U.S. patent application number 16/533246 was filed with the patent office on 2020-01-30 for transmucosal drug delivery devices for use in chronic pain relief.
This patent application is currently assigned to BioDelivery Sciences International, Inc.. The applicant listed for this patent is BioDelivery Sciences International, Inc.. Invention is credited to Andrew Finn, Niraj Vasisht.
Application Number | 20200030227 16/533246 |
Document ID | / |
Family ID | 50974907 |
Filed Date | 2020-01-30 |
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United States Patent
Application |
20200030227 |
Kind Code |
A1 |
Finn; Andrew ; et
al. |
January 30, 2020 |
TRANSMUCOSAL DRUG DELIVERY DEVICES FOR USE IN CHRONIC PAIN
RELIEF
Abstract
Provided herein are methods for treating chronic pain by
administering low doses of buprenorphine twice daily (or once
daily) via a transmucosal drug delivery device. The methods and
devices efficiently treat chronic pain without significant side
effects.
Inventors: |
Finn; Andrew; (Raleigh,
NC) ; Vasisht; Niraj; (Cary, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioDelivery Sciences International, Inc. |
Raleigh |
NC |
US |
|
|
Assignee: |
BioDelivery Sciences International,
Inc.
Raleigh
NC
|
Family ID: |
50974907 |
Appl. No.: |
16/533246 |
Filed: |
August 6, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15871017 |
Jan 14, 2018 |
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16533246 |
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13724959 |
Dec 21, 2012 |
9901539 |
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15871017 |
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61578755 |
Dec 21, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/00 20130101; A61K
31/485 20130101; A61K 9/006 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/485 20060101 A61K031/485 |
Claims
1. A method of treating chronic pain, the method comprising:
administering to a subject in need thereof a mucoadhesive
bioerodable drug delivery device, wherein, the device is
administered once or twice daily, wherein the device comprises: a
bioerodable mucoadhesive layer comprising about 100 .mu.g to about
0.9 mg buprenorphine and buffered to a pH of between about 4.0 and
about 6.0; and a backing layer buffered to a pH of between about
4.0 and about 4.8 and that does not include an opioid antagonist;
wherein the device provides a steady-state C.sub.max of plasma
buprenorphine concentration in a range between about 0.156 and
about 0.364 ng/mL; wherein the subject is an opioid-experienced
subject; and wherein the subject treated experiences mild or
moderate common opioid adverse effects, or no common opioid adverse
effects.
2-20. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/724,959, filed on Dec. 21, 2012, which claims the benefit of
U.S. Provisional Patent Application No. 61/578,755, filed Dec. 21,
2011. The entire contents of this application are incorporated
herein by reference.
[0002] This application is 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 Sep. 1, 1998; U.S. patent application Ser. No.
09/144,827, filed on Sep. 1, 1998, now U.S. Pat. No. 6,159,498,
issued on Dec. 12, 2000; U.S. patent application Ser. No.
11/069,089, filed on Mar. 1, 2005, now U.S. Pat. No. 7,579,019,
issued on Aug. 25, 2009; 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; U.S. patent application Ser.
No. 13/834,306, filed on Jul. 15, 2011, now U.S. Pat. No.
8,147,866, issued on Apr. 3, 2012; U.S. patent application Ser. No.
13/590,094, filed on Aug. 20, 2012, the entire contents of which
are incorporated herein by reference.
BACKGROUND
[0003] Chronic pain is pain that persists beyond the expected
healing time, if resulting from injury, and can progress from a
bothersome nuisance to a profound affliction. Chronic pain can
cause a marked alteration in behavior with depression and anxiety,
restriction in daily activities and excessive use of medication and
medical services in an afflicted individual. The treatment of
chronic pain is difficult, often inadequate and associated with
high economic and psychological cost.
[0004] Buprenorphine is a partial .mu.-opiate receptor agonist, an
ORL1/nociceptin receptor agonist with high affinity and a slow
dissociation rate and a .kappa.-opiate receptor antagonist.
Buprenorphine is metabolized by the liver, via the CYP3A4 isozyme
of the cytochrome P450 enzyme system, into norbuprenorphine (by
N-dealkylation) and other metabolites. Buprenorphine has a low oral
bioavailability due to very high first-pass metabolism.
[0005] Buprenorphine is an analgesic, available commercially as
Temgesic.RTM. 0.2 mg sublingual tablets, and as Buprenex.RTM. in a
0.3 mg/ml parenteral formulation. Buprenorphine is also available
as a sublingual preparation (Subutex.RTM.) and as a sublingual
abuse-resistant formulation with naloxone (Suboxone.RTM.). The FDA
approved Suboxone/Subutex in 2002 as a treatment of opioid
dependence. Sublingual buprenorphine has been used for opioid
detoxification and maintenance.
[0006] A recent open-label study used sublingual buprenorphine
(Suboxone.RTM.) for the treatment of chronic pain to those chronic
opioid users (Malinoff et al., 2005, American Journal of
Therapeutics 12, 379-384). Patients were treated with daily
buprenorphine doses that ranged from 2-20 mg (mean 8 mg). The
treatment lasted from 2.4 months to 16.6 months (mean 8.8 months).
