opioid dependent subjects. The secondary
objective of the study was to determine whether administration of a
0.75 mg dose of buprenorphine without naloxone will produce a
withdrawal response in opioid dependent subjects.
Study Population
[0108] The study was designed to include a total of 12 adult
subjects that completed the 4-period crossover. Subjects were
eligible for inclusion in the study if all the following criteria
applied:
[0109] subjects experienced chronic moderate to severe non-cancer
pain that has been treated >100 mg morphine equivalents per day
for at least 3 months prior to the study;
[0110] subjects displayed signs and symptoms of withdrawal (i.e.,
COWS score .gtoreq.5) following naloxone administration during the
Naloxone Challenge.
Description of Study Medication
[0111] During the inpatient Treatment Visit subjects received a
single, 3 mL IV bolus dose of each of the following treatments
separated by at least 72 hours:
[0112] a) Buprenorphine 0.75 mg (B)
[0113] b) Buprenorphine 0.75 mg+naloxone 0.1 mg (BN1)
[0114] c) Buprenorphine 0.75 mg+naloxone 0.2 mg (BN2)
[0115] d) Placebo (5% dextrose) (P)
Study Procedures
[0116] Eligible subject exhibited signs of withdrawal, e.g., had a
positive response (COWS .gtoreq.5) to the Naloxone Withdrawal Test,
following administration of up to eight 0.05 mg IV doses of
naloxone.
Clinical Opiate Withdrawal Scale
[0117] The Clinical Opiate Withdrawal Scale (COWS) was used to
evaluate symptoms of opioid withdrawal. The scale contains 11 items
to rate signs and symptoms of opioid withdrawal including pulse
rate, gastrointestinal upset, sweating, tremor, restlessness,
yawning, pupil size, anxiety or irritability, bone or joint aches,
gooseflesh skin, runny nose, tearing. Each symptom is rated on a
unique scale. Total scores for the scale range from 0 to 48 with
scores of 5-12 indicating mild withdrawal; scores of 13-24
indicating moderate withdrawal; scores of 25-36 indicating
moderately severe withdrawal; and scores >36 indicating severe
withdrawal.
Opioid Agonist Scale
[0118] Subjects were asked to evaluate the following items:
nodding, heavy or sluggish feeling, dry mouth, carefree, good mood,
energetic, turning of stomach, skin itchy, relaxed, coasting,
soapbox, pleasant sick, drive, drunken, friendly, and nervous using
a 5-point Likert scale (0=not at all, 1=a little, 2=moderately,
3=quite a bit, and 4=extremely).
Statistical Analysis
[0119] Descriptive statistics were used to summarize the results
from the PD analyses at each timepoint for each treatment group,
without formal statistical testing. A mixed effect model was fitted
to the data for the change from baseline in total score where the
model included factors for: the overall mean change; fixed effects
due to sequence; treatment, time and period; and a random effect
for subject nested within sequence. The least squares mean changes
and standard errors were obtained and used to construct 95% CI for
differences between treatments in a pair-wise fashion. Subject data
collected after rescue time (i.e., time at which the subjects
reaches COWS total score of 13 or more) were excluded to minimize
the confounding effect of rescue on the PD analyses.
[0120] For COWS total score only, Time-to-Total score of >13 was
calculated as time (hours) from first dose until the subject
reports a total score of >13. Subjects who did not reach a total
score of 13 or more were censored at 24 hours. This endpoint was
summarized using the Kaplan-Meier method and 95% CI presented for
median for each treatment arm.
Results
COWS Total-Score, and Rescue Results
[0121] The number of subjects with COWS total score of at least 7
in the first hour post dose is shown on the left side of FIG. 4.
Eight subjects on buprenorphine alone had a COWS value of at least
7 compared with 9 in the buprenorphine plus naloxone 0.1 mg group,
12 subjects in the buprenorphine plus naloxone 0.2 mg group, and
two on placebo. Similarly, COWS .gtoreq.13 were recorded for 6
buprenorphine subjects, 9 buprenorphine and naloxone 0.1 mg
subjects, 10 buprenorphine and naloxone 0.2 mg, and 2 placebo
patients. Two of the 15 subjects experienced withdrawal on each of
the study treatments, including placebo.
[0122] In the buprenorphine alone group, 7(47%) of the 15 subjects
experienced moderate withdrawal with COWS score of at least 13, and
all 7 were rescued. In the 8 subjects that did not receive rescue,
the median COWS at 1 hour post dose was 1.
[0123] In the buprenorphine plus 0.1 mg of naloxone group, 9
subjects (60%) had COWS .gtoreq.13 and all 9, plus an additional
subject that was rescued. In the 5 subjects that did not receive
rescue, the median COWS at one hour post dose was 0.
[0124] In the buprenorphine plus 0.2 mg of naloxone group, 11
subjects (73%) had COWS scores of at least 13 and each of these
received rescue. In the 4 subjects that were not rescued, the
median COWS at one hour post dose was 3.
TABLE-US-00010 TABLE 10 Summary of COWS Total Scores and Rescue
Results B BN1 BN2 P Parameter (n = 15) (n = 15) (n = 15) (n = 15)
COWS >= 13, n (%) 7 (47%) 9 (60%) 11 (73%) 2 (1%) Rescued n (%)
7 (47%) 10 (67%) 11 (73%) 2 (1%) Median COWS 1 0 3 0 at One Hour
Post Dose
Drug Effect Questionnaire (DEQ)--Observed Median Values 1 Hour Post
Dose
[0125] Median DEQ responses at one hour in those subjects that were
not rescued are shown in Table 6 below.
[0126] The median DEQ scores for each parameter in all but the BN2
group were zero or nearly zero at one hour post dose. In contrast,
the BN2 group had significantly higher scores on drug effect,
nausea, bad effect, dizziness, and feeling sick.
[0127] The median score for good effect and how high are you was
zero at one hour in all treatment groups.
TABLE-US-00011 TABLE 11 Median DEQ responces at one hour in
subjects who were not rescued. B BN1 BN2 P Parameter (n = 15) (n =
15) (n = 15) (n = 15) Drug effect 2 0 49 0 Nausea 0 0 38 0 Like
drug 0 0 0 0 Good effect 0 0 0 0 Bad Effect 0 0 27 0 Dizzy 0 0 14 0
Feel Sleepy 0 0 0 0 Feel sick 0 0 30 0 How high are you 0 0 0 0
[0128] The results of this double-blind, placebo controlled study
in opioid dependent subjects indicate that intravenous
buprenorphine doses of 0.75 mg have little abuse potential, and
that the addition of naloxone increases both the incidence of
withdrawal as well as negative drug evaluations. Thus, naloxone at
doses of 0.1 and 0.2 mg, provide an abuse deterrent effect to a
0.75 mg dose of buprenorphine when administered intravenously to
opioid dependent subjects.
EQUIVALENTS
[0129] While the present invention has been described in
conjunction with various embodiments and examples it is not
intended that the present teachings be limited to such embodiments
or examples. On the contrary, the present invention encompasses
various alternatives, modifications, and equivalents, as will be
appreciated by those of skill in the art.
* * * * *