U.S. patent application number 14/847211 was filed with the patent office on 2016-08-04 for method of providing sustained analgesia with buprenorphine.
The applicant listed for this patent is Purdue Pharma L.P.. Invention is credited to Paul D. Goldenheim, Robert F. Kaiko, Robert F. Reder.
Application Number | 20160220559 14/847211 |
Document ID | / |
Family ID | 26715643 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160220559 |
Kind Code |
A1 |
Reder; Robert F. ; et
al. |
August 4, 2016 |
METHOD OF PROVIDING SUSTAINED ANALGESIA WITH BUPRENORPHINE
Abstract
A method of effectively treating pain in humans is achieved by
administering buprenorphine in accordance with first order kinetics
over an initial three-day dosing interval, such that a maximum
plasma concentration from about 20 pg/ml to about 1052 pg/ml is
attained, and thereafter maintaining the administration of
buprenorphine for at least an additional two-day dosing interval in
accordance with substantially zero order kinetics, such that the
patients experience analgesia throughout the at least two-day
additional dosing interval.
Inventors: |
Reder; Robert F.; (Winnetka,
IL) ; Goldenheim; Paul D.; (Cambridge, MA) ;
Kaiko; Robert F.; (Weston, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Purdue Pharma L.P. |
Stamford |
CT |
US |
|
|
Family ID: |
26715643 |
Appl. No.: |
14/847211 |
Filed: |
September 8, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14331966 |
Jul 15, 2014 |
|
|
|
14847211 |
|
|
|
|
14080168 |
Nov 14, 2013 |
|
|
|
14331966 |
|
|
|
|
13663033 |
Oct 29, 2012 |
|
|
|
14080168 |
|
|
|
|
12888298 |
Sep 22, 2010 |
|
|
|
13663033 |
|
|
|
|
12558920 |
Sep 14, 2009 |
|
|
|
12888298 |
|
|
|
|
12393616 |
Feb 26, 2009 |
|
|
|
12558920 |
|
|
|
|
11442512 |
May 26, 2006 |
|
|
|
12393616 |
|
|
|
|
10402288 |
Mar 28, 2003 |
|
|
|
11442512 |
|
|
|
|
10033056 |
Dec 27, 2001 |
|
|
|
10402288 |
|
|
|
|
09756419 |
Jan 8, 2001 |
6344212 |
|
|
10033056 |
|
|
|
|
09311997 |
May 14, 1999 |
6231886 |
|
|
09756419 |
|
|
|
|
08939068 |
Sep 29, 1997 |
5968547 |
|
|
09311997 |
|
|
|
|
60038919 |
Feb 24, 1997 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/7023 20130101;
A61P 25/00 20180101; A61K 9/7061 20130101; A61K 9/7053 20130101;
A61P 25/04 20180101; A61K 31/485 20130101; A61K 31/4748 20130101;
A61P 29/00 20180101; A61K 9/0014 20130101; A61P 25/36 20180101;
A61K 9/0019 20130101 |
International
Class: |
A61K 31/4748 20060101
A61K031/4748; A61K 9/70 20060101 A61K009/70; A61K 9/00 20060101
A61K009/00 |
Claims
1. A method of effectively treating pain in humans, comprising
administering buprenorphine to human patients in a manner such that
the following mean plasma concentrations are achieved over a 72
hour dosing interval: a mean plasma concentration from about 0.3 to
about 113 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 3 to about 296
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 7 to about 644 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval; and thereafter
administering the buprenorphine in a manner such that the mean
plasma concentrations are maintained from about 19 to about 1052
pg/ml over at least the next 48 hours.
2. The method of claim 1, further comprising administering the
buprenorphine in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
23 to about 1052 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 23 to about
1052 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 22 to about 970
pg/ml at about 144 hours after initiation of the dosing interval;
and a mean plasma concentration from about 19 to about 841 pg/ml at
about 168 hours after initiation of the dosing interval.
3. The method of claim 1 wherein said administration of
buprenorphine is accomplished via a mode selected from the group
consisting of transdermal, continuous infusion, and a mixture of
transdermal and continuous infusion.
4. The method of claim 1, wherein said administration is
accomplished by applying a transdermal delivery system to the skin
of a patient, and maintaining said transdermal delivery system in
contact with the patient's skin for at least 5 days.
5. The method of claim 4, further comprising maintaining a mean
relative release rate from about 3 ug/hr to about 86 ug/hr from the
initiation of the dosing interval until about 72 hours after the
initiation of the dosing interval; and a mean relative release rate
from about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of dosing
interval.
6.-34. (canceled)
35. A method of effectively treating pain in humans, comprising
administering buprenorphine transdermally to human patients such
that mean relative release rates are achieved over a dosing
interval as follows: a mean relative release rate of from about 3
ug/hr to about 86 ug/hr from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 0.3 ug/hr to about 9
ug/hr from about 72 hours after the initiation of the dosing
interval until the end of the dosing interval.
36.-41. (canceled)
42. A method of effectively treating pain in humans, comprising
applying transdermal delivery systems containing buprenorphine as
the active ingredient onto the skin of patients which provide a
substantially first order release rate of buprenorphine over a
first three-day dosing interval, such that a mean plasma
concentration from about 21 to about 1052 pg/ml is attained about
72 hours after application of said transdermal delivery system; and
maintaining said transdermal delivery systems on the skin of the
patients for at least an additional two-day dosing interval during
which said transdermal delivery system provides substantially zero
order kinetics, such that a mean relative release rate from about
0.3 .mu.g/hr to about 9 .mu.g/hr is maintained over said at least
two-day additional dosing interval and the patients experience
analgesia throughout the at least two-day additional dosing
interval.
43. The method of claim 42, wherein from about 68% to about 95% of
the buprenorphine is contained in the transdermal delivery system
at the end of the dosing interval.
44. The method of claim 43, wherein the Tmax occurs from about 3 to
about 5 days after application of said transdermal delivery
system.
45.-62. (canceled)
63. A method of effectively treating pain in humans, comprising
applying a transdermal delivery system containing buprenorphine as
the active ingredient onto the skin of patients which provide a
first order release rate of buprenorphine over a three-day dosing
interval, such that a maximum plasma concentration from about 20
pg/ml to about 1052 pg/ml is attained, and maintaining said
transdermal delivery systems on the skin of the patients for at
least an additional two-day dosing interval during which said
transdermal delivery system provides substantially zero order
kinetics, such that the patients experience analgesia throughout
the at least two-day additional dosing interval.
64.-67. (canceled)
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/331,966, filed Jul. 15, 2014, which is a
continuation of U.S. patent application Ser. No. 14/080,168, filed
Nov. 14, 2013, which is a continuation of U.S. patent application
Ser. No. 13/663,033, filed Oct. 29, 2012, which is a continuation
of U.S. patent application Ser. No. 12/888,298, filed on Sep. 22,
2010, now abandoned, which is a continuation of U.S. patent
application Ser. No. 12/558,920, filed on Sep. 14, 2009, now
abandoned, which is a continuation of U.S. patent application Ser.
No. 12/393,616, filed on Feb. 26, 2009, now abandoned, which is a
continuation of U.S. patent application Ser. No. 11/442,512, filed
on May 26, 2006, now abandoned, which is a continuation of U.S.
patent application Ser. No. 10/402,288, filed on Mar. 28, 2003, now
abandoned, which is a continuation of U.S. patent application Ser.
No. 10/033,056, filed on Dec. 27, 2001, now abandoned, which is a
continuation of Ser. No. 09/756,419, filed on Jan. 8, 2001, which
issued as U.S. Pat. No. 6,344,212, (now RE41,489, which issued from
U.S. patent application Ser. No. 11/799,611, filed on May 1, 2007,
which is a continuation of U.S. patent application Ser. No.
11/033,108, filed on Jan. 11, 2005, now abandoned), which is a
continuation of U.S. patent application Ser. No. 09/311,997, filed
on May 14, 1999, which issued as U.S. Pat. No. 6,231,886, (now
RE41,408, which issued from U.S. patent application Ser. No.
11/799,608, filed on May 1, 2007, which is a continuation of U.S.
patent application Ser. No. 11/033,107, filed on Jan. 11, 2005, now
abandoned), which is a continuation of U.S. patent application Ser.
No. 08/939,068, filed on Sep. 29, 1997, which issued as U.S. Pat.
No. 5,968,547, (now RE41,571, which issued from U.S. patent
application Ser. No. 11/799,610, filed on May 1, 2007, which is a
continuation of U.S. patent application Ser. No. 11/033,106, filed
on Jan. 11, 2005, now abandoned), which claims benefit of U.S.
Provisional Patent Application No. 60/038,919, filed on Feb. 24,
1997.
BACKGROUND OF THE INVENTION
[0002] It is the intent of all sustained-release pharmaceutical
preparations to provide a longer period of pharmacologic effect
after the administration of a drug than is ordinarily experienced
after the administration of immediate release preparations of the
same drug. Such longer periods of efficacy can provide many
inherent therapeutic benefits that are not achieved with
corresponding immediate release preparations. The benefits of
prolonged analgesia afforded by sustained release oral analgesic
preparations have become universally recognized and oral opioid
analgesic sustained-release preparations are commercially
available.
[0003] Prolonged analgesia is particularly desirable in patients
suffering from moderate to severe pain, such as cancer patients.
Available oral preparations provide a duration of effect lasting
e.g., about twelve hours (and sometimes 24 hours) such that a drug
may only have to be administered to a patient one to three times a
day. For example, morphine, which has been considered to be the
prototypic opioid analgesic, has been formulated into twice-daily,
oral controlled release formulations (e.g., MS Contin.RTM. tablets,
commercially available from The Purdue Frederick Company).
[0004] Another approach to sustained delivery of a therapeutically
active agent are transdermal delivery systems, such as transdermal
patches. Generally, transdermal patches contain a therapeutically
active agent (e.g., an opioid analgesic), a reservoir or matrix
containing the opioid or other active ingredient(s) and an adhesive
which allows the transdermal device to adhere to the skin, allowing
for the passage of the active agent from the device through the
skin of the patient. Once the active agent has penetrated the skin
layer, the drug is absorbed into the blood stream where it can
exert a desired pharmacotherapeutic effect, such as analgesia.
[0005] Transdermal delivery systems in which an opioid analgesic is
the active ingredient have been contemplated. For example, a
commercially available opioid analgesic transdermal formulation is
Duragesic.RTM. (commercially available from Janssen Pharmaceutical;
active ingredient is fentanyl). The Duragesic.RTM. patch is said to
provide adequate analgesia for up to 48 to 72 hours (2 to 3
days).
[0006] Buprenorphine, a partially synthetic opiate, has also been
contemplated for prolonged analgesia. Although other types of
opioid analgesic transdermal formulations have been reported in the
literature (such as fentanyl, discussed above), buprenorphine
transdermal delivery systems are of particular interest because
buprenorphine is a potent, partial agonist opioid analgesic with
desirable therapeutic properties. For example, buprenorphine is 50
to 100 times more potent than morphine, but has a much safer
therapeutic index than morphine (see Wallenstein S L, et al.,
Crossover Trials in Clinical Analgesic Assays: Studies of
Buprenorphine and Morphine, Pharmacotherapy, G(5): 225-235, 1986
hereby incorporated by reference). Further, the partial agonist
properties of buprenorphine are useful in the treatment of opioid
addiction.
[0007] There are several types of transdermal formulations of
buprenorphine reported in the literature. See, for example, U.S.
Pat. No. 5,240,711 (Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka
et al.), U.S. Pat. No. 5,069,909 (Sharma et al.), U.S. Pat. No.
4,806,341 (Chien et al.), and U.S. Pat. No. 5,026,556 (Drust et
al.), all of which are hereby incorporated by reference.