The article reports that patients experienced improvement in their
condition and reported a decrease in their sensation of pain.
[0007] Still, effective methods for treating chronic pain that are
not associated with adverse effects are needed, especially to those
opioid naive or opioid experienced patients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a schematic representation of the design of a
clinical study for evaluating the efficacy and safety of twice
daily administration of BEMA buprenorphine in subjects with chronic
low back pain.
[0009] FIG. 2 is a schematic representation of disposition of
subjects who participated in the clinical study to evaluate the
efficacy and safety of twice daily administration of BEMA
buprenorphine in subjects with chronic low back pain.
[0010] FIG. 3 is a graph showing mean change from baseline in daily
pain intensity experienced by the subjects with chronic low back
pain after twice daily administration of BEMA buprenorphine.
SUMMARY OF THE INVENTION
[0011] The present teachings provide methods for treating chronic
pain by administering low doses of buprenorphine twice daily (or
once daily) via a mucoadhesive bioerodable drug delivery device.
The methods and devices efficiently treat chronic pain without
significant side effects, for example, less than 15% (preferably
less than 10%, more preferably less than 5%) patients experience
constipation.
[0012] The devices comprise about 100 .mu.g to 0.9 mg
buprenorphine, and provide steady-state C.sub.max of plasma
buprenorphine concentration in a range between about 0.1 and about
1.2 ng/mL, such that the subject is treated for chronic pain.
[0013] In one embodiment, the buprenorphine delivery device
comprises a bioerodable mucoadhesive layer comprising a
therapeutically effective amount of buprenorphine disposed in a
buffered polymeric diffusion environment, wherein the polymeric
diffusion environment is a buffered environment having a pH of
between about 4 and about 6. In another embodiment, the
buprenorphine delivery device further comprises a barrier layer
comprising a polymeric barrier environment disposed adjacent to the
mucoadhesive layer to provide a unidirectional gradient upon
application to a mucosal surface for the rapid and efficient
delivery of buprenorphine, wherein the unidirectional gradient
delivers buprenorphine across the buffered polymeric diffusion
environment upon application to the mucosal surface. In still
another embodiment, the device comprises 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.
[0014] In one embodiment, the device comprises about 120 .mu.g to
0.9 mg buprenorphine.
[0015] The methods and devices disclosed therein can be used to
treat a subject with chronic low back pain, such as moderate to
severe chronic low back pain, or a subject with neuropathic pain or
osteoarthritic pain.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention provides methods of treating chronic
pain with low doses of buprenorphine. The present method of
treating pain is also associated with lack of significant opioid
adverse effects. For example, the subject is treated without
experiencing any severe common opioid adverse effects. Or, the
subject is treated experiencing mild or moderate common opioid
adverse effects, or no common opioid adverse effects.
[0017] The present invention also provides effective chronic pain
relief with twice daily administration of buprenorphine. The
present invention is based, at least in part, on the surprising
discovery that a transmucosal drug delivery device containing low
doses of buprenorphine can be administered twice daily to opioid
experienced subjects for effective management and relief of chronic
pain, such as chronic low back pain. The present invention is also
based on the discovery that this therapy does not result in
substantial side effects associated with opioids, such as
constipation and nausea.
Definitions
[0018] The following definitions are provided as guidance as to the
meaning of certain terms used herein.
[0019] 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.
[0020] 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.
[0021] 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
"bioavailability", "absolute bioavailability" or "total
bioavailability" refers to the total bioavailability including
amounts that are absorbed through the oral mucosal membrane (i.e.,
transmucosally) and through the GI mucosa of the lower GI tract. In
some embodiments, the transmucosal drug delivery devices of the
present invention provide bioavailability of buprenorphine of
between 65% and 85%. In some embodiments, the bioavailability of
buprenorphine is 80%.
[0022] 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 to which the active
ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar
conditions in an appropriately designed study. The pharmacokinetic
parameters C.sub.max and AUC for bioequivalent actives fall within
the 80%-125% range of each other.
[0023] As used herein, the term "chronic pain" refers to pain which
persists beyond the usual recovery period for an injury or illness.
In one embodiment, chronic pain is the pain that lasts longer than
one week. 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.
[0024] As used herein, the term "chronic low back pain" refers to a
muscoskeletal disorder, wherein the subject experiences pain in the
lumbar, or low back region for at least 12 weeks. In a specific
embodiment, a subject experiences chronic low back pain for at
least 3 months.
[0025] As used herein, the term "moderate to severe chronic low
back pain" refers to the chronic low back pain characterized, e.g.,
by pain intensity of .gtoreq.5 on an 11-point Numerical Rating
Scale (NRS, wherein 0 represents no pain and 10 represents the
worst pain imaginable).
[0026] As used herein, the term "neuropathic pain" refers to a
complex, chronic pain that usually is accompanied by tissue injury
and results from lesions or diseases affecting the somatosensory
system. With neuropathic pain, the nerve fibers themselves may be
damaged, dysfunctional or injured. These damaged nerve fibers send
incorrect signals to other pain centers. The impact of nerve fiber
injury includes a change in nerve function both at the site of
injury and areas around the injury.
