NZ622610B2 - Abuse-resistant mucoadhesive devices for delivery of buprenorphine - Google Patents
Abuse-resistant mucoadhesive devices for delivery of buprenorphine Download PDFInfo
- Publication number
- NZ622610B2 NZ622610B2 NZ622610A NZ62261012A NZ622610B2 NZ 622610 B2 NZ622610 B2 NZ 622610B2 NZ 622610 A NZ622610 A NZ 622610A NZ 62261012 A NZ62261012 A NZ 62261012A NZ 622610 B2 NZ622610 B2 NZ 622610B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- buprenorphine
- naloxone
- mucoadhesive
- backing layer
- dose
- Prior art date
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Abstract
The present disclosure 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. In one embodiment the mucoadhesive layer comprises between about 0.075 and about 12 mg of buprenorphine buffered to a pH of between about 4.0 and about 6.0 and the backing layer comprises between about 0.0125 and about 2 mg of naloxone buffered to a pH between about 4.0 and about 4.8. ises between about 0.075 and about 12 mg of buprenorphine buffered to a pH of between about 4.0 and about 6.0 and the backing layer comprises between about 0.0125 and about 2 mg of naloxone buffered to a pH between about 4.0 and about 4.8.
Description
ABUSE-RESISTANT MUCOADHESIVE DEVICES FOR DELIVERY OF
BUPRENORPHINE
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 61/525,094,
filed on August 18, 2011. This application is also related to U.S. Patent Application No.
08/734,519, filed on October 18, 1996, now U.S. Patent No. 5,800,832, issued on
September 1, 1998; U.S. Patent Application No. 11/639,408, filed on December 13,
2006; U.S. Patent Application No. 11/817,915, filed on September 6, 2007; and U.S.
Patent Application No. 13/184,306, filed on July 15, 2011, now U.S. Patent No.
8,147,866, issued on April 3, 2012. The entire contents of each of the foregoing
applications are incorporated herein by reference.
BACKGROUND
Buprenorphine is a partial Lit-opiate receptor agonist, an ORL1/nociceptin
receptor agonist with high affinity, and slow association and dissociation from the
receptors, and a lc-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
Buprenex®
been generally available as Temgesic® 0.2 mg sublingual tablets and as in a
0.3 mg/ml parenteral formulation, both indicated for the treatment of moderate to severe
pain.
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® 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
FIGURE 1 is a schematic representation of exemplary embodiments of the
present invention.
FIGURE 2 is a graph showing assessment of dose-proportionality of
buprenorphine C. 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.
FIGURE 3 is a graph showing assessment of dose-proportionality of
buprenorphine AUCia 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.
FIGURE 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.
FIGURE 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
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.
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.
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.
In some embodiments, the present invention provides an abuse deterrent
mucoadhesive device for use in managing pain or opioid dependence, the device
comprising:
a mucoadhesive layer comprising 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.
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.
In some embodiments, the present invention provides an abuse deterrent
mucoadhesive device for use in managing pain or opioid dependence, the device
comprising:
a mucoadhesive layer comprising 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;
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%.
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.
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%.
In some embodiments, the present invention provides an abuse deterrent
mucoadhesive device for use in managing pain or opioid dependence, the device
comprising:
a mucoadhesive layer comprising buprenorphine and buffered to a first
a backing layer buffered to a second pH;
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.
In some embodiments, the invention also provides an abuse deterrent
mucoadhesive device for use in managing pain or opioid dependence, the device
comprising:
a mucoadhesive layer comprising buprenorphine and buffered to a first
a backing layer buffered to a second pH,
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.
In some embodiments, an abuse deterrent mucoadhesive device for use in
managing pain or opioid dependence comprises:
a mucoadhesive layer comprising buprenorphine and buffered to a first pH and a
backing layer buffered to a second pH;
wherein the first pH is between about 4.0 and about 6.0;
wherein the second pH is between about 4.0 and about 4.8.
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.
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.