[0008] Buprenorphine has a low oral bioavailability and has been
considered by certain of those skilled in the art to be like other
narcotics which are habit-forming (see, e.g., U.S. Pat. No.
5,240,711 to Hille, et al.) and induce tolerance (see, e.g., U.S.
Pat. No. 5,613,958 to Kochinke, et al.). As reported in Hille, et
al., experts are of the opinion that the form of administration of
a medicinal drug contributes to the risk of addiction, and higher
than necessary blood levels created immediately after
administration of a drug such as buprenorphine, followed by a
drastic decrease (causing in succession euphoria and then
ineffective pain treatment), cause the patient to start to long for
the next dosage (referred to as an "iatrogenic" addiction). In the
case of buprenorphine, Hille, et al. reported that continuous
infusion would be considered the most suitable mode to avoid such
an iatrogenic addition by providing constant blood levels; however,
continuous infusion requires physician control and insertion of a
cannula (which may cause inflammation at the site). This problem is
considered to be overcome by Hille, et al. by virtue of their use
of a transdermal delivery system which includes buprenorphine or
one of its pharmaceutically compatible salts and which releases the
drug over a period of at least 24 hours in a controlled manner, and
ensures that the buprenorphine does not notably decompose when the
transdermal delivery system is stored, and which further ensures
that the buprenorphine in-vivo penetrates through the skin at the
required amount.
[0009] Kochinke et al. describe a transdermal system for the
modulated administration of tolerance-inducing drugs. Buprenorphine
is identified therein as such a drug. The system is designed to
deliver the drug through the patient's skin via a three-phase drug
delivery profile. In the first phase, which begins with patch
application and ends at 2-10 hours after patch application, plasma
levels of the drug are obtained. This phase is followed by a second
phase in which therapeutic plasma levels of the drug are
maintained. The second phase begins at about two to ten hours after
patch application and ends at about 8-18 hours after patch
application. In a third phase, sub-therapeutic levels of the drug
are maintained, via inherent patch design and/or patch removal. The
rationale behind the drug delivery profile of Kochinke et al. is
that initial high blood levels may be more effective when followed
by a period of decreasing dosage (down to sub-therapeutic levels),
than if the blood levels are maintained either at the higher or
lower level (i.e., sub-therapeutic levels) throughout the entire
administration period. By virtue of this modulated profile, it is
said that the onset of tolerance to the drug being administered can
be prevented or greatly reduced.
[0010] Despite these advances in the art, there remains a need for
methods of treating patients with buprenorphine that provide
effective analgesic levels of buprenorphine for prolonged periods
of time while eliminating or minimizing dependence, tolerance, and
side effects, thus providing a safe and effective method of pain
management.
OBJECTS AND SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to provide a method
which allows for reduced plasma concentrations of buprenorphine
over a prolonged time period than possible according to prior art
methods, while still providing effective pain management.
[0012] It is a further object of the present invention to provide a
method for treating patients in pain with buprenorphine which
achieves prolonged and effective pain management, while at the same
time provides the opportunity to reduce side effects, dependence
and tolerance which the patients may experience when subjected to
prolonged treatment with a narcotic such as buprenorphine.
[0013] It is yet a further object to provide a method for the
treatment of pain in patients by utilizing a transdermal delivery
system which contains buprenorphine in a manner which maximizes the
dosage interval, i.e., the interval during which the transdermal
delivery system is maintained in contact with the skin, and
minimizes the plasma concentrations in the patients during the
dosage interval, while maintaining effective pain management.
[0014] A further object of the invention is to provide a method for
treating opioid-addicted patients in a manner which gradually
reduces the plasma concentration of opioid in the patients' plasma
while at the same time providing effective plasma concentrations
for those patients to be detoxified.
[0015] The invention is directed in part to the result that
effective pain management is provided by providing a substantially
first order rate of increase of blood plasma concentrations of
buprenorphine over about a three day (e.g., 72 hours) time
interval, followed by a prolonged time period of at least about two
days (e.g., 48 hours) during which the plasma concentrations of
buprenorphine are maintained according to substantially zero order
pharmacokinetics.
[0016] In accordance with the above objects and others, the
invention relates in part to a method of effectively treating pain
in humans, comprising administering buprenorphine to human patients
in a manner such that the following mean plasma concentrations are
achieved over a 72 hour dosing interval: a mean plasma
concentration from about 0.3 to about 113 pg/ml at about 6 hours
after initiation of the dosing interval; a mean plasma
concentration from about 3 to about 296 pg/ml at about 12 hours
after initiation of the dosing interval; a mean plasma
concentration from about 11 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 630 pg/ml at about 30 hours
after initiation of the dosing interval; a mean plasma
concentration from about 15 to about 715 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 914 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 24 to about 850 pg/ml at about 72 hours
after initiation of the dosing interval; and thereafter
administering the buprenorphine in a manner such that the mean
plasma concentrations are maintained from about 19 to about 850
pg/ml over at least the next 48 hours. In certain preferred
embodiments, the dosing interval is maintained over a seven day
period.
[0017] Any mode of administration may be utilized to attain the
above plasma concentrations over time. For example, the
buprenorphine may be administered transdermally, parenterally,
sublingually, orally, buccally, rectally, etc. Oral bioavailability
of buprenorphine is very low (estimated as 15%). In order to better
control plasma concentrations of buprenorphine within the
concentrations desired in the herein-described inventive methods,
it is preferred that the buprenorphine is administered via a
transdermal delivery system or via continuous infusion.
[0018] In a further preferred embodiment of the invention, the
method comprises applying a transdermal delivery system containing
buprenorphine as the active ingredient onto the skin of patients
which provide a release rate of buprenorphine over about a 72 hour
dosing interval such that a maximum plasma concentration from about
20 pg/ml to about 850 pg/ml is attained (depending upon the dosage
levels needed to maintain analgesia in the particular patients),
and then maintaining the transdermal delivery systems on the skin
of the patients for at least an additional 24 hour interval during
which the plasma concentrations of buprenorphine in the patients
are maintained above minimum effective concentrations of the drug
and the patients continue to experience effective pain management
during this additional dosing interval.
[0019] The invention is further directed to a method of effectively
treating pain in humans, comprising administering buprenorphine
transdermally to human patients such that mean relative release
rates are achieved as follows: a mean relative release rate of from
about 3 ug/hr to about 86 ug/hr from initiation of the dosing
interval until about 72 hours thereafter; and a mean relative
release rate of about 0.3 ug/hr to about 9 ug/hr from about 72
hours after the initiation of the dosing interval until at least
about 120 hour hours after the initiation of the dosing interval.
In certain preferred embodiments, the mean relative release rate of
about 0.3 ug/hr to about 9 ug/hr is maintained from about 72 hours
after the initiation of the dosing interval until at least about
168 hours after the initiation of the dosing interval.
[0020] The present invention is further related to a method of
effectively treating pain in humans, comprising administering
buprenorphine transdermally to human patients such that a mean
relative release rate from about 3 ug/hr to about 86 ug/hr of
buprenorphine is achieved until about 72 hours after the
application of a transdermal delivery system, and thereafter
providing (with the same transdermal delivery system) a mean
relative release rate of about 0.3 ug/hr to about 9 ug/hr from
about 72 hours after the initiation of the dosing interval until at
least about 120 hours after the initiation of the dosing interval,
and preferably until at least about 168 hours after the initiation
of the dosing interval.
[0021] In preferred embodiments, the method comprises the
application of a transdermal delivery system which is designed to
provide analgesia for about 72 hours, and which provides a release
rate of the drug when applied to the skin which generally follows
first order pharmacokinetics over that 72 hour period, and further
comprises taking advantage of the fact that such transdermal
delivery systems typically provide a dramatic drop-off in the
release rate of buprenorphine after the first 72 hours, but
nevertheless provide a relatively small but sufficient release of
buprenorphine to maintain analgesia and desirable plasma
concentrations in the patients over a further period of time of at
least, e.g., preferably at least 48 hours, by leaving the
transdermal delivery system in contact with the skin of the patient
for such additional desired dosing interval, which may be as long
as, e.g., an additional 96 hours or more. It has been found that
such transdermal dosage systems exhibit substantially zero order
release after about the initial 72 hour dosage interval, and
therefore are capable of maintaining effective plasma
concentrations of buprenorphine for a much longer period than
previously reported in the prior art.
[0022] The present invention is also related, in part, to a method
of effectively treating pain in patients, comprising applying onto
the skin of the patients a transdermal delivery system containing
buprenorphine which transdermal delivery system delivers the
buprenorphine substantially according to first order kinetics to
provide a mean plasma concentration from about 24 to about 850
pg/ml about 3 days after application, and then maintaining the
transdermal buprenorphine formulation in contact with the skin of
the human patient for about 2 to about 6 additional days without
removing the transdermal formulation, such that the patient
continues to receive effective analgesia from the transdermal
buprenorphine formulation.
[0023] The invention also provides, in certain preferred
embodiments, an improvement in a method of treating pain in human
patients by applying a 3 day transdermal delivery system containing
buprenorphine onto the skin of the patient and maintaining the
transdermal delivery system in contact with the skin for a 3 day
dosing interval, the transdermal delivery system containing an
amount of buprenorphine sufficient to provide effective analgesia
in the patient for about 3 days, the improvement comprising
maintaining the transdermal dosage form in contact with the
patient's skin for at least 2 to about 6 additional days beyond the
3 day dosing interval.
[0024] The present invention also relates to a method of treating
opioid addiction by administering buprenorphine transdermally to
human patients which provides a release rate of the drug when
applied to the skin which generally follows first order
pharmacokinetics over a 72 hour period, such that the addict
attains a buprenorphine plasma concentration from about 1000 to
about 10,000 pg/ml, and preferably from about 5000 to about 8000
pg/ml, about 72 hours after application of a buprenorphine
transdermal delivery system, and thereafter maintaining the
transdermal delivery system in contact with the skin of the addict
such that a mean relative release rate of buprenorphine
approximating zero order kinetics over an additional dosing
interval of at least about 48 hours, to provide the desired
therapeutic effect (detoxification). In preferred embodiments the
transdermal delivery system is maintained in contact with the
addict's skin for about 7 days.
[0025] The methods of the present invention are described in
further detail in the following sections. However, it should be
understood that for purposes of the present invention, the
following terms have the following meanings:
[0026] The term "effective analgesia" is defined for purposes of
the present invention as a satisfactory reduction in or elimination
of pain, along with the process of a tolerable level of side
effects, as determined by the human patient.
[0027] The term "effective pain management" means for purposes of
the present invention as the objective evaluation of a human
patient's response (pain experienced versus side effects) to
analgesic treatment by a physician as well as subjective evaluation
of therapeutic treatment by the patient undergoing such treatment.
The skilled artisan will understand that effective analgesia will
vary according to many factors, including individual patient
variations.
[0028] The term "breakthrough pain" means pain which the patient
experiences despite the fact that the patient is being administered
generally effective amounts of, e.g., an opioid analgetic such as
buprenorphine.
[0029] The term "rescue" refers to a dose of an analgesic which is
administered to a patient experiencing breakthrough pain.
[0030] The term "first order" pharmacokinetics is defined as plasma
concentrations which increase over a specified time period. Drug
release from suspension matrices according to first order kinetics
may be defined as follows:
Amount released per area unit Q= {square root over
(D.sub.eff(2C.sub.O-C.sub.s)C.sub.st)} (First order kinetics)
D.sub.eff=apparent diffusion coefficient M/ {square root over
(t)}=2C.sub.O {square root over (D.sub.eff/.pi.)} C.sub.O=initial
drug concentration in the transdermal delivery system
C.sub.S=saturation concentration t=time Assumptions: perfect sink;
diffusion of dissolved drug is rate controlling; therefore
Q.apprxeq.const. {square root over (t)}
[0031] Drug release from solution matrices according to first order
kinetics may be defined as follows:
Amount released per area unit Q= {square root over
(D.sub.eff(2C.sub.O(D.sub.efft/.pi.))} (First order kinetics)
Assumptions: perfect sink; diffusion of dissolved drug is rate
controlling; M.sub.t.ltoreq.0.4 M.sub.0 therefore Q.apprxeq.const.