[0027] As used herein, the term "osteoarthritic pain" refers to
pain resulting from osteoarthritis, a degenerative joint disease
and the most common type of arthritis. It is associated with the
degradation and loss of a cartilage that covers and cushions the
ends of bones in normal joints. Osteoarthritis causes the cartilage
in a joint to become stiff and lose its elasticity, making it more
susceptible to damage. Over time, the cartilage may wear away in
some areas, greatly decreasing its ability to act as a shock
absorber. As the cartilage wears away, tendons and ligaments
stretch, causing pain. If the condition worsens, the bones could
rub against each other, causing even more pain and loss of
movement.
[0028] 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. 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.
[0029] Buprenorphine derivatives include, but are not limited to,
etorphine and diprenorphine. General buprenorphine derivatives are
described in International Application Publication No. WO
2008/011194, which is hereby incorporated by reference.
[0030] 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.
[0031] As used herein, "non-parenteral" refers to modes of
administration other than by direct systemic delivery of the
medicament. As such, "non-parenteral" excludes the use of
intravenous (IV) injection, intramuscular (IM) injection,
Intraperitoneal (IP) injection, subcutaneous (SC) injection, etc.
for administration of the medicament and includes transdermal, oral
transmucosal administration, and administration via the GI tract,
generally.
[0032] 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 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.
[0033] As used herein, the term "backing layer" or "barrier
environment" 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, or reducing flux of a medicament from
the mucoadhesive layer into the oral cavity. In some embodiments,
the backing layer may contain a second medicament intended for
dissolution in the saliva. In such cases, the pH of the backing
layer is adjusted, such that it impedes flux of the medicament
toward the mucoadhesive layer where transmucosal absorption may
occur. 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
oral 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 oral mucosal application, 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, until the backing layer dissolves.
[0034] 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).
[0035] 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.
[0036] 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, the dosage
may be administered once daily, or may be divided into two
individual dosages for twice daily administration. The dose may
also be proportionally reduced as indicated by the exigencies of
the therapeutic situation.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] As used herein, the term "opioid tolerance" refers to the
phenomenon in which a subject is less susceptible to the effect of
an opioid drug as a consequence of its prior administration. "Acute
tolerance" describes tolerance that develops very rapidly following
either a single dose or a few doses of opioids given over a short
period of time. "Chronic tolerance" describes the observation that
opioid administration over a longer period of time produces reduced
effects. Associative tolerance is best expressed with low doses of
opioids at long interdose intervals and is readily modified by
behavioral or environmental interventions. Nonassociative tolerance
is best expressed with high doses of drugs at short interdose
intervals and is not modified by behavioral or environmental
interventions.
[0041] As used herein, the term "opioid tolerant subject" refers to
a subject currently receiving opioid therapy. In one embodiment,
the subject is taking >60 mg oral morphine/day or equianalgesic
dose of another opioid for 1 week or longer, as specified in the
Table 1 below.
TABLE-US-00001 TABLE 1 Approximate Opioid Equianalgesic Oral Doses
Morphine 60 mg Tramadol 300 mg Hydromorphone 12 mg Oxycodone 30 mg
Hydrocodone 30 mg Oxymorphone 20 mg Codeine 400 mg
[0042] As used herein, the term "opioid experienced subject" refers
to a subject currently receiving opioid therapy. In one embodiment,
the subject's daily use of opioids does not exceed the daily doses
of opioids as specified in the Table 1 above.
[0043] As used herein, the term "opioid naive subject" refers to a
subject who is not currently receiving opioid therapy. In one
embodiment, the subject has not been exposed to opioids for 1 week
or longer.
[0044] As used herein, the term "abusive" or "abusive manner"
refers to uses of the devices beyond oral transmucosal
administration such as by extracting the drug and injecting or
snorting.
[0045] As used herein, the term "low dose of buprenorphine" refers
to the daily dose less than 1.8 mg (e.g., about 200 .mu.g to about
1800 .mu.g, or about 240 .mu.g to 1800 .mu.g) of buprenorphine.
[0046] As used herein, the term "steady-state plasma concentration"
refers to the state, wherein the fluctuation in plasma drug
concentrations are the same or similar after each dose. The term
"steady-state C.sub.max of plasma buprenorphine concentration"
refers to the state, wherein the post dose maximum plasma
concentration of buprenorphine does not differ from one dose to
another. The term "steady-state C.sub.min of plasma buprenorphine
concentration" refers to the state, wherein the post-dose minimum
plasma concentration of buprenorphine does not differ from one dose
to another. In one embodiment, the devices used in the present
invention provide steady-state C.sub.max of plasma buprenorphine
concentration in a range between about 0.1 and about 1.0 ng/mL. In
another embodiment, the devices used in the present invention
provide steady-state C.sub.max of plasma buprenorphine
concentration in a range between about 0.1 and about 0.5 ng/mL.
[0047] As used herein, the term "common opioid adverse effects"
refers to adverse effects commonly experienced by the subjects
taking opioid analgesics. These common opioid adverse effects
include, among others, headache, constipation, nausea or vomiting,
pruritus, somnolence or cognitive impairment, dry mouth, tolerance
or dependence and urinary retention.