In some embodiments, an abuse deterrent mucoadhesive device for use in
managing pain or opioid dependence comprises:
a mucoadhesive layer comprising buprenorphine and buffered to a first pH and a
backing layer buffered to a second pH;
wherein the first pH is between about 4.0 and about 6.0;
wherein the second pH is between about 4.0 and about 4.8; and
wherein bioavailability of buprenorphine absorbed from the device is
greater than 40%. In some embodiments, the backing layer comprises naloxone.
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.
In a preferred embodiment, the abuse deterrent mucoadhesive device for use in
managing pain or opioid dependence comprises:
a mucoadhesive layer comprising buprenorphine and buffered to a first pH and a
backing layer comprising naloxone and buffered to a second pH;
wherein the first pH is about 4.75;
wherein the second pH is about 4.25; and
wherein buprenorphine and naloxone disposed in the device are present
in w/w ratio of about 6:1 of buprenorphine:naloxone.
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
The following definitions are provided as guidance as to the meaning of certain
terms used herein.
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.
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 AUCin
f and Cmax.
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.
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%.
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 Cmax 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®
sublingual tablet. Pharmacokinetic parameters, e.g., C. and Suboxone®
AUCinf,
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®, which is incorporated herein by reference
in its entirety.
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.
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:
.p H34
IIIII
R60 OCH3
or pharmaceutically acceptable salts or esters thereof, wherein
'is \
is a double or single bond; R3 is selected from a -C14 alkyl group or a
cycloalkyl-substituted-C14 alkyl group; R4 is selected from a -C14 alkyl; R5 is —OH, or
taken together, R4 and R5 form a =0 group; and R6 is selected from —H or a -C14 alkyl
group.
Buprenorphine derivatives include, but are not limited to, etorphine and
diprenorphine. General buprenorphine derivatives are described in ,
which is hereby incorporated by reference.
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:
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
As used herein, the term "abusive" or "abusive manner" refers to uses of the
devices beyond transmucosal administration such as by injecting or snorting.
As used herein, the term "disposed" refers to the uniform or non-uniform
distribution of an element within another.
Maintenance Treatment of Opioid Dependence
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
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
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.
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
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.
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
j.tg to about 20 mg of buprenorphine. In other embodiments related to the treatment of
pain, the dose of buprenorphine can range from about 60 [tg 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.
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).
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.
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.
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.
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.
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.
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
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.
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 m.g to 5
mg of naloxone for the treatment of dependence, and from 60 j.tg 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
[tg of naloxone. In another embodiment, the dose is 580 [tg of naloxone. In yet another
embodiment, the dose is 870 [tg 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.
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.
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.
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.
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 EudragitTM 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.
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.
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.
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.
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
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
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 I. Formulations of the invention
Formulation pH pH Buprenorphine Naloxone Ratio of
No. backing mucoadhesive (mg) (mg) buprenorphine
layer layer to naloxone
(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
4.25 4.75 0.875 0.15 6:1
4.25 4.75
6 3.5 0.6 6:1
7 4.25 4.75 5.25 0.875 6:1
The ingredients used to prepare the mucoadhesive layer for Formulations 2, 4
and 6 are summarized in the Table 2 below:
Table 2. Ingredients for preparing the mucoadhesive layer at pH 4.75
Ingredient Amount (mg)
Formulation 2 Formulation 4 Formulation 6
3.11 cm2 film 3.11 cm2 film 3.58 cm2 film
Constitutes Constitutes Constitutes
88.911% w/w of 88.911% w/w of 88.911% w/w of
Purified Water the wet blend the wet blend the wet blend
Propylene Glycol 0.704 0.704 0.822
Sodium Benzoate 0.082 0.082 0.095
Methylparaben 0.137 0.137 0.160
Propylparaben 0.038 0.038 0.045
Yellow Ferric Oxide 0.082 0.082 0.095
Citric Acid, Anhydrous 0.082 0.082 0.096
Vitamin E Acetate
0.008 0.008 0.010
Monobasic Sodium
0.521 0.520 0.607
Phosphate, Anhydrous
Buprenorphine HC1 3.234 3.234 3.773
Polycarbophil 0.980 0.979 1.143
Hydroxypropyl Cellulose 1.051 1.051 1.226
Hydroxyethyl Cellulose 3.144 3.143 3.668
8.399 8.398 9.799
Carboxymethylcellulose
Sodium
Sodium Hydroxide 0.043 0.043 0.051
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 cm2. 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 cm2 for formulation 5 and 5.37 cm2 for Formulation 7.