{square root over (t)}
[0032] The term "zero order" pharmacokinetics contemplates an
amount of drug released from a buprenorphine formulation which
substantially maintains plasma concentrations at a relatively
constant level. For purposes of the present invention, a relatively
constant plasma concentration is defined as a concentration which
does not decrease more than about 30% over a 48 hour time
period.
[0033] Drug release from membrane-controlled systems may be defined
as follows:
Amount released per area unit Q=const (zero order kinetics)
[0034] The term "mean relative release rate" is determined from the
amount of drug released per unit time from the transdermal delivery
system through the skin and into the bloodstream of a human
patient. Mean relative release rate may be expressed, e.g, as .mu.g
drug/cm.sup.2/hr. For example, a transdermal delivery system that
releases 1.2 mg of buprenorphine over a time period of 72 hours is
considered to have a relative release rate of 16.67 .mu.g/hr. For
purposes of the invention, it is understood that relative release
rates may change between any particular time points within a
particular dosing interval, and the term therefore only reflects
the overall release rate during the particular dosing interval. For
purposes of the present invention, relative release rate should be
considered synonomous with the term "flux rate".
[0035] The term "sustained release" is defined for purposes of the
present invention as the release of the drug (opioid analgesic)
from the transdermal formulation at such a rate that blood (e.g
plasma) concentrations (levels) are maintained within the
therapeutic range (above the effective analgesic concentration or
"MEAC") but below toxic levels over a period of time of about 3
days or longer.
[0036] The term "steady state" means that the blood plasma
concentration curve for a given drug has been substantially
repeated from dose to dose.
[0037] The term "minimum effective analgesic concentration" is
defined for purposes of this invention as the minimum effective
therapeutic blood plasma level of the drug at which at least some
pain relief is achieved in a given patient. It will be well
understood by those skilled in the medical art that pain
measurement is highly subjective and great individual variations
may occur among patients.
[0038] For purposes of the present invention, the term
"buprenorphine" shall include buprenorphine base, pharmaceutically
acceptable salts thereof, stereoisomers thereof, ethers and esters
thereof, and mixtures thereof.
[0039] The term "overage" means for the purposes of the present
invention the amount of buprenorphine contained in a transdermal
delivery system which is not delivered to the patient. The overage
is necessary for creating a concentration gradient by means of
which the active agent (e.g., buprenorphine) migrates through the
layers of the transdermal dosage form to the desired site on a
patient's skin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0041] FIG. 1 is a graphical representation of the mean plasma
concentration (pg/ml) versus time (days) for Example 1;
[0042] FIG. 2 is a graphical representation of pharmacodynamic
variables versus time (days) for Example 1;
[0043] FIG. 3 is a graphical representation of the plasma
concentration (pg/ml) over time (hours) for Comparative Example
A;
[0044] FIG. 4 is a graphical representation of the plasma
concentration (pg/ml) over time (hours) for Comparative Example B
(intravenous concentrations divided by 100);
[0045] FIG. 5 is a graphical representation of the plasma
concentration (pg/ml) over time (hours) for Comparative Example
C;
[0046] FIG. 6 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example A;
[0047] FIG. 7 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example B;
[0048] FIG. 8 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example C;
[0049] FIG. 9 is a graphical representation of the plasma
concentration (pg/ml) over time (hours) for Comparative Example
D;
[0050] FIG. 10 is a graphical representation of the plasma
concentration (pg/ml) over time (hours) for Comparative Example
E;
[0051] FIG. 11 is a graphical representation of the plasma
concentration (pg/ml over time (hours) for Comparative Example
F;
[0052] FIG. 12 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example D;
[0053] FIG. 13 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example E; and
[0054] FIG. 14 is a graphical representation pharmacodynamic
variables versus time (hours) for Comparative Example F.
DETAILED DESCRIPTION
[0055] While chronic pain is often manageable with the use of the
combination of "mild" analgesics, and nonpharmacologic
interventions, selected patients continue to experience
unacceptably intense pain. Some patients with chronic pain cannot
tolerate therapeutic doses of "mild" analgesics, while others
develop pain of such severity that "strong" analgesics should be
considered for subacute or chronic use.
[0056] The phrase "strong analgesics" encompasses, inter alia,
several classes of opioid analgesics, including the partial
agonists. Parenteral buprenorphine (a Schedule V drug under the
Controlled Substances Act) is the only example of a partial agonist
opioid analgesic currently marketed in the United States.
[0057] Partial agonists provide several therapeutic advantages in
many patients when compared to morphine-like agonists and mixed
agonists-antagonists. For example, unlike the mixed
agonists-antagonists (e.g., pentazocine, butorphanol, nalbuphine),
buprenorphine is devoid of psychotomimetic adverse reactions; in
comparison with agonists (e.g., morphine and fentanyl), the
dose-responsive relationship for respiratory depression with
buprenorphine is relatively low and the abuse liability of
buprenorphine is less.
[0058] The chemical of name of buprenorphine is
21-cyclopropyl-7-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6-
,7,8,14-tetrahydrooripavine. The molecular weight of buprenorphine
base is 467.7; the empirical formula is
C.sub.29H.sub.41NO.sub.4.
[0059] The structural formula of buprenorphine is shown below:
##STR00001##
[0060] Buprenorphine is an opioid partial agonist and shares many
of the actions, such as analgesia, of opioid agonists. A "ceiling
effect" to analgesia (i.e., no additional analgesia with increasing
dose) is well documented with respect to buprenorphine in many
animal models. It is highly lipophilic and dissociates slowly from
opioid receptors. Buprenorphine is considered in the art to be a
partial agonist at .mu. opioid receptors in the central nervous
system ("CNS") and peripheral tissues. It is further thought that
buprenorphine binds with high affinity to .mu. and .kappa..sub.1
receptors, and, with lower affinity, to .delta. receptors. The
intrinsic agonist activity at the .kappa. receptor seems to be
limited and most evidence suggests that buprenorphine has
antagonist activity at .kappa. receptors. The lack of .kappa.
agonism accounts for buprenorphine's freedom from the dysphoric and
psychotomimetic effects often seen with agonist/antagonist drugs.
Other studies suggest that the opioid antagonist effects of
buprenorphine may be mediated via an interaction with .delta.
opioid receptors.
[0061] It is known in the art that buprenorphine binds slowly with,
and dissociates slowly from, the .mu. receptor. The high affinity
of buprenorphine for the .mu. receptor and its slow binding to, and
dissociation from, the receptor is thought to possibly account for
the prolonged duration of analgesia, and in part, for the limited
physical dependence potential observed with the drug. The high
affinity binding may also account for the fact that buprenorphine
can block the .mu. agonist effects of other administered
opioids.
[0062] Like other opioid agonists, buprenorphine produces
dose-related analgesia. The exact mechanism has not been fully
explained, but analgesia appears to result from a high affinity of
buprenorphine for .mu. and possibly .kappa. opioid receptors in the
CNS. The drug may also alter the pain threshold (threshold of
afferent nerve endings to noxious stimuli). On a weight basis, the
analgesic potency of parenteral buprenorphine appears to be about
25 to about 50 times that of parenteral morphine, about 200 times
that of pentazocine, and about 600 times that of meperidine.
Buprenorphine may produce sex-related differences in analgesia,
with females requiring substantially less drug than males to
produce adequate analgesia.
[0063] For a study of transdermal delivery of buprenorphine through
cadaver skin, see Roy, Samir D. et al., "Transdermal Delivery of
Buprenorphine Through Cadaver Skin", Journal of Pharmaceutical
Sciences, Vol. 83, No. 2, pp. 126-130, (1994), hereby incorporated
by reference. For a discussion of buprenorphine pharmacokinetics
resulting from application of a fillable transdermal therapeutic
system, see Wilding, I. R. et al., "Pharmacokinetic evaluation of
transdermal buprenorphine in man," International Journal of
Pharmaceutics, 132 (1996) pp. 81-87, hereby incorporated by
reference. For a discussion of the permeation of buprenorphine and
alkyl esters thereof, see Imoto, et al., "Transdermal Prodrug
Concepts: Permeation of Buprenorphine and its Alkyl Esters Through
Hairless Mouse Skin and Influence of Vehicles," Biol. Pharm. Bull.,
19(2)263-267 (1996), hereby incorporated by reference.
[0064] Buprenorphine has a low abuse liability compared to full
agonist opioids. Although infrequent, however, buprenorphine may
also produce limited physical dependence, and signs and symptoms of
mild withdrawal may appear following discontinuance of prolonged
therapy with the drug alone. Due to buprenorphine's slow binding
with and slow dissociation from the .mu. receptor, elimination of
the drug from the CNS is prolonged following abrupt discontinuance;
consequently, signs and symptoms of acute withdrawal are less
intense than those produced by morphine and are delayed in
appearance.
[0065] In patients physically dependent on opioids, buprenorphine
produces many of the subjective and objective effects of opioids;
however, the drug may not be a satisfactory substitute for opioid
agonists in all patients physically dependent on opioids. Tolerance
to the opioid agonist activity of the drug reportedly develops
rarely, if at all.
[0066] Buprenorphine may produce psychological dependence.
Buprenorphine is a partial opioid agonist with behavioral and
psychic effects similar to morphine. Unlike pentazocine, however,
buprenorphine rarely causes psychotomimetic effects. Like other
opioid agonists, buprenorphine may produce increases in
cerebrospinal fluid pressure.
[0067] The pharmacokinetics of buprenorphine administered
parenterally and sublingually are known. Intravenous administration
of a single dose of about 0.3 mg of buprenorphine has been shown to
provide mean peak plasma drug concentrations of about 18 ng/ml
which occur within about 2 minutes; plasma concentrations declined
to about 9 and about 0.4 ng/ml after about 5 minutes and about 3
hours, respectively. Following intramuscular administration of a
second 0.3-mg dose 3 hours after the initial intravenous dose, mean
peak plasma buprenorphine concentrations of about 3.6 ng/ml occur
within about 2 to about 5 minutes and decline to about 0.4 ng/ml
after about 3 hours. Approximately 10 minutes after administration,
plasma concentrations of buprenorphine are similar following
intravenous or intramuscular injection.
[0068] A parenteral solution of buprenorphine hydrochloride (0.3 mg
buprenorphine/ml) is commercially available as Buprenex.RTM.
(Reckitt & Colman) for intramuscular and intravenous
administration. The usual adult dose (over age 13) is 0.3 mg IM or
IV every 6 to 8 hours as needed for moderate to severe pain. The
pediatric dose in patients age 2 to 12 is 2-6 mcg/kg of body weight
every 4-6 hours. The increased frequency of administration in the
pediatric population is believed to be caused by increased
clearance of buprenorphine compared to the adult population. The
mean duration of analgesia generally is six hours following single
intramuscular or intravenous doses of 0.2 to 0.3 mg or 2 to 4
.mu.g/kg; however, in some studies, the mean duration of analgesia
reportedly ranged from 4 to 10 hours following single intramuscular
doses of 0.2 to 0.6 mg and 2 to 24 hours following single
intravenous doses of 0.3 mg or 2 to 15 .mu.g/kg.