[0048] The term "mild common opioid adverse effects" refers to
adverse effects that do not require a special treatment and do not
interfere with the subject's daily activities. The term "moderate
common opioid adverse effects" refers to adverse effects that
introduce a low level of inconvenience or concern to the subjects
and could interfere with daily activities, but are usually
ameliorated by simple therapeutic measures. The term "severe common
opioid adverse effects" refers to adverse effects that interrupt
usual daily activity and typically require systemic drug therapy or
other treatment.
[0049] The term "significant constipation" refers to chronic or
severe constipation associated with the continuous use of morphine
or other opioids.
[0050] The term "significant nausea" refers to a severe condition
of nausea that is commonly known in the art. In some embodiments,
the term "significant nausea" is defined with a visual analog scale
(VAS) score of greater than or equal to 25 mm on a 0 to 100 mm
scale.
[0051] As used herein, the term "disposed" refers to the uniform or
non-uniform distribution of an element within another.
Pain Management
[0052] 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. Chronic pain can arise from many sources
including, cancer, Reflex Sympathetic Dystrophy Syndrome (RSDS),
and migraine. Acute pain is typically directly related to tissue
damage, and lasts for a relatively short amount of time, e.g.,
hours to days, or up to 7 days. In other embodiments, the pain is
breakthrough cancer pain.
[0053] In some aspects, the present invention provides methods of
managing or treating chronic pain in a subject. In some
embodiments, the subject is opioid experienced, opioid tolerant or
opioid naive, as defined above. In a specific embodiment, the
subject is opioid tolerant. In another embodiment, the subject has
not responded to previous treatment with the maximal doses of
non-steroidal anti-inflammatory drugs.
[0054] In some embodiments, the chronic pain is chronic lower back
pain (CLBP). In some embodiments, the chronic lower back pain is
moderate to severe chronic lower back pain. In other embodiments,
the pain is neuropathic pain or osteoarthritic pain. In a specific
embodiment, the subject to be treated for moderate to severe
chronic low back pain is an opioid experienced subject.
[0055] It has also been presently found that twice daily (or once
daily) administration of low doses of buprenorphine via
transmucosal drug delivery devices of the present invention is
associated with low incidence or absence of common opioid adverse
effects associated with opioid analgesics. In one embodiment, the
adverse effect is nausea. In another embodiment, the adverse effect
is constipation.
Administration and Dosing of Buprenorphine
[0056] In some embodiments, transmucosal drug delivery devices of
the present invention (e.g., BEMA Buprenorphine) are administered
once daily or twice daily. In some embodiments, the total daily
dose of buprenorphine administered is between 200 .mu.g and 1800
.mu.g, e.g., 200 .mu.g, 220 .mu.g, 240 .mu.g, 280 .mu.g, 300 .mu.g,
320 .mu.g, 350 .mu.g, 360 .mu.g, 400 .mu.g, 450 .mu.g, 480 .mu.g,
500 .mu.g, 550 .mu.g, 600 .mu.g, 620 .mu.g, 650 .mu.g, 700 .mu.g,
720 .mu.g, 750 .mu.g, 800 .mu.g, 860 .mu.g, 900 .mu.g, 960 .mu.g,
1000 .mu.g, 1100 .mu.g, 1200 .mu.g, 1250 .mu.g, 1300 .mu.g, 1400
.mu.g, 1500 .mu.g, 1600 .mu.g, and 1800 .mu.g.
[0057] In some embodiments, the transmucosal drug delivery devices
of the present invention comprise low doses of buprenorphine. In
one embodiment, the low dose of buprenorphine contained in the
devices is defined as the dose of about 100 .mu.g to about 900
.mu.g of buprenorphine. In some embodiments, the low dose of
buprenorphine comprised in the mucoadhesive device of the invention
is 100 .mu.g, 110 .mu.g, 120 .mu.g, 140 .mu.g, 150 .mu.g, 160
.mu.g, 175 .mu.g, 180 .mu.g, 200 .mu.g, 225 .mu.g, 240 .mu.g, 250
.mu.g, 275 .mu.g, 300 .mu.g, 310 .mu.g, 325 .mu.g, 350 .mu.g, 360
.mu.g, 375 .mu.g, 400 .mu.g, 430 .mu.g, 450 .mu.g, 480 .mu.g, 500
.mu.g, 550 .mu.g, 600 .mu.g, 625 .mu.g, 650 .mu.g, 700 .mu.g, 750
.mu.g, 800 .mu.g, 900 .mu.g, 1000 .mu.g, 1200 .mu.g, 1250 .mu.g,
1300 .mu.g, 1400 .mu.g, 1500 .mu.g, 1600 .mu.g, and 1800 .mu.g.
Transmucosal Pharmaceutical Delivery Device
[0058] Preparation of transmucosal pharmaceutical delivery devices
have been previously described, e.g., in U.S. patent application
Ser. No. 08/734,519, filed on Oct. 18, 1996, now U.S. Pat. No.
5,800,832, issued Sep. 1, 1998; U.S. patent application Ser. No.
09/144,827, filed on Sep. 1, 1998, now U.S. Pat. No. 6,159,498,
issued on Dec. 12, 2000; U.S. patent application Ser. No.