The ingredients used to prepare the backing layer in Formulation 2 are
summarized in the Table 3 below:
Table 3. Ingredients for preparing the backing layer at pH 2.8 and 4.25
Ingredient Amount (mg)
Formulation 2 Formulation 4
Formulation 6
3.11 cm2 film 3.11 cm2 film 3.58 cm2 film
Constitutes 88.911% Constitutes 88.911% Constitutes 88.911%
Purified Water w/w of the wet blend w/w of the wet blend w/w of the wet blend
Hydroxypropyl - 46.337 56.164
Cellulose
Hydroxyethyl 65.182 22.920 27.740
Cellulose
Sodium Benzoate 0.296
0.371 0.449
Methylparaben 0.296 0.337 0.408
Propylparaben 0.074 0.067 0.082
Dibasic Sodium - 0.167 0.203
Phosphate
Citric acid, 2.955 0.412 0.498
anhydrous
Vitamin E acetate 0.030 0.034 0.041
Saccharin Sodium 1.786 1.416 0.054
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
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 cm2. 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 cm2 for
Formulation 5 and 5.37 cm2 for Formulation 7.
Example 2. Absorption profiles for Formulations 1 and 2.
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® 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 4. Selected Pharmacokinetic Parameters for Buprenorphine and Total
Naloxone for low dose formulations.
Pharmacokinetic Formulation 1 (0.75 mg Suboxone® (2.0 mg
Parameter buprenorphine / 0.1875 mg buprenorphine / 0.5 mg
naloxone, backing layer at pH naloxone)
2.8)
Buprenorphine Total Buprenorphine Total
Naloxone Naloxone
2.29 1.29 1.75
Mean T. (hr) 0.92
Mean 0.564 2.24 1.28 5.88
Cmax
(ng/mL)
Mean 3.379 4.021 9.177 12.38
AUCiasi
(hr*ng/mL)
Mean AUCinf 3.868 4.585 10.92 13.26
(hr*ng/mL)
.72 2.58 23.72 4.15
Mean
T1/2
46% 25%'
Absolute
Bioavailability
Table 5. Selected Pharmacokinetic Parameters for Buprenorphine and Total
Naloxone for high dose formulations
Pharmacokinetic Formulation 2 (3.0 mg Suboxone® (8.0 mg
Parameter buprenorphine / 0.75 mg buprenorphine / 2.0 mg
naloxone, backing layer at pH naloxone)
2.8)
Buprenorphine Total Buprenorphine Total
Naloxone Naloxone
2.29 1.29 1.75 0.92
Mean Tmax (hr)
0.564 2.24 1.28 5.88
Mean
Cmax
(ng/mL)
4.021 9.177
Mean 3.379 12.38
AUCiast
(hr*ng/mL)
Mean AUCinf 3.868 4.585 10.92 13.26
(hr*ng/mL)
.72 23.72 4.15
2.58
Mean T1/2
Absolute 50% 25%
Bioavailability
The results indicate that Cmax and AUC inf values for buprenorphine and total
naloxone from Formulations 1 and 2 are less than the values observed from the control
Suboxone® tablets.
Example 3. Absorption profiles for Formulations 3 and 4.
This study was designed to compare the plasma pharmacokinetic parameters of
buprenorphine and naxolone from formulations 3 and 4 with Suboxone® sublingual
1 Roy, S. D. et al., Transdermal delivery of buprenorphine through cadaver skin (1994), J. Pharm. Sci.,
83:126-130.