[0069] For reference, the mean peak plasma buprenorphine
concentration, time to peak concentration, and systemic
availability for a 0.4 mg and 0.8 mg single-dose sublingual dose of
buprenorphine has been reported by Cowan, Alan and Lewis John, W.,
Buprenorphine: Combating Drug Abuse With a Unique Opioids,
Wiley-Liss, Inc., New York, pp. 137-147 (1995), hereby incorporated
by reference in its entirety. For a 0.4 mg sublingual dose, the
Cmax was reported as 0.50.+-.0.06 ng/ml; the Tmax was reported
210.+-.40 minutes; and a systemic availability of 57.7%.+-.6. For a
0.8 mg sublingual dose, the Cmax was reported as 1.04.+-.0.27
ng/ml; the Tmax was reported 192.+-.49 minutes; and a systemic
availability of 54.1%.+-.12.7.
[0070] It has previously been reported that a usual sublingual
analgesic dose of buprenorphine is 0.2 to 0.4 mg every 8 hours
(e.g., Kuhlman, J J et al. J Analyt Toxicol 1996: 20(10)). For a
transdermal patch which might provide a nominal delivery rate of
about 12.5 ug/hr, the total buprenorphine administered over a 24
hour period would be about 0.3 mg, and the sublingual equivalent
dose over the same period would be about 0.6 mg. For a transdermal
delivery system (e.g., a transdermal patch) which might provide a
nominal delivery rate of about 25 ug/hr, the total buprenorphine
administered over a 24 hour period would be about 0.6 mg, and the
sublingual equivalent dose over the same period would be about 1.2
mg. For a transdermal patch which might provide a nominal delivery
rate of about 50 ug/hr, the total buprenorphine administered over a
24 hour period would be about 1.2 mg, and the sublingual equivalent
dose over the same period would be about 2.4 mg, It is contemplated
that one of ordinary skill in the art will appreciate that by
simple pharmaceutical calculations, the equivalent doses for
achieving the inventive buprenorphine plasma concentration set
forth herein can be determined regardless of the mode of
administration. In the present discussion, the comparison is made
between transdermal dose and sublingual dose.
[0071] Distribution of buprenorphine into human body tissues and
fluids has not been well characterized. Following oral or
intramuscular administration in rats, buprenorphine distributes
into the liver, brain, placenta, and GI tract; highest
concentrations were attained in the liver within 10 or 40 minutes
following oral or intramuscular administration, respectively. The
hepatic extraction ratio of buprenorphine is approximately 1. The
drug and its metabolites are distributed into bile. Following
intravenous administration in humans, the drug rapidly distributes
into cerebro spinal fluid ("CSF") (within several minutes). CSF
buprenorphine concentrations appear to be approximately 15% to 25%
of concurrent plasma concentrations. Buprenorphine is approximately
96% bound to plasma proteins, mainly to .alpha. and .beta.
globulins; the drug does not appear to bind substantially to
albumin.
[0072] Buprenorphine is almost completely metabolized in the liver,
principally by N-dealkylation, to form norbuprenorphine
(N-dealkylbuprenorphine); buprenorphine and norbuprenorphine also
undergo conjugation with glucuronic acid. Like the metabolites of
other opioid agonists, norbuprenorphine may have weak analgesic
activity; however, studies to determine the analgesic activity of
the metabolites of buprenorphine have not been performed.
Buprenorphine and its metabolites are excreted principally in feces
via biliary elimination and also in urine. Buprenorphine is
excreted in feces mainly as unchanged drug; small amounts of
norbuprenorphine are also excreted in feces. The drug and its
metabolites are believed to undergo enterohepatic circulation.
Norbuprenorphine appears to be excreted principally in urine at a
slower rate than the parent drug. Total plasma clearance of
buprenorphine reportedly is approximately 1.28 l/minute in
conscious postoperative patients. Limited data indicate that there
is considerable interindividual variability in buprenorphine
pharmacokinetics in children; however, clearance of the drug
appears to be increased in children (e.g., those 5 to 7 years of
age) compared with that in adults. Optimal dosing interval of
buprenorphine may have to be decreased in pediatric patients.
[0073] Achieving effective analgesic plasma opioid concentrations
in patients is very complicated and involves a host of
considerations, including the inherent chemical and physical
properties of the opioid itself. Further considerations include
in-vivo metabolism, individual patient response and tolerance.
Generally, however, there is a "minimally effective analgesic
concentration" (MEAC) in plasma for a particular opioid below which
no analgesia is provided. There is relationship between plasma
opioid levels and analgesia. Higher plasma levels are generally
associated with greater pain relief, and (possibly) greater
incidence and severity of side effects.
[0074] In preferred embodiments of the present invention where the
patient(s) is being treated for moderate to severe pain, the
buprenorphine is administered in a manner such that the following
mean plasma concentrations are achieved over a 72 hour dosing
interval: a mean plasma concentration from about 0.3 to about 113
pg/ml at about 6 hours after initiation of the dosing interval; a
mean plasma concentration from about 3 to about 296 pg/ml at about
12 hours after initiation of the dosing interval; a mean plasma
concentration from about 7 to about 644 pg/ml at about 24 hours
after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 753 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 19 to about 1052 pg/ml
over at least the next 48 hours. In further preferred embodiments,
this method further comprises maintaining the dosing of
buprenorphine during the at least next 48 hours in accordance with
zero order kinetics. Preferably, the mean plasma concentrations are
maintained after the 72 hour dosing interval as follows: a mean
plasma concentration from about 23 to about 1052 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 23 to about 1052 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 22 to about 970 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 19 to about 841 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In this embodiment where a transdermal delivery system
is used, a mean relative release rate from about 3 ug/hr to about
86 ug/hr is preferably maintained from the initiation of the dosing
interval until about 72 hours after the initiation of the dosing
interval; and a mean relative release rate is preferably maintained
from about 0.3 ug/hr to about 9 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval.
[0075] Preferably, the administration of buprenorphine is
accomplished via a mode selected from the group consisting of
transdermally, continuous infusion, and a mixture of transdermally
and continuous infusion. Most preferably, the administration is
accomplished by applying a transdermal delivery system to the skin
of a patient, and maintaining said transdermal delivery system in
contact with the patient's skin for at least 5 days.
[0076] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 1
to about 28 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 14 to about 74
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 30 to about 161 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 51 to about 188 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 62 to about 246 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 79 to about 246 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 85 to about 263 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, buprenorphine
is administered in a manner such that the mean plasma
concentrations are maintained from about 77 to about 263 pg/ml over
at least the next 48 hours. Preferably, the plasma concentrations
are maintained after the 72 hour dosing interval as follows: a mean
plasma concentration from about 92 to about 263 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 94 to about 263 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 86 to about 243 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 77 to about 210 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In this embodiment wherein a transdermal delivery system
is used, it is preferred that a mean relative release rate of from
about 13 ug/hr to about 21 ug/hr is maintained from the initiation
of the dosing interval until about 72 hours after the initiation of
the dosing interval; and that a mean relative release rate of about
1 ug/hr to about 2 ug/hr from about 72 hours after the initiation
of the dosing interval until the end of the dosing interval is
maintained (e.g., about 168 hours after initiation for a seven-day
dosing interval).
[0077] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 0.3
to about 7 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 4 to about 19
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 7 to about 40 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 13 to about 47 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 16 to about 62 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 21 to about 62 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 20 to about 66 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 19 to about 66 pg/ml over
at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
23 to about 66 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 23 to about
66 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 22 to about 61
pg/ml at about 144 hours after initiation of the dosing interval;
and a mean plasma concentration from about 19 to about 53 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate is maintained
from about 3 ug/hr to about 5 ug/hr from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 0.3
ug/hr to about 0.6 ug/hr from about 72 hours after the initiation
of the dosing interval until the end of the dosing interval (e.g.,
about 168 hours after initiation of a seven-day dosing
interval).
[0078] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 0.7
to about 14 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 7 to about 37
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 15 to about 80 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 25 to about 94 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 31 to about 123 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 40 to about 123 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 42 to about 132 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 38 to about 132 pg/ml over
at least the next 48 hours. Preferably, the buprenorphine is
further administered in a manner such that the mean plasma
concentrations are maintained as follows: a mean plasma
concentration from about 46 to about 132 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 47 to about 132 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 43 to about 121 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 38 to about 105 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In embodiments where a transdermal delivery system is
used, a mean relative release rate from about 6 ug/hr to about 11
ug/hr is maintained from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 0.7 ug/hr to about 1
ug/hr is maintained from about 72 hours after the initiation of the
dosing interval until the end of the dosing interval (e.g., about
168 hours after initiation of a seven day dosing interval).
[0079] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 3
to about 57 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 28 to about 148
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 59 to about 322 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 102 to about 377 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 124 to about 492 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 159 to about 492 ml at about 60 hours;
after initiation of the dosing interval; a mean plasma
concentration from about 169 to about 526 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 153 to about 526 pg/ml
over at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
184 to about 526 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 187 to
about 526 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 173 to about 485
pg/ml at about 144 hours after initiation of the dosing interval; a
mean plasma concentration from about 153 to about 420 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate from about 26
ug/hr to about 43 ug/hr is maintained from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 2 ug/hr
to about 4 ug/hr is maintained from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
[0080] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 4
to about 85 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 42 to about 222
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 89 to about 483 pg/ml at about
24 hours after initiation of the dosing interval; a mean plasma
concentration from about 152 to about 565 pg/ml at about 36 hours
after initiation of the dosing interval; a mean plasma
concentration from about 186 to about 738 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 238 to about 738 pg/ml at 60 hours after
initiation of the dosing interval; a mean plasma concentration from
about 254 to about 789 pg/ml at about 72 hours after initiation of
the dosing interval. Thereafter; the buprenorphine is administered
in a manner such that the mean plasma concentrations are maintained
from about 230 to about 789 pg/ml over at least the next 48 hours.
Preferably, the buprenorphine is administered in a manner such that
the mean plasma concentrations are maintained as follows: a mean
plasma concentration from about 276 to about 789 pg/ml at about 96
hours after initiation of the dosing interval; a mean plasma
concentration from about 281 to about 789 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 259 to about 727 pg/ml at about 144 hours
after initiation of the dosing interval; a mean plasma
concentration from about 230 to about 630 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval). In embodiments where a transdermal delivery system is
used, a mean relative release rate of from about 38 ug/hr to about
64 ug/hr is maintained from the initiation of the dosing interval
until about 72 hours after the initiation of the dosing interval;
and a mean relative release rate of about 4 ug/hr to about 7 ug/hr
is maintained from about 72 hours after the initiation of the
dosing interval until the end of the dosing interval (e.g., about
168 hours after the initiation of a seven-day dosing interval).
[0081] In a further preferred embodiment of the invention,
buprenorphine is administered to human patients in a manner such
that the following mean plasma concentrations are achieved over a
72 hour dosing interval: a mean plasma concentration from about 5
to about 113 pg/ml at about 6 hours after initiation of the dosing
interval; a mean plasma concentration from about 55 to about 296
pg/ml at about 12 hours after initiation of the dosing interval; a
mean plasma concentration from about 118 to about 644 pg/ml at
about 24 hours after initiation of the dosing interval; a mean
plasma concentration from about 203 to about 753 pg/ml at about 36
hours after initiation of the dosing interval; a mean plasma
concentration from about 247 to about 984 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 317 to about 984 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 339 to about 1052 pg/ml at about 72 hours
after initiation of the dosing interval. Thereafter, the
buprenorphine is administered in a manner such that the mean plasma
concentrations are maintained from about 306 to about 1052 pg/ml
over at least the next 48 hours. Preferably, the buprenorphine is
administered in a manner such that the mean plasma concentrations
are maintained as follows: a mean plasma concentration from about
369 to about 1052 pg/ml at about 96 hours after initiation of the
dosing interval; a mean plasma concentration from about 374 to
about 1052 pg/ml at about 120 hours after initiation of the dosing
interval; a mean plasma concentration from about 346 to about 970
pg/ml at about 144 hours after initiation of the dosing interval; a
mean plasma concentration from about 306 to about 841 pg/ml at
about 168 hours after initiation of the dosing interval (for a
seven day dosing interval). In embodiments where a transdermal
delivery system is used, a mean relative release rate of from about
51 ug/hr to about 86 ug/hr is maintained from the initiation of the
dosing interval until about 72 hours after the initiation of the,
e.g., dosing interval; and a mean relative release rate of about 5
ug/hr to about 9 ug/hr is maintained from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval, e.g., about 168 hours after the initiation of a seven-day
dosing interval (e.g., about 168 hours after the initiation of a
seven-day dosing internal).