11/069,089, filed on Mar. 1, 2005, Now U.S. Pat. No. 7,579,019,
issued on Aug. 25, 2009; U.S. patent application Ser. No.
11/639,408, filed on Dec. 13, 2006, published as US 2007/0148097;
U.S. patent application Ser. No. 11/817,915, filed on Sep. 6, 2007,
published as US 2010/0015183; U.S. patent application Ser. No.
13/834,306, filed on Jul. 15, 2011, now U.S. Pat. No. 8,147,866,
issued on Apr. 3, 2012; U.S. patent application Ser. No.
13/590,094, filed on Aug. 20, 2012; U.S. patent application Ser.
No. 12/537,571, filed on Aug. 7, 2009, published as US
2011/0033541; and U.S. patent application Ser. No. 12/537,580,
filed on Aug. 7, 2009, published as US 2011/0033542, the entire
contents of which are incorporated herein by reference.
i. Mucoadhesive Layer
[0059] In some embodiments, the devices of the present invention
adhere to a mucosal surface of the subject within about 5 seconds
following application. In some embodiments, the devices of the
present invention comprise an opioid agonist. In some embodiments,
the devices of the present invention include a bioerodable- or
water-erodable mucoadhesive layer, and the opioid agonist is
comprised in the mucoadhesive layer. In one embodiment, the opioid
agonist is buprenorphine. 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 20 .mu.g to about 20 mg, or from about 120 .mu.g to about
2000 .mu.g of buprenorphine.
ii. Backing Layer
[0060] In some embodiments, 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.
[0061] 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 backing layer of the device of the present
invention can range from about 2.5 .mu.g to about 5 mg 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 some embodiments, the amount of
buprenorphine and the amount of naloxone disposed in the device are
present in a 4:1 w/w ratio.
EXEMPLIFICATION OF THE INVENTION
[0062] 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
[0063] Transmucosal devices are configured in the form of a disc,
rectangular in shape with round corners, yellow on one or both
sides of the cheek). Buprenorphine is present in the mucoadhesive
layer, and this side is to be placed in contact with the buccal
mucosa (inside the cheek). The drug is delivered into and across
the mucosa as the disc erodes in the mouth. The non-adhesive,
backing layer controls the rate erosion of the disc, and minimizes
the amount of buprenorphine dissolved in saliva and ultimately
swallowed, a pathway of lower absorption due first pass metabolism.
The mucoadhesive polymeric diffusion layer and the backing layer
are bonded together and do not delaminate during or after
application.
[0064] The mucoadhesive layer for the transmucosal devices of the
present invention comprising the desired dosage of buprenorphine is
prepared by mixing purified water, propylene glycol (about 4.6%
total formulation, by dry weight), sodium benzoate (about 0.5%
total formulation, by dry weight), methylparaben (about 0.9% total
formulation, by dry weight), propylparaben (about 0.2% total
formulation, by dry weight), vitamin E acetate (about 0.06% total
formulation, by dry weight), citric acid (about 0.5% total
formulation, by dry weight), yellow iron oxide (about 0.5% total
formulation, by dry weight), monobasic sodium phosphate (about 3.4%
total formulation, by dry weight). The above ingredients are added
sequentially to a mixing vessel. After the components are
dissolved, buprenorphine HCl (about 1.3% total formulation, by dry
weight) is added, and the vessel was heated to 120.degree. F. to
130.degree. F. After dissolution, the polymer mixture
(hydroxypropyl cellulose (about 6.8% total formulation, by dry
weight), hydroxyethyl cellulose (about 20.3% total formulation, by
dry weight), polycarbophil (about 6.3% total formulation, by dry
weight), and carboxy methyl cellulose (about 54.3% total
formulation, by dry weight)) are added to the vessel, and stirred
until dispersed. Subsequently, heat is removed from the mixing
vessel. As the last addition step, tribasic sodium phosphate and
sodium hydroxide are added to adjust the blend to a desired pH. The
blend is mixed under vacuum for a few hours. Each prepared mixture
is stored in an air-sealed vessel until its use in the coating
operation.
[0065] The backing layer is prepared by adding purified water to a
mixing vessel followed by sequential addition of sodium benzoate
(about 0.5% total formulation, by dry weight), methylparaben (about
0.4% total formulation, by dry weight), propylparaben (about 0.1%
total formulation, by dry weight), citric acid (about 0.5% total
formulation, by dry weight), vitamin E acetate (about 0.05% total
formulation, by dry weight), sodium saccharin (about 0.5% total
formulation, by dry weight). Subsequently, a mixture of the
polymers hydroxypropyl cellulose (about 63% total formulation, by
dry weight) and hydroxyethyl cellulose (about 32% total
formulation, by dry weight) are added and stirred at a temperature
between about 120.degree. F. and 130.degree. F., until evenly
dispersed. Upon cooling to room temperature, titanium dioxide
(about 2.5% total formulation, by dry weight) and peppermint oil
(about 0.8% total formulation, by dry weight) are then added to the
vessel and stirred. The prepared mixture is stored in an air-sealed
vessel until it is ready for use in the coating operation.