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® tablets in random sequence, each separated by at least 5 days. Group 1
subjects received a single low dose Suboxone® 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® 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 6. Selected Pharmacokinetic Parameters for Buprenorphine and Free
Naloxone for low dose formulations
Pharmacokinetic Formulation 3 (0.75 mg Suboxone® (2.0 mg
Parameter buprenorphine / 0.1875 mg buprenorphine / 0.5 mg
naloxone, backing layer at pH naloxone)
4.25)
Buprenorphine Free Buprenorphine Free
Naloxone Naloxone
Mean T. (hr) 2.11 1.17 1.8 0.85
1.10 0.0528 0.853 0.0441
Mean
Cmax
(ng/mL)
.325 0.1297 6.321 0.1151
Mean
AUCiasi
(hr*ng/mL)
.938 0.1346 7.339 0.1208
Mean AUCinf
(hr*ng/mL)
.10 1.22 20.33 2.06
Mean
T1/2
Absolute 75% 25%
Bioavailability
Table 7. Selected Pharmacokinetic Parameters for Buprenorphine and Free
Naloxone for high dose formulations
Pharmacokinetic Formulation 4 (3.0 mg
Suboxone® (8.0 mg
Parameter buprenorphine / 0.75 mg buprenorphine / 2.0 mg
naloxone, backing layer at pH naloxone)
4.25)
Buprenorphine Buprenorphine Free
Free
Naloxone Naloxone
2.17 1.70
Mean Tmax (hr) 1.05 0.92
3.44 3.21
Mean 0.233 0.152
Cmax
(ng/mL)
Mean 19.46 0.5815 23.05 0.4529
AUCiast
(hr*ng/mL)
Mean AUCmf 21.50 0.5884 29.76 0.471
(hr*ng/mL)
18.82 2.80 29.21 6.33
Mean T112
Absolute 65% 25%
Bioavailability
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.
The results also indicate that Cmax values for buprenorphine from Formulations 3
and 4 are comparable to values from the control Suboxone® tablets and that the AUCinf
values for buprenorphine from the devices of the invention are slightly less than the
values from the corresponding Suboxone® tablets. Further, the C. and AUCi f values
for free (unconjugated) naloxone are greater than the values from the corresponding
Suboxone® tablets.
Example 4. Absorption profiles for Formulations 5, 6 and 7.
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 x 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).
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 x 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 8. Selected Pharmacokinetic Parameters for Buprenorphine and Free
Naloxone for formulations 5 and 7
Pharmacokinetic Formulation 5 (0.875 mg Formulation 7 (5.25 mg
Parameter buprenorphine / 0.15 mg buprenorphine / 0.875 mg
naloxone, backing layer at pH naloxone, backing layer at pH
4.25) 4.25)
Buprenorphine Buprenorphine
Free Free
Naloxone Naloxone
Mean Tmax (hr) 2.84 1.13 2.71 1.38
1.15 0.0443 5.13 0.182
Mean
Cmax
(ng/mL)
7.372 0.1166 33.28 0.4892
Mean AUCiast
(hr*ng/mL)
8.380 0.1202 36.19 0.5233
Mean AUCinf
(hr*ng/mL)
Absolute - 60% - 60%
Bioavailability
Table 9. Selected Pharmacokinetic Parameters for Buprenorphine and Free
Naloxone for formulation 6 and formulation 5 administered as 4 doses
Pharmacokinetic Formulation 6 (3.5 mg 4 x Formulation 5 (0.875 mg
Parameter buprenorphine / 0.6 mg buprenorphine / 0.15 mg
naloxone, backing layer at pH naloxone, backing layer at pH
4.25) 4.25)
Buprenorphine Free Buprenorphine Free
Naloxone Naloxone
Mean T. (hr) 2.78 1.48 2.75 1.38
4.03 0.179 3.89 0.182
Mean
Cmax
(ng/mL)
Mean 24.77 0.4801 25.33 0.4892
AUCiast
(hr*ng/mL)
27.32 0.4883 27.29 0.5233
Mean AUCinf
(hr*ng/mL)
- 60%
Absolute
Bioavailability
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 Cmax and
AUCia of buprenorphine from formulations 5, 6 and 7 is dose proportional. Dose
proportionality of buprenorphine Cmax and AUCia are also illustrated by the graphs
shown in Figures 2 and 3, respectively.