[0082] In further embodiments of the invention, the method
comprises the administration of buprenorphine transdermally to
human patients according to very different relative release rates
for the first 3 day portion of the dosing interval (indicative of
substantially first order release), and the additional at least 2
day long portion of the dosing interval (substantially zero order
release) such that mean relative release rates are achieved over
the dosing interval as follows: a mean relative release rate of
from about 3 ug/hr to about 86 ug/hr from the initiation of the
dosing interval until about 72 hours after the initiation of the
dosing interval; and a mean relative release rate of about 0.3
ug/hr to about 9 ug/hr from about 72 hours after the initiation of
the dosing interval until the end of the dosing interval (e.g.,
about 168 hours after the initiation of a seven-day dosing
interval).
[0083] In one preferred embodiment, the mean relative release rates
achieved over the dosing interval are as follows: a mean relative
release rate of from about 3 ug/hr to about 5 ug/hr from the
initiation of the dosing interval until about 72 hours after the
initiation of the dosing interval; and a mean relative release rate
of about 0.3 ug/hr to about 0.6 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
[0084] In another preferred embodiment, the mean relative release
rates achieved over the dosing interval are as follows: a mean
relative release rate of from about 6 ug/hr to about 11 ug/hr from
the initiation of the dosing interval until about 72 hours after
the initiation of dosing interval; and a mean relative release rate
of about 0.7 ug/hr to about 1 ug/hr from about 72 hours after the
initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
[0085] In another preferred embodiment, the mean relative release
rates achieved over the dosing interval are as follows: a mean
relative release rate of from about 13 ug/hr to about 21 ug/hr from
the initiation of the dosing interval until about 72 hours after
the initiation of the dosing interval; and a mean relative release
rate of about 1 ug/hr to about 2 ug/hr from about 72 hours after
the initiation of the dosing interval until the end of the dosing
interval (e.g., about 168 hours after initiation of a seven-day
dosing interval).
[0086] In yet another preferred embodiment, the mean relative
release rates achieved over the dosing interval are as follows: a
mean relative release rate of from about 26 ug/hr to about 43 ug/hr
from the initiation of the dosing interval until about 72 hours
after the initiation of the dosing interval; and a mean relative
release rate of about 3 ug/hr to about 4 ug/hr from about 72 hours
after the initiation of the dosing interval until the end of the
dosing interval (e.g., about 168 hours after the initiation of a
seven-day dosing interval).
[0087] In yet a further preferred embodiment, the mean relative
release rates achieved over the dosing interval are as follows: a
mean relative release rate of from about 39 ug/hr to about 64 ug/hr
from the initiation of the dosing interval until about 72 hours
after the initiation of the dosing interval; and a mean relative
release rate of about 4 ug/hr to about 7 ug/hr from about 72 hours
after the initiation of the dosing interval until the end of the
dosing interval (e.g., about 168 hours after the initiation of a
seven-day dosing interval).
[0088] In yet a further preferred embodiment, the mean relative
release rates achieved over the dosing interval are as follows: a
mean relative release rate of from about 51 ug/hr to about 86 ug/hr
from the initiation of the dosing interval until about 72 hours
after the initiation of the dosing interval; and a mean relative
release rate of about 5 ug/hr to about 9 ug/hr from about 72 hours
after the initiation of the dosing interval until the end of the
dosing interval, e.g., about 168 hours after the initiation of the
dosing interval.
[0089] The method of the present invention may be accomplished by
any mode of administration useful for buprenorphine known to those
skilled in the art. However, certain modes of administration are
more practical than others. Preferably, the mode of administration
is via continuous infusion, through the oral mucosa, or most
preferably, transdermally.
[0090] In embodiments of the invention where the plasma
concentrations described herein are accomplished intravenous
infusion, the pattern of plasma concentrations seen through time in
this invention can be achieved by using the injectable, parenteral
form of, e.g., buprenorphine hydrochloride suitably diluted in an
intravenous infusion solution. The infusion rate would be
controlled by a programmable infusion pump, to provide the desired
plasma profile.
[0091] In preferred embodiments of the invention, the mode of
administration of the buprenorphine is transdermal. Transdermal
delivery of active agents is measured in terms of "relative release
rate" or "flux", i.e., the rate of penetration of the active agent
through the skin of an individual. Skin flux may be generally
determined from the following equation:
dM/dt=J=P*C
[0092] where J is the skin flux, P is the permeability coefficient
and C is the concentration gradient across the membrane, assumed to
be the same as the donor concentration. M represents the cumulative
amount of drug entering the blood stream. The variables dM and dt
represent the change in cumulative amount of drug entering the
blood stream and change in time, respectively.
[0093] It is well understood in the art of transdermal delivery
systems that in order to maintain a desired flux rate for a desired
dosing period, it is necessary to include an overage of active
agent in the transdermal delivery system in an amount that is
substantially greater than the amount to be delivered to the
patient over the desired time period. For example, to maintain the
desired flux rate for a three day time period, it is considered
necessary to include much greater than 100% of a three day dose of
an active agent in a transdermal delivery system. This overage is
necessary for creating a concentration gradient by means of which
the active agent migrates through the layers of the transdermal
delivery system to the desired site on a patient's skin. The
remainder of the active agent remains in the transdermal delivery
system. It is only the portion of active agent that exits the
transdermal delivery system that becomes available for absorption
into the skin. The total amount of active agent absorbed into the
patient's blood stream is less than the total amount available. The
amount of overage to be included in a transdermal delivery system
is dependent on these and other factors known to the skilled
artisan.
[0094] It has been found that it is possible to treat pain
according to the present invention by providing a transdermal
delivery system containing a sufficient amount of opioid, e.g.
buprenorphine, to provide a desired relative release rate for up to
3 days, and after single administration (application) of the
transdermal dosage form, leaving the dosage form on the skin for
approximately a 5 to 8 day time period, thereby resulting in the
flux being maintained over the prolonged period and effective blood
plasma levels and pain management being maintained over the
prolonged period. Preferably, the desired flux is maintained at
least about 5, preferably at least about 8 days after application
of the transdermal delivery system. If the transdermal delivery
system is removed 3 days after its administration, no analgesia is
present a short time after removal. However, if the same
transdermal delivery system is maintained in contact with the skin
for an about 5 to about 8 day period, analgesia is maintained over
the prolonged period of contact, but the patient continues to
experience analgesia. In other words, inclusion of the
aforementioned overage of buprenorphine provides analgesia for at
least about twice the expected 3 day dosing interval.
[0095] Any type of transdermal delivery system may be used in
accordance with the methods of the present invention so long as the
desired pharmacokinetic and pharmacodynamic response(s) are
attained over at least 3 days, e.g., from about 5 to about 8 days.
Preferable transdermal delivery systems include e.g., transdermal
patches, transdermal plasters, transdermal discs, iontophoretic
transdermal devices and the like.
[0096] Transdermal dosage forms used in accordance with the
invention preferably include a backing layer made of
pharmaceutically acceptable material which is impermeable to the
buprenorphine. The backing layer preferably serves as a protective
cover for the active agent, e.g. buprenorphine and may also provide
a support function. Examples of materials suitable for making the
backing layer are films of high and low density polyethylene,
polypropylene, polyvinylchloride, polyurethane, polyesters such as
poly(ethylene phthalate), metal foils, metal foil laminates of such
suitable polymer films, textile fabrics, if the components of the
reservoir cannot penetrate the fabric due to their physical
properties and the like. Preferably, the materials used for the
backing layer are laminates of such polymer films with a metal foil
such as aluminum foil. The backing layer can be any appropriate
thickness which will provide the desired protective and support
functions. A suitable thickness will be from about 10 to about 200
microns. Desirable materials and thickness will be apparent to the
skilled artisan.
[0097] In certain preferred embodiments, the transdermal dosage
forms used in accordance with the invention contain a polymer
matrix layer. Generally, the polymers used to form the biologically
acceptable polymer matrix are those capable of forming thin walls
or coatings through which pharmaceuticals can pass at a controlled
rate. A non-limiting list of exemplary materials for inclusion in
the polymer matrix includes polyethylene, polypropylene,
ethylene/propylene copolymers, ethylene/ethylacrylate copolymers,
ethylenevinyl acetate copolymers, silicones, rubber, rubber-like
synthetic homo-, co- or block polymers, polyacrylic esters and the
copolymers thereof, polyurethanes, polyisobutylene, chlorinated
polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate
copolymer, polymethacrylate polymer (hydrogel), polyvinylidene
chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol
copolymer, ethylene-vinyloxyethanol copolymer, silicones including
silicone copolymers such as polysiloxane-polymethacrylate
copolymers, cellulose polymers (e.g., ethyl cellulose, and
cellulose esters), polycarbonates, polytetrafluoroethylene and
mixtures thereof.
[0098] Preferred materials for inclusion in the polymer matrix
layer are silicone elastomers of the general polydimethylsiloxane
structures, (e.g., silicone polymers). Preferred silicone polymers
cross-link and are pharmaceutically acceptable. Other preferred
materials for inclusion in the polymer matrix layer include:
silicone polymers that are cross-linkable copolymers having
dimethyl and/or dimethylvinyl siloxane units which can be
crosslinked using a suitable peroxide catalyst. Also preferred are
those polymers consisting of block copolymers based on styrene and
1,3-dienes (particularly linear styrene-isoprene-block copolymers
of styrene-butadiene-block copolymers), polyisobutylenes, polymers
based on acrylate and/or methacrylate.
[0099] The polymer matrix layer may optionally include a
pharmaceutically acceptable cross-linking agent. Suitable
crosslinking agents include, e.g., tetrapropoxy silane.
[0100] Preferred transdermal delivery systems used in accordance
with the methods of the present invention include an adhesive layer
to affix the dosage form to the skin of the patient for a desired
period of administration, e.g., about 5 to about 8 days. If the
adhesive layer of the dosage form fails to provide adhesion for the
desired period of time, it is possible to maintain contact between
the dosage form with the skin by, for instance, affixing the dosage
form to the skin of the patient with an adhesive tape, e.g,
surgical tape. It is not critical for purposes of the present
invention whether adhesion of the dosage form to the skin of the
patient is achieved solely by the adhesive layer of the dosage form
or in connection with a peripheral adhesive source, such as
surgical tape, provided that the dosage form is adhered to the
patient's skin for the requisite administration period.
[0101] The adhesive layer preferably includes using any adhesive
known in the art that is pharmaceutically compatible with the
dosage form and preferably hypoallergenic, such as polyacrylic
adhesive polymers, acrylate copolymers (e.g., polyacrylate) and
polyisobutylene adhesive polymers. In other preferred embodiments
of the invention, the adhesive is a pressure-sensitive contact
adhesive, which is preferably hypoallergenic.
[0102] The transdermal dosage forms which can be used in accordance
with the present invention may optionally include a permeation
enhancing agent. Permeation enhancing agents are compounds which
promote penetration and/or absorption of the buprenorphine into the
blood stream of the patient. A non-limiting list of permeation
enhancing agents includes polyethylene glycols, surfactants, and
the like.
[0103] Alternatively, permeation of buprenorphine may be enhanced
by occlusion of the dosage form after application to the desired
site on the patient with, e.g. an occlusive bandage. Permeation may
also be enhanced by removing hair from the application site by,
e.g. clipping, shaving or use of a depilatory agent. Another
permeation enhancer is heat. It is thought that heat enhancement
can be induced by, among other things, using a radiating heat form,
such as an infrared lamp, onto the application site after
application of the transdermal dosage form. Other means of
enhancing permeation of buprenorphine such as the use of
iontophoretic means are also contemplated to be within the scope of
the present invention.