[0066] The layers are cast in series onto a St. Gobain polyester
liner. First, the backing layer is cast using a knife-on-a-blade
coating method. The backing layer is then cured in a continuous
oven at about 65.degree. C. to 95.degree. C. and dried. After two
coating and drying iterations, an approximately 8 mil (203 to 213
micrometers) thick backing layer is obtained. Subsequently, the
mucoadhesive polymeric diffusion environment is cast onto the
backing layer, cured in an oven at about 65.degree. C. to
95.degree. C. and dried. The devices are then die-cut by kiss-cut
method and removed from the casting surface.
Example 2. Placebo-Controlled, Double-Blind Study to Evaluate the
Efficacy of BEMA Buprenorphine in Subjects with Moderate to Severe
Chronic Low Back Pain
[0067] A 12-week, placebo-controlled, double-blind randomized
withdrawal study was conducted to evaluate the efficacy and safety
of buprenorphine delivered twice daily via transmucosal drug
delivery device with enhanced uptake (BEMA buprenorphine) in
subjects with moderate to severe chronic low back pain. The study
was also designed to define the range of BEMA Buprenorphine doses
effective for management of moderate to severe chronic lower back
pain.
i. Study Design
[0068] The study consisted of an open-label dose titration period
lasting up to 4 weeks, followed by a randomized, double-blind,
placebo-controlled treatment period of 12 weeks. The subjects
continued on their current pain therapy during the initial
screening period (days -14 to -1) and until 12 to 24 hours prior to
Day 0/1 of the open-label dose titration period. Predose
assessments were performed on open-label titration period Day 0 and
the first dose of study drug was taken on open-label titration
period Day 1.
[0069] During the open-label titration period, the subjects were
administered BEMA Buprenorphine approximately every 12 hours, and
dose adjustments were performed at intervals over a period of up to
4 weeks until a stabilized dose was found (i.e., the dose that
provided meaningful pain relief and was well tolerated). The
titration sequence of BEMA Buprenorphine is illustrated in the
Table 4 below. The subjects for whom a stabilized dose could not be
found were discontinued from the study.
TABLE-US-00002 TABLE 4 BEMA Buprenorphne Titration Schedule
Titration Sequence - BEMA Buprenorphine Study Days Low Dose (Q12
hours) 1 A 7 (.+-.3 days) 2 .times. A 14 (.+-.3 days) 3 .times. A
21 (.+-.3 days) 4 .times. A
[0070] The subjects for whom a stabilized dose was identified and
who had taken that dose at least 12 times over the last 7 days
entered a 12-week, double-blind treatment period, in which half of
subjects received BEMA Placebo and half continued receiving BEMA
Buprenorphine at the stabilized dose. Each subject's participation
in the entire study lasted 19 weeks. The schematic showing the
study design is shown in FIG. 1.
ii. Subject Population Used in the Study
[0071] The subjects who were selected for the inclusion in the
study were opioid naive or opioid experienced, as defined earlier
in this application. Opioid experienced subjects were subjects
taking .ltoreq.60 mg oral daily dose of morphine or equianalgesic
dose of another allowed opioid for 1 week or longer. Opioid naive
subjects were not taking any opioids for 1 week or longer.
[0072] A total of 334 subjects entered the study, of which 332
subjects entered the 4-week open-label dose titration period. As 97
subjects discontinued intervention during the open-label titration
period, a total of 235 subjects continued on to the 12-week
double-blind treatment period. Of the 117 subjects who received
BEMA Buprenorphine, 28 discontinued intervention, and 89 subjects
completed the study. Of the 118 subjects who received placebo, 37
discontinued intervention, and 81 subjects completed the study.
Subject disposition during the study is summarized in FIG. 2, and
the characteristics of the population who participated in the study
are summarized in the Table 5 below:
TABLE-US-00003 TABLE 5 Study Population Characteristics Open Label
Double Blind Titration Treatment Double Blind BEMA BEMA Treatment
Buprenorphine Buprenorphine Placebo Number of subjects 332 117 118
Mean Age (yrs.) 51 51 51 Women, n (%) 55.5 53 56 Opioid Naive (%)
62.7 62.4 69.5 Mean Pain Intensity at 7 Screening Mean Pain
Intensity at NA 3.23 3.26 Baseline
iii. Analgesic Efficacy of BEMA Buprenorphine
[0073] Analgesic efficacy was assessed daily by having the subject
record their average pain intensity over the past 24 hours on a
scale of 0 to 10, where 0 represents no pain and 10 represents the
worst pain imaginable (11-point Numerical Rating Scale, NRS). The
mean change in daily pain intensity from baseline (CBL) to final
visit during double blind treatment period is presented in Tables
6-12 below. Tables 6-8 present the mean change data for different
subject groups, and Tables 9-12 present the mean change data for
the subject groups treated with different doses of
buprenorphine.