Example 5. Naloxone Withdrawal Study
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® 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
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:
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;
subjects displayed signs and symptoms of withdrawal (i.e., COWS score >5)
following naloxone administration during the Naloxone Challenge.
Description of Study Medication
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:
a) Buprenorphine 0.75 mg (B)
b) Buprenorphine 0.75 mg + naloxone 0.1 mg (BN1)
c) Buprenorphine 0.75 mg + naloxone 0.2 mg (BN2)
d) Placebo (5% dextrose) (P)
Study procedures
Eligible subject exhibited signs of withdrawal, e.g., had a positive response
(COWS > 5) to the Naloxone Withdrawal Test, following administration of up to eight
0.05 mg IV doses of naloxone.
Clinical Opiate Withdrawal Scale
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
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
-point Likert scale (0=not at all, 1=a little, 2=moderately, 3=quite a bit, and
4=extremely).
Statistical Analysis
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.
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
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 FIGURE 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 > 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.
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.
In the buprenorphine plus 0.1 mg of naloxone group, 9 subjects (60%) had
COWS >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.
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 10. Summary of COWS Total Scores and Rescue Results
Parameter B (n=15) BN1 (n=15) BN2 (n=15) P (n=15)
7 11 2 (1%)
COWS >= 13, n (47%) 9 (60%) (73%)
7 10 11 2 (1%)
Rescued n (%) (47%) (67%) (73%)
Median COWS 1 0 3 0
at One Hour Post
Dose
Drug Effect Questionnaire (DEQ) — Observed Median Values 1 Hour Post Dose
Median DEQ responses at one hour in those subjects that were not rescued are
shown in Table 6 below.
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.
The median score for good effect and how high are you was zero at one hour in
all treatment groups.
Table 11. Median DEQ responces at one hour in subjects who were not rescued.
Parameter B (n=15) BN1 (n=15) BN2 (n=15) P (n=15)
Drug effect 0 49 0
Nausea 0 0 38 0
Like drug 0 0 0 0
0 0 0 0
Good effect
Bad Effect 0 0 27 0
Dizzy 0 0 14 0
0 0 0 0
Feel Sleepy
Feel sick 0 0 30 0
How high are 0 0 0 0
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
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.
Throughout this specification and the claims which follow, unless the context requires
otherwise, the word "comprise", and variations such as "comprises" or "comprising", will
be understood to imply the inclusion of a stated integer or step or group of integers or steps
but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it),
or to any matter which is known, is not, and should not be taken as an acknowledgment or
admission or any form of suggestion that that prior publication (or information derived
from it) or known matter forms part of the common general knowledge in the field of
endeavour to which this specification relates.
Claims (9)
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%.
9. An abuse deterrent mucoadhesive device for use in managing pain or opioid dependence, the device comprising: a mucoadhesive layer comprising about 0.075 to about 12 mg buprenorphine buffered to a pH of between about 4.0 and about 6.0; and a backing layer comprising about 0.0125 to about 2 mg of naloxone buffered to a pH between about 4.0 and about 4.8, H:\cdl\Interwoven\NRPortbl\DCC\CDL\10080092_1.docx-
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US61/525,094 | 2011-08-18 | ||
PCT/US2012/051618 WO2013026064A1 (en) | 2011-08-18 | 2012-08-20 | Abuse-resistant mucoadhesive devices for delivery of buprenorphine |
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