[0104] A preferred transdermal dosage form which may be used in
accordance with the present invention includes a non-permeable
backing layer made, for example, of polyester; an adhesive layer
made, for example of a polyacrylate; and a matrix containing the
buprenorphine and other desirable pharmaceutical aids such as
softeners, permeability enhancers, viscosity agents and the
like.
[0105] The active agent may be included in the device in a drug
reservoir, drug matrix or drug/adhesive layer. Preferably, the
active agent is buprenorphine or a pharmaceutically acceptable salt
thereof.
[0106] Certain preferred transdermal delivery systems also include
a softening agent. Suitable softening agents include higher
alcohols such as dodecanol, undecanol, octanol, esters of
carboxylic acids, wherein the alcohol component may also be a
polyethoxylated alcohol, diesters of dicarboxylic acids, such as
di-n-butyladiapate, and triglycerides particularly medium-chain
triglycerides of the caprylic/capric acids or coconut oil, have
proved to be particularly suitable. Further examples of suitable
softeners are multivalent alcohols, for example, levulinic acid,
caprylic acids glycerol and 1,2-propanediol which can also be
etherified by polyethylene glycols.
[0107] A buprenorphine solvent may also be included in the
transdermal delivery systems of the present invention. Preferably,
the solvents dissolve the buprenorphine to a sufficient extent
thereby avoiding complete salt formation. A non-limiting list of
suitable solvents include those with at least one acidic group.
Particularly suitable are monoesters of dicarboxylic acids such as
monomethylglutarate and monomethyladipate.
[0108] Other pharmaceutically acceptable compounds which may be
included in the reservoir or matrix include: solvents, for example
alcohols such as isopropanol; permeation enhancing agents such as
those described above; and viscosity agents, such as cellulose
derivatives, natural or synthetic gums, such as guar gums and the
like.
[0109] In preferred embodiments, the transdermal dosage form
includes a removable protective layer. The removable protective
layer is removed prior to application, and consists of the
materials used for the production of the backing layer described
above provided that they are rendered removable, for example, by a
silicone treatment. Other removable protective layers, for example,
are polyletra-fluoroethylene, treated paper, allophane, polyvinyl
chloride, and the like. Generally, the removable protective layer
is in contact with the adhesive layer and provides a convenient
means of maintaining the integrity of the adhesive layer until the
desired time of application.
[0110] The composition of the transdermal dosage forms used in
accordance with the invention and the type of device used are not
considered critical to the method of the invention, provided that
the device delivers the active agent, e.g. buprenorphine, for the
desired time period and at the desired flux rate and/or the desired
delivery rate of the transdermal dosage form.
[0111] Certain preferred transdermal dosage forms for use in
accordance with the present invention are described in U.S. Pat.
No. 5,240,711 (Hille, et al.; assigned to LTS Lohmann
Therapie-Systeme GmbH & Co.), hereby incorporated by reference.
Such buprenorphine transdermal delivery systems may be a laminated
composite having an impermeable backing layer containing
buprenorphine, and optionally, a permeation enhancer combined with
a pressure-sensitive adhesive. A preferred transdermal dosage form
in accordance with the '711 patent includes: (i) a polyester
backing layer which is impermeable to buprenorphine; (ii) a
polyacrylate adhesive layer; (iii) a separating polyester layer;
and (iv) a matrix containing buprenorphine, a solvent for the
buprenorphine, a softener and a polyacrylate adhesive. The
buprenorphine solvent may or may not be present in the final
formulation. The transdermal delivery device described therein
includes a backing layer which is impermeable to the active
substance, a pressure-sensitive adhesive reservoir layer and
optionally, a removable protective layer. Preferably, the reservoir
layer includes about 10 to about 95%-wt polymeric material, about
0.1 to about 40%-wt softener, about 0.1 to about 30%-wt
buprenorphine. A solvent for the buprenorphine base or
pharmaceutically acceptable salt thereof may be included as about
0.1 to about 30%-wt.
[0112] In a preferred embodiment, the transdermal delivery system
is prepared in accordance with Example 1 appended hereto. If in
this example, the transdermal delivery system was prepared in
accordance with the disclosure of International Patent Application
No. WO 96/19975 (Hille, et. al.; assigned to LTS Lohmann
Therapie-Systeme GMBH), hereby incorporated by reference. In this
device, the buprenorphine transdermal delivery device contains
resorption-promoting auxiliary substances. The resorption-promoting
auxiliary substance forms an undercooled mass. The delivery system
contains 10% buprenorphine base, 10-15% acid (such as levulinic
acid), about 10% softener (such as oleyl oleate); 55-70%
polyacrylate; and 0-10% polyvinylpyrrolidone (PVP).
[0113] In embodiments of the present invention wherein the
buprenorphine plasma concentrations described herein are achieved
via the use of a transdermal delivery device prepared in accordance
with WO 96/19975, it is contemplated for example that the nominal
delivery rate of buprenorphine from such patches will be, e.g.,
from about 12.5 to about 100 ug/hr. In certain preferred
embodiments, in order to achieve a nominal delivery rate of 12.5
ug/hr, the total of buprenorphine included in the transdermal patch
is about 5 mg, the active surface area is about 6.25 cm.sup.2 and
the patch size may be, e.g., about 19.4 cm.sup.2. In certain
preferred embodiments, in order to achieve a nominal delivery rate
of 25 ug/hr, the total of buprenorphine included in the transdermal
patch is about 10 mg, the active surface area is about 12.5
cm.sup.2 and the patch size may be, e.g., about 30.6 cm.sup.2. In
certain preferred embodiments, in order to achieve a nominal
delivery rate of 50 ug/hr, the total of buprenorphine included in
the transdermal patch is about 20 mg, the active surface area is
about 25 cm.sup.2 and the patch size may be, e.g., about 51.8
cm.sup.2. In certain preferred embodiments, in order to achieve a
nominal delivery rate of 75 ug/hr, the total of buprenorphine
included in the transdermal patch is about 30 mg, the active
surface area is about 37.5 cm.sup.2 and the patch size may be,
e.g., about 69.8 cm.sup.2. In certain preferred embodiments, in
order to achieve a nominal delivery rate of 100 ug/hr, the total of
buprenorphine included in the transdermal patch is about 40 mg, the
active surface area is about 50 cm.sup.2 and the patch size may be,
e.g., about 87.8 cm.sup.2.
[0114] The above-described transdermal delivery system has been
designed to be adhered to the patient for only three days and is
expected to release analgetically effective doses of buprenorphine
for only about 3 days. Instead, in accordance with the present
invention, the transdermal delivery device is maintained in contact
with the skin of the patient for much longer time period, e.g.,
from about 5 to about 8 days, without any change in the formulation
of the transdermal device itself. It has been found that analgesia
is maintained for this extended period of time (the time beyond the
useful life designed for the transdermal formulation).
[0115] In other embodiments, the buprenorphine transdermal delivery
system may be a plaster such as that described in U.S. Pat. No.
5,225,199 to Hidaka et al., hereby incorporated by reference. Such
plasters include a film layer including a polyester film of about
0.5 to about 4.9 .mu.m thickness, about 8 to about 85 g/mm
strength, respectively in the two directions intersecting
substantially at right angles, about 30 to about 150% elongation,
in the two directions intersecting substantially at right angles
and an elongation ratio of A to B of about 1.0 to about 5.0,
wherein A and B represent data in two directions intersecting at
right angles, and A is greater than B and wherein said polyester
film includes about 0.01 to about 1.0% by weight, based on the
total weight of the polyester film, of solid fine particles in
which the average particle size is about 0.001 to about 3.0 .mu.m
and an adhesive layer which is composed of an adhesive containing
transdermally absorbable drugs; wherein the adhesive layer is
laminated on said film layer over the surface in about 2 to about
60 .mu.m thickness. The average particle size is substantially not
more than 1.5 times the thickness of the polyester film.
[0116] The transdermal delivery system used in the present
invention may also be prepared in accordance with U.S. Pat. No.
5,069,909 (Sharma et al.), hereby incorporated by reference. This
patent describes a laminated composite for administering
buprenorphine transdermally to treat pain. The composite includes
an impermeable backing layer providing a protective covering for
the composite which may be made from an alastomeric polymer such as
polyurethane, polyether amide, or copolyester and may be about
15-250 microns in thickness. The composite further includes a
reservoir lamina composed of buprenorphine (base or HCl) in an
amount of 1-12% by weight and a pressure-sensitive adhesive, e.g.,
polyisobutylene, or a silicone adhesive such as silastic, or an
acrylate adhesive, and 2-35% permeation enhancer (comprising
propylene glycol monolaurate in combination with capric acid or
oleic acid). The amounts of buprenorphine and permeation enhancer
are sufficient to cause the buprenorphine to pass through the skin
at a rate of about 1 to 100 .mu.g/cm.sup.2/hr.
[0117] The transdermal delivery system used in the present
invention may also be prepared in accordance with U.S. Pat. No.
4,806,341 (Chien et al.), hereby incorporated by reference. This
patent describes a transdermal morphinan narcotic analgesic or
antagonist (including buprenorphine) pharmaceutical polymer matrix
dosage unit having a backing layer which is substantially
impervious to the buprenorphine, and a polymer matrix disc layer
which is adhered to the backing layer and which has microdispersed
therein effective dosage amounts of the buprenorphine. The polymer
matrix may be a silicon polymer or copolymer, such as methyl
silicone polymer or copolymer, or methylvinyl silicone polymer or
copolymer. The polymer matrix layer preferably has dispersed
therein a skin permeation enhancing agent such as isopropyl
myristate, azone, or a combination of ethyl caprylate and capryl
alcohol.
[0118] The transdermal delivery system used in the present
invention may also be that described in U.S. Pat. No. 5,026,556
(Drust et al.), hereby incorporated by reference. Therein,
compositions for the transdermal delivery of buprenorphine comprise
buprenorphine in a carrier of a polar solvent material selected
from the group consisting of C.sub.3-C.sub.4 diols, C.sub.3-C.sub.6
triols, and mixtures thereof, and a polar lipid material selected
from the group consisting of fatty alcohol esters, fatty acid
esters, and mixtures thereof; wherein the polar solvent material
and the lipid material are present in a weight ratio of solvent
material:lipid material of from 60:40 to about 99:1.
[0119] The transdermal delivery system used in the present
invention may also be that described in U.S. Pat. No. 4,588,580
(Gale, et. al.), hereby incorporated by reference. That system
comprises a reservoir for the drug having a skin proximal, material
releasing surface area in the range of about 5-100 cm.sup.2 and
containing between 0.1 and 50% by weight of a skin permeable form
of the buprenorphine. The reservoir contains an aqueous gel
comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%
buprenorphine, and release rate controlling means disposed in the
flow path of the drug to the skin which limits the flux of the
buprenorphine from the system through the skin. The release rate
controlling means is more permeable to the buprenorphine than to
the ethanol, and may be for example low density polyethylene
(LDPE), ehtylene-vinyl acetate (EVA) copolymers, heat sealable
polyesters, and elastomeric polyester block copolymers, such as
HYTREL.RTM. from DuPont. This system is said to be capable of
providing an administration rate of about 10-300 .mu.g/hr. It is
contemplated that each of the transdermal delivery systems
described herein (other than the system exemplified in Example 1
appended hereto) would require minor manipulation in order to
achieve the methods of the invention. Such modifications are within
the abilities of one skilled in the art of formulating such
transdermal delivery systems.