TABLE-US-00004 TABLE 6 Average Daily Pain Intensity - All Subjects
Parameter BEMA Buprenorphine Placebo Number of subjects 117 118
Primary Analysis, mean (SD) Baseline 3.23 (1.19) 3.26 (1.22) Final
3.59 (1.91) 3.77 (2.22) Least Squares Mean Difference 0.35 0.51
Treatment comparison of Change -0.16 from Baseline (CBL) Beta
Buprenorphine (CBL BB) minus placebo p-value 0.53
TABLE-US-00005 TABLE 7 Average daily pain intensity -opioid
experienced subjects Parameter BEMA Buprenorphine Placebo Number of
subjects 44 36 Primary Analysis, mean (SD) Baseline 3.50 (1.14)
3.43 (0.87) Final 4.05 (2.04) 4.86 (2.03) Least Squares Mean
Difference 0.57 1.41 Treatment comparison -0.84 of CBL BB minus
placebo p-value 0.067
TABLE-US-00006 TABLE 8 Average daily pain intensity in opioid naive
subjects Parameter BEMA Buprenorphine Placebo Number of subjects 73
82 Primary Analysis, mean (SD) Baseline 3.07 (1.20) 3.19 (1.33)
Final 3.31 (1.78) 3.29 (2.1) Least Squares Mean Difference 0.21
0.13 Treatment comparison of CBL 0.08 BB minus placebo p-value
0.78
[0074] As shown in Table 7, the change from baseline in average
daily pain score on BEMA Buprenorphine compared to placebo is
nearly statistically significant in the opioid experienced
population.
TABLE-US-00007 TABLE 9 Average daily pain intensity in subjects
treated with the daily dose of A .mu.g of buprenorphine BEMA
Buprenorphine Parameter Dose A mcg Placebo N 28 33 Primary
Analysis, mean (SD) Baseline 2.79 (1.51) 3.12 (1.38) Final 3.58
(1.79) 2.88 (2.18) Least Squares Mean Difference 0.72 -0.24
Treatment comparison of CBL 0.90 BB minus placebo p-value 0.085
TABLE-US-00008 TABLE 10 Average daily pain intensity in subjects
treated with the daily dose of 2 .times. A .mu.g of buprenorphine
BEMA Buprenorphine Parameter Dose 2 .times. A mcg Placebo N 31 33
Primary Analysis, mean (SD) Baseline 3.25 (1.13) 3.33 (1.12) Final
3.23 (1.73) 4.04 (2.27) Least Squares Mean Difference -0.03 0.72
Treatment comparison of CBL -0.74 BB minus placebo p-value 0.17
TABLE-US-00009 TABLE 11 Average daily pain intensity in subjects
treated with the daily dose of 3 .times. A .mu.g of buprenorphine
BEMA Buprenorphine Parameter Dose 3 .times. A mcg Placebo N 22 31
Primary Analysis, mean (SD) Baseline 3.43 (0.87) 3.48 (1.25) Final
4.24 (2.48) 4.0 (2.23) Least Squares Mean Difference 0.79 0.53
Treatment comparison of CBL 0.26 BB minus placebo p-value 0.70
TABLE-US-00010 TABLE 12 Average daily pain intensity in subjects
treated with the daily dose of 4 .times. A .mu.g of buprenorphine
BEMA Buprenorphine Parameter Dose 4 .times. A mcg Placebo N 36 21
Primary Analysis, mean (SD) Baseline 3.45 (1.09) 3.04 (1.05) Final
3.69 (1.75) 4.27 (1.92) Least Squares Mean Difference 0.29 1.13
Treatment comparison of CBL -0.84 BB minus placebo p-value 0.11
[0075] Graphed in FIG. 3 is the mean change from baseline in daily
pain intensity for all subjects; all subjects receiving 2xA .mu.g,
3xA .mu.g, or 4xA .mu.g, BEMA Buprenorphine; all opioid experienced
subjects; and all opioid experienced subjects receiving 2xA .mu.g,
3xA .mu.g, or 4xA .mu.g BEMA Buprenorphine.
iv. Incidence of Adverse Events
[0076] Adverse events (AE) were recorded for all subjects in the
study. AE was defined as any untoward medical occurrence in a
patient or clinical investigation subject administered a
pharmaceutical product and which does not necessarily have a causal
relationship with this treatment. The total number of adverse
events recorded for both the open label titration and double blind
treatment periods are listed in the Table 13 below.
TABLE-US-00011 TABLE 13 Total Treatment Emergent Adverse Events
(TEAEs) Open Label Double Blind Titration Treatment BEMA BEMA
Buprenorphine, Buprenorphine Placebo Adverse event profile n (%) n
(%) n (%) Subjects with .gtoreq.1 AE 219 (66) 73 (62) 68 (58)
Subjects with .gtoreq.1 AE 6 (5) 3 (2) causing discontinuation
Discontinued due to opioid withdrawal Subjects with .gtoreq.1 SAE 1
(1) 0 AEs reported in .gtoreq.5% of subjects Nausea 108 (32) 11 (9)
10 (8) Vomiting 20 (6) 6 (5) 4 (3) Constipation 36 (11) 7 (6) 3 (2)
Dizziness 30 (9) 4 (3) 1 (1) Headache 39 (12) 12 (10) 5 (4)
[0077] The intensity of AEs was characterized as mild, moderate, or
severe as follows:
[0078] Mild: AEs that were transient, did not require a special
treatment and did not interfere with the subject's daily
activities.
[0079] Moderate: AEs that introduced a low level of inconvenience
or concern to the subject and could interfere with daily
activities, but were usually ameliorated by simple therapeutic
measures.
[0080] Severe: AEs that interrupted a subject's usual daily
activity and typically required systemic drug therapy or other
treatment.