[0120] The present invention may also be accomplished via the use
of a sustained oral mucosal delivery system. Such a system is
described by McQuinn, R. L. et al., "Sustained Oral Mucosal
Delivery in Human Volunteers J. Controlled Release; (34) 1995
(243-250). Therein, oral mucosal patches were prepared by
homogeneously mixing buprenorphine free base (8%), Carbopol 934
(52%), polyisobutylene (35%) and polyisoprene (5%, w/w) via a
two-roll mill and then compressing the mixture to the appropriate
thickness. A membrane backing (ethylcellulose) was applied to one
side of the compressed material and then circular disks (0.5
cm.sup.2) were punched from the material. The backing was included
in order to retard drug release from one side of the disk and to
prohibit adhesion to opposing side tissues. Each soft, flexible
disk was approximately 0.6 mm thick and contained 2.9 mg
buprenorphine. These patches were worn by the subjects for 12
hours. Gum and lip application was tested, although adhesion at the
gum site was considered superior. After the initial appearance of
serum buprenorphine (.gtoreq.25 pg/ml), levels generally increased
relatively rapidly and persisted until the patch was removed. After
the patch was removed, buprenorphine levels fell promptly and were
at a relatively low (but measureable) level by 24 hours post-dose.
It was estimated that 0.42.+-.0.18 mg were delivered via the gum
treatment. From this discussion, it is apparent that an oral
mucosal patch can be prepared which will provide plasma
concentrations considered desirable according to the present
invention.
[0121] A significantly higher incidence in side effects such as
nausea, vomiting or drowsiness would normally be expected when high
blood levels of opioid analgesics are administered. The present
invention, by maintaining a lower blood level of drug over the 7
day dosing period while maintaining effective pain management, has
a lower incidence of side effects. In comparison, a much higher
plasma concentration is seen in patients over the same period of
time when a new transdermal delivery device of the same strength is
put on every three days, and therefore increased side effects are
expected with each new 3 day transdermal application.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0122] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever:
Example 1
[0123] A seven day pharmacokinetic/pharmacodynamic study was
conducted on 24 healthy human patients. The subjects were comprised
of approximately an equal number of male and female subjects. In
this study, the buprenorphine was administered via a transdermal
patch which is described in WO 96/19975.
[0124] The transdermal patch is prepared in accordance with the
disclosure of WO 96/19975 for Example 1 therein as follows:
[0125] 1.139 g of a 47.83 w/% polyacrylate solution with a
selfnetting acrylate copolymers containing 2-ethylhexylacrylates,
vinyl acetates, acrylic acid (dissolving
agent:ethylacetate:heptan:isopropanol:toluol:acetylacetonate in the
ratio of 37:26:26:4:1), 100 g levulinic acid, 150 g oleyl oleate,
100 g polyvinylpyrrolidone, 150 g ethanol, 200 g ethyl acetate and
100 g buprenorphine base are homogenized. The mixture is stirred
for about 2 hours and then examined visually to determine if all
solid substances have been dissolved. One has to control the
evaporation loss by method of weighing back and makes up for the
solvent with the help of ethylacetate, if necessary. Thereafter,
the mixture is put onto a 420 mm wide, transparent polyester foil,
since the surface weight of the dried layer of paste is 80 g per
m.sup.2. The polyester foil which can be dissolved again with
treatment of silicone serves as a protective layer. The solvent is
removed by drying with heated air which is led over a moist lane.
With this treatment of warmth not only do solvents evaporate but
the laevulinic acid melts as well. Thereafter, the sealing film is
covered with a polyester foil 15 .mu.ab. A surface of about 16
cm.sup.2 is cut with the help of the appropriate cutting tool, and
the rims that have been left between the individual systems are
removed.
[0126] The formulation utilized for Example 1 is substantially the
same as that described in Example 3 of WO 96/19975, which is
prepared in accordance with Example 1 and is stated therein to
include 10% buprenorphine, 10% levulinic acid, 10%
polyvinylpyrrolidone, 10% oleyl oleate, and 60% polyacrylate.
[0127] In order to achieve the nominal delivery rate of 25 ug/hr
expected for the formulation of Example 1, the total of
buprenorphine included in the transdermal patch is about 10 mg, the
active surface area is about 12.5 cm.sup.2 and the patch size may
be, e.g., about 30.6 cm.sup.2.
[0128] The dosing regimen was one (1) patch containing 10 mg
buprenorphine base/patch reservoir applied to the subject's skin
and maintained in contact with the skin for a time period of seven
(7) days.
[0129] The adhesive patch with the medication being tested was
placed on the right midaxillary line at the level of the 5th
intercostal space at approximately 0800 hr on day 1. For patch
application, the skin was washed with lukewarm soapy water, then
rinsed with clear water and left to air dry. The skin was not
rubbed while it was being washed. The application site was
relatively hairless. Hair was not clipped or shaven. The patches
were removed at approximately 0800 hr on day 8. Following patch
removal, the patch site was not washed or rubbed until the last
blood collection for that treatment period was over. Each patch was
placed unfolded onto its release liner and the patch/release liner
unit was placed back in the correct pouch, which was then sent to a
bioanalytical laboratory for residual buprenorphine assay.
[0130] Blood sampling (10 ml at each time point) started on day 1,
and continued thereafter at the following times: 1 hr (pre-dose)
and at regular intervals thereafter during the 7 day dosing
interval.
[0131] Patch site skin observations of the patch sites were
performed by the investigator/staff rating the quality of the skin
at the site of the actual medication reservoir of the patch at 0 hr
(prior to patch placement) and 30 minutes after patch removal. The
rating scale was as follows:
[0132] Erythema: 0=No visible redness; 1=Very slight redness (just
perceptible); 2=Slight but well-defined redness; 3=Moderately
intense redness; 4=Severe erythema (dark red discoloration of the
skin).
[0133] Edema: 0=No visible reactions; 1=Very mild edema (just
perceptible); 2=Mild edema (corners of the area are well defined
due to noticeable swelling); 3=Moderate edema (up to 1 mm swelling
in diameter); 4=Severe edema (more than 1 mm swelling in diameter,
protruding over the edges of the patch).
[0134] The following pharmacokinetic parameters were estimated:
AUC.sub.(0-last) (pghr/ml)--the area under the curve from time zero
to the time of last non-zero plasma buprenorphine concentration,
calculated by the linear trapezoidal method; C.sub.max
(pg/ml)--maximum observed plasma buprenorphine concentration over
the dosing interval; if C.sub.max occurs at more than one time
point, T.sub.max is defined as the time point for the first
C.sub.max; residual=buprenorphine remaining in used patches
(mg/patch).
[0135] A summary of the plasma buprenorphine concentrations
(provided in picograms per milliliter, or pg/ml), is set forth in
Table 1 below:
TABLE-US-00001 TABLE 1 HOURS.sup.1 MEAN.sup.2 STD. DEV.sup.3 CV
%.sup.4 6 1.76 6.20 352.77 12 18.47 26.00 140.78 18 39.45 36.16
91.67 24 58.94 44.66 75.76 30 67.69 48.78 72.06 36 82.44 53.02
64.32 42 107.61 65.43 60.81 48 104.69 60.69 57.97 54 105.81 66.68
63.02 60 112.93 63.02 55.81 66 129.25 64.37 49.80 72 130.55 64.16
49.14 78 122.83 54.97 44.75 84 129.03 51.50 39.92 90 139.50 68.26
48.93 96 146.70 62.76 42.78 102 130.19 57.68 44.31 108 135.49 67.72
49.98 114 150.24 71.69 47.72 120 136.22 63.62 46.70 126 130.25
57.77 44.35 132 124.78 52.82 42.34 138 138.55 58.34 42.11 144
115.23 48.30 41.92 150 116.30 49.04 42.16 156 120.07 50.88 42.38
162 117.66 52.71 44.80 168 102.00 49.92 48.94 .sup.1hours after
administration of dose (e.g., application of patch) .sup.2mean
blood plasma concentration for the 24 test subjects (pg/ml)
.sup.3standard deviation of mean blood plasma concentrations
.sup.4coefficient of variation (%)
[0136] The mean plasma concentrations are further depicted in FIG.
1 (concentration pg/ml vs. time (days)). It is apparent from the
pharmacokinetic results obtained with respect to Example 1 that the
mean blood plasma concentrations rose steadily and peaked at about
the 3-day time point during the dosing interval (e.g., about 72
hours after application of the patch), and thereafter remained
relatively steady throughout the remaining portion of the dosing
interval (e.g., to about the 7-day time point, 168 hours after
initiation of the dosing interval). Further, it is apparent from
the buprenorphine plasma concentrations that first order kinetics
were present during the first 72 hours of the dosing interval, and
substantially zero order kinetics were present thereafter.
[0137] A summary of the pharmacokinetic parameters obtained for
Example 1 are set forth in Table 2 below:
TABLE-US-00002 TABLE 2 STD. GEOMETRIC MEAN DEV. MEAN CV % AUC
17740.68 7503.50 16263.88 42.30 (0-168 hrs) Cmax (pg/ml) 184.80
68.84 171.78 37.25 Tmax (hrs) 110.50 26.48 23.96
[0138] The following pharmacodynamic parameters were assessed 5
minutes prior to each blood collection by having each patient
respond to several questions by placing a vertical mark at the
appropriate spot on a 100 mm visual analog scale ("VAS") anchored
on one end by "not at all" and on the other end by "an awful lot".
The first question asked to the subjects was "Do you feel any
effect of the drug?" After the patient marked his/her response on
the VAS to this question, responses were obtained via the VAS as to
whether the subjects had experienced (i) nausea, (ii) dizziness,
and (iii) sleepiness. The results are set forth in Table 3. All
pharmacodynamic parameters were summarized and tabulated. Then a
mixed (linear or non-linear) effect was used to model the
pharmacokinetic and pharmacodynamic relationships. The results
concerning pharmacodynamic parameters (VAS) are set forth in FIG.
2.
TABLE-US-00003 TABLE 3 SUMMARY OF SEVERITY FOR THE MOST COMMONLY
REPORTED (>=10% OF SUBJECTS) ADVERSE EVENTS (RELATED TO
TREATMENT) (N = 24) MILD MODERATE SEVERE TOTAL N (%) N (%) N (%) N
(%) CONSTIPATION 3 12.5 0 0.0 0 0.0 3 12.5 DIZZINESS 8 33.3 0 0.0 0
0.0 8 33.3 HEADACHE 7 29.2 0 0.0 0 0.0 7 29.2 NAUSEA 6 25.0 0 0.0 0
0.0 6 25.0 RASH 20 83.3 0 0.0 0 0.0 20 83.3 SOMNOLENCE 11 45.8 0
0.0 0 0.0 11 45.8 VOMITING 2 8.3 1 4.2 0 0.0 3 12.5
[0139] As can be seen from the results set forth in Table 3, there
was only one incident of a moderate adverse event, and no incidents
of severe adverse events reported by the test subjects during the
application interval. Further, turning to FIG. 2, it can be seen
that the level of dizziness, nausea and sleepiness significantly
decreased after day 3 of the dosage interval. Other side effects
such as headache, vomiting and constipation were also low in
occurrence.
[0140] Table 4 provides a summary of the amount of drug which was
measured as remaining in the patches which were removed from the
subjects after 7 days.
TABLE-US-00004 TABLE 4 AMOUNT LEFT IN PATCH (mg) MEAN 8.59 SE 0.11
% RELEASED (ASSAY) MEAN 14.02 SE 1.08
Comparative Examples A-C
[0141] A three (3) treatment, randomized, crossover study was
conducted in normal volunteers. The treatments consisted of
Comparative Example A (a single application buprenorphine
transdermal delivery system); Comparative Example B (a single dose
of buprenorphine administered intravenously) and Comparative
Example C (3 sequential applications, every three days, of the
buprenorphine transdermal delivery system used in Comparative
Example A). A 10-14 day washout period intervened between the first
dosing (application) day of each treatment. For the buprenorphine
transdermal delivery system, the wash-out started when the third
sequential patch was removed. This study was not analytically
blinded due to analytical chemistry considerations and: different
sampling times.