[0081] Table 14 below shows the number and percent of subjects who
experienced TEAEs during the open label titration period involving
330 subjects, with all TEAEs characterized by event intensity and
relationship to the study drug. Table 15 below shows analogous data
for the double blind treatment period and buprenorphine treatment
group involving 117 subjects. The maximum intensity ever recorded
for each event and the drug relationship at that intensity were
used to categorize adverse events. "Drug-related" category is
listed as "R" and includes adverse events with
investigator-assessed relation to drug of "probably" or "possibly".
"Non drug-related" category is listed as "NR".
TABLE-US-00012 TABLE 14 TEAEs by Event Intensity and Drug
Relationship During Open Label Titration Period. AE Intensity and
Drug Relationship AE Profile Not Mild Moderate Severe Reported
Overall Rn NRn Rn NRn Rn NRn Rn NRn Rn NRn (%) (%) (%) (%) (%) (%)
(%) (%) (%) (%) No. of 49 52 63 34 12 10 0 0 124 96 subject (14.8)
(15.8) (19.1) (10.3) (3.6) (3.0) (37.6) (29.1) with .gtoreq.1 TEAE
Constipation 23 4 5 1 3 0 0 0 31 5 (7.0) (1.2) (1.5) (0.3) (0.9)
(9.4) (1.5) Nausea 50 9 42 1 5 1 0 0 97 11 (15.2) (2.7) (12.7)
(0.3) (1.5) (0.3) (29.4) (3.3) Vomiting 3 6 7 0 2 1 0 0 12 7 (0.9)
(1.8) (2.1) (0.6) (0.3) (3.6) (2.1) Dizziness 13 3 10 1 3 0 0 0 26
4 (3.9) (0.9) (3.0) (0.3) (0.9) (7.9) (1.2) Headache 15 9 8 3 3 1 0
0 26 13 (4.5) (2.7) (2.4) (0.9) (0.9) (0.3) (7.9) (3.9)
TABLE-US-00013 TABLE 15 TEAEs by Event Intensity and Drug
Relationship During Double Blind Treatment Period. AE Intensity and
Drug Relationship AE Profile Not Mild Moderate Severe Reported
Overall Rn NRn Rn NRn Rn NRn Rn NRn Rn NRn (%) (%) (%) (%) (%) (%)
(%) (%) (%) (%) No. of 9 24 11 23 1 5 0 0 21 52 subject (7.7)
(20.5) (9.94) (19.7) (0.9) (4.3) (17.9) (44.4 with .gtoreq.1 TEAE
Constipation 3 0 4 0 0 0 0 0 7 0 (2.6) (3.4) (6.0) Nausea 5 3 3 0 0
0 0 0 8 3 (4.3) (2.6) (2.6) (6.8) (2.6) Vomiting 0 2 2 1 1 0 0 0 3
3 (1.7) (1.7) (0.9) (0.9) (2.6) (2.6) Dizziness 1 0 2 0 1 0 0 0 4 0
(0.9) (1.7) (0.9) (3.4) Headache 1 7 2 1 0 1 0 0 3 9 (0.9) (0.6)
(1.7) (0.9) (0.9) (2.6) (7.7)
Example 3. Pharmacokinetic Profiles for BEMA Buprenorphine
[0082] Pharmacokinetic parameters for the BEMA Buprenorphine doses
used in the treatment of chronic pain were determined in a
separate, multiple dose study. BEMA Buprenorphine contained
buprenorphine doses of 2xA .mu.g, and 4xA .mu.g. Each dose was
administered twice daily for 3 days with serial blood samples
collected. Selected pharmacokinetic parameters are shown in the
Table 16 below.
TABLE-US-00014 TABLE 16 Selected Pharmacokinetic Parameters for
BEMA Buprenorphine Buccal Films comprising 1 .times. A .mu.g, 2
.times. A .mu.g, 3 .times. A .mu.g and 4 .times. A .mu.g
buprenorphine Pharmacokinetic Parameters (Mean values) 1 .times. 2
.times. 3 .times. 4 .times. A .mu.g A .mu.g A .mu.g A .mu.g
T.sub.max (hr) 2.90 2.61 2.00 2.20 C.sub.max (ng/mL) 0.0766 0.156
0.216 0.364 C.sub.min (ng/mL) 0.0157 0.0371 0.0558 0.0862 C.sub.avg
(ng/mL) 0.0409 0.0805 0.113 0.195 AUC.sub.0-.tau.(hr*ng/mL) 0.4903
0.9658 1.358 2.343 AUC.sub.last (hr*ng/mL) 0.4085 0.7902 1.111
5.033 T.sub.max refers to the time to reach the steady-state
C.sub.max of plasma buprenorphine concentration. C.sub.max refers
to the maximum concentration in plasma in steady-state. C.sub.min
refers to the minimum concentration in plasma in steady-state.
C.sub.avg refers to the average concentration in plasma in
steady-state. AUC.sub.0-.tau. refers to the area under the plasma
concentration time curve from time-zero through the dosing interval
AUC.sub.last refers to the area under the concentration-time curve
from time-zero to the time of the last quantifiable
concentration.
* * * * *