[0142] The buprenorphine transdermal delivery system (patch) used
in Comparative Examples A and C contained 20 mg buprenorphine base,
and is prepared in accordance with Example 1. It was contemplated
that the buprenorphine patch of Comparative Examples A and C would
provide approximately double the dose and approximately double the
relative release rate as compared to the buprenorphine patch of
Example 1. For Comparative Examples A and C, it was contemplated
that approximately 1.2 mg buprenorphine would be released from the
patch per day, which is equivalent to an intravenous dose of 0.3 mg
every 6 hours. The reference buprenorphine intravenous injection
(Comparative Example B) was 0.3 mg (Temgesic.RTM.) Injectable 0.3
mg/ml, [1 ml/vial]
[0143] In Comparative Example A, the buprenorphine transdermal
delivery system (single dose) was adhered to a relatively hairless
area of a subject's right thorax at the level of the fifth
intercostal space in the midaxillary line at approximately 8 am on
day 1 and removed at approximately 8 am on day 4. For Comparative
Example A (buprenorphine transdermal delivery system single dose),
blood sampling was conducted as follows: Day 1: 0, (buprenorphine
transdermal delivery system adhered) 2, 3, 4, 6, 8, 10, 12, and 16
hr; Day 2: 0, 6, 12 hr; Day 3: 0, 12 hr; Day 4: 0 (prior to
removal), 0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hr post-removal; Day 5:
0, 12 hr; Day 6: 0, 12 hr; Day 7: 0 hr
[0144] With respect to Comparative Example B, buprenorphine
intravenous (IV) injection, 0.3 mg was infused over 2 minutes at
approximately 8 am on day 1 through an in-dwelling cannula in the
right anticubital vein. The buprenorphine intravenous 0.3 mg blood
sampling was conducted as follows: Day 1: 0, 1, 2, 3, 5, 10, 15,
20, 25, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 10, 12, 24 hr;
arterial blood sampling (left radial artery) for the first 4 hours;
venous blood sampling from 2 hours post-dose to 24 hours post-dose.
Therefore arterial and venous blood sampling occurred
simultaneously 2, 3 and 4 hours post-dose.
[0145] With respect to Comparative Example C, the buprenorphine
transdermal delivery system (3 sequential applications), was
adhered to a relatively hairless area of a subject's right thorax
at the level of the fifth intercostal space in the midaxillary line
at approximately 8 am on day 1 and removed at approximately 8 am on
day 4. The second buprenorphine transdermal delivery system 50
.mu.g/hr was placed just adjacent to the first patch after the
first was removed on day 4 at approximately 8 am and removed on day
7 at approximately 8 am. The third buprenorphine transdermal
delivery system 50 .mu.g/hr was placed just adjacent to the second
patch but not in the same place as the first patch after the second
patch is removed on day 7 at approximately 8 am and removed on day
10 at approximately 8 am. Blood samples for Comparative Example C,
buprenorphine transdermal delivery system 3 sequential
applications, were obtained as follows: Day 1: 0, (buprenorphine
transdermal delivery system adhered), 2, 3, 4, 6, 8, 10, 12, and 16
hr; Day 2: 0, 6, 12 hr; Day 3: 0, 12 hr; Day 4: 0 (prior to
removal), and 2, 3, 4, 6, 8, 10, 12, 16 hrs (after second
buprenorphine transdermal delivery system adhered); Day 5: 0, 6, 12
hr; Day 6: 0, 12 hr; Day 7: 0 (prior to removal), and 2, 3, 4, 6,
8, 10, 12, 16 hrs (after third buprenorphine transdermal delivery
system adhered); Day 8: 0, 6, 12 hr; Day 9: 0, 12 hr; Day 10: 0
(prior to buprenorphine transdermal delivery system removal), and
0.25, 0.5, 0.75, 1, 2, 3, 6, 12 hr (post-removal); the wash-out
period started after patch removal on Day 10; Day 11: 0, 12 hr; Day
12: 0, 12 hr; and Day 13: 0.
[0146] The pharmacokinetic variables determined for Comparative
Examples A-C were as follows:
[0147] AUC.sub.(0-last):pg-hr/ml--The area under the curve, as
calculated by the linear trapezoidal method, up to the last
observed value;
[0148] AUC.sub.inf:pg-hr/ml--The area under the curve, calculated
using the linear trapezoidal method;
[0149] C.sub.max:pg/ml--Maximum measured plasma buprenorphine over
the time span specified;
[0150] T.sub.max:hrs--Time of the maximum measured plasma
buprenorphine; when the maximum value occurs in more than one time
point, T.sub.max is defined as the first time point with this
value;
[0151] T.sub.(1/2)elm: The plasma half life of buprenorphine
elimination, defined as 1n2/K.sub.elm, where K.sub.elm is the
apparent first order elimination constant. The elimination rate
constant was obtained from the slope of the terminal portion of the
plasma-concentration time curve determined by regression analysis
techniques;
[0152] T.sub.(1/2)abs: The absorption half life of transdermal
buprenorphine elimination, defined as 1n2/K.sub.abs, where
K.sub.abs is the apparent first order absorption constant.
Absorption rate was calculated only for the transdermal
buprenorphine;
[0153] C1:ml/min or l/hr--Total clearance characterizes the
clearing of the hypothetical plasma volume of drug per unit
time;
[0154] V.sub.d:1 or 1/kg--Hypothetical volumes in which the drug is
distributed in the body; and
[0155] Absorption Rate:.mu.g/hr--The rate at which buprenorphine
enters the systemic circulation.
[0156] Plasma concentration data was analyzed using standard
noncompartmental and compartmental techniques to derive
pharmacokinetic parameters. In addition, various exploratory
methods including fitting the intravenous data to pharmacokinetic
models to determine which model best describes the data, and
deconvolution analysis to determine the absorption rate was
employed. Other parameters such as clearance, volumes of
distribution, absorption rate, amount absorbed and bioavailability
were determined by either standard noncompartmental or
compartmental analysis or exploratory methods. The intravenous data
was also analyzed utilizing compartmental modeling techniques.
[0157] A summary of plasma buprenorphine concentrations for
Comparative Example A is provided in Table 5 below:
TABLE-US-00005 TABLE 5 Comparative Example A MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 2 2.04 5.87 287.10 3 7.96 16.28 204.47 4
14.84 18.63 125.51 6 23.49 25.81 109.85 8 42.34 37.91 89.52 10
72.03 71.36 99.07 12 85.96 68.69 79.90 16 133.89 103.43 77.25 24
175.58 120.17 68.44 30 169.15 108.65 64.23 36 200.16 134.45 67.17
48 251.10 156.66 62.39 60 250.11 125.01 49.98 72 286.50 131.58
45.92 78 168.73 61.26 36.30 84 114.68 52.72 45.97 96 90.75 39.12
43.11 108 56.82 25.66 45.17 120 44.85 23.80 53.06 132 30.40 21.87
71.95 144 29.14 20.27 69.58
[0158] A summary of plasma buprenorphine concentrations (pg/ml) for
Comparative Example C at each sampling time is set forth in Table 6
below:
TABLE-US-00006 TABLE 6 Comparative Example C MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 2 0.54 2.63 489.90 3 5.70 13.18 231.23 4
10.33 14.64 141.71 6 28.84 31.19 108.13 8 54.62 65.83 120.52 10
78.92 81.23 102.93 12 95.14 75.70 79.57 16 162.26 114.80 70.75 24
218.57 153.58 70.27 30 206.10 141.70 68.75 36 205.08 110.76 54.01
48 265.04 123.66 46.66 60 256.18 133.48 52.11 72 306.02 152.77
49.92 74 278.22 135.14 48.57 75 245.91 112.66 45.82 76 237.01 83.41
35.19 78 213.54 94.42 44.22 80 215.45 103.75 48.15 82 216.00 107.68
49.85 84 210.52 107.67 51.14 88 219.77 110.46 50.26 96 269.91
134.61 49.87 102 205.54 102.03 49.64 108 225.11 87.97 39.08 120
310.27 153.57 49.50 132 300.34 157.05 52.29 144 305.99 159.75 52.21
146 301.39 141.37 46.91 147 289.96 132.91 45.84 148 287.68 151.93
52.81 150 260.04 130.19 50.07 152 236.61 119.77 50.62 154 284.15
158.84 55.90 156 271.83 145.11 53.38 160 303.46 182.37 60.10 168
340.71 209.87 61.60 174 302.22 179.74 59.47 180 322.67 183.63 56.91
192 395.95 220.27 55.63 204 344.83 201.90 58.55 216 415.33 229.92
55.36 216.25 388.64 186.67 48.03 216.50 390.97 208.34 53.29 216.75
392.63 188.89 48.11 217 399.51 197.86 49.53 218 312.65 173.12 55.37
219 295.17 148.13 50.18 222 201.37 85.54 42.48 228 173.89 75.96
43.68 240 119.13 48.99 41.13 252 84.21 49.61 58.91 264 72.33 37.86
52.42 276 50.18 25.83 51.47 288 43.06 26.61 61.79
[0159] A summary of mean plasma buprenorphine concentrations
(pg/ml) at each sampling time for Comparative Example B
(buprenorphine intravenous 0.3 mg single dose) is provided in Table
7 below:
TABLE-US-00007 TABLE 7 Comparative Example B MEAN PLASMA HOUR CONC.
(pg/ml) STD. DEV CV % 0.02 14812.04 11319.10 76.42 0.03 31052.04
16156.81 52.03 0.05 24547.00 16461.86 67.06 0.08 6418.80 1976.26
30.79 0.17 3360.76 2457.58 73.13 0.25 1747.96 465.81 26.65 0.33
1210.08 219.28 18.12 0.42 1050.00 242.10 23.06 0.50 931.52 207.25
22.25 0.75 692.92 175.29 25.30 1.00 584.40 148.93 25.48 1.50 457.44
131.44 28.73 2.00 335.12 79.36 23.68 3.00 238.80 63.03 26.39 4.00
170.87 49.84 29.17
[0160] A summary of the mean maximum concentration (Cmax) for
Comparative Examples A-C measured in pg/ml is set forth in Table 8
below:
TABLE-US-00008 TABLE 8 C.sub.max Values for Comparative Examples
A-C Comparative Example A Comparative Example C Mean 318.20 477.33
Std. Dev. 151.24 216.92 Geometric Mean 291.13 435.50 CV % 47.53
45.44 Cmax (pg/ml) - Comparative Example B Mean 38635.56 Std. Dev.
14499.55 Geometric Mean 35251.92 CV % 37.53
[0161] A summary of mean Tmax values obtained for Comparative
Examples A-C is set forth in Table 9 below:
TABLE-US-00009 TABLE 9 Tmax Prior to Patch Removal (hrs)
Comparative Example A Comparative Example C Mean 61.92 168.39 (out
of 72 hrs total) (out of 260 hrs total) Std. Dev. 13.27 42.68 CV %
21.43 25.35 Tmax (hrs) Comparative Example B Mean 0.04 Std. Dev.
0.01 CV % 26.26
[0162] Table 10 provides a summary of the area under the curve
(AUC) (0-t) for Comparative Examples A-C:
TABLE-US-00010 TABLE 10 Comparative Comparative Comparative Example
A Example C Example B Mean 18,289.13 65,217.25 3,699.91 Std. Dev.
9,136.12 31,124.37 526.64 Geometric Mean 16,760.39 57,794.90
3,666.65 CV % 48.52 47.72 14.23
[0163] The pharmacodynamics were determined via VAS "drug effect"
observations. The subject was asked "do you feel any effect of the
drug?". The subject then rated the item by placing a vertical mark
along a 100 mm visual analog scale (VAS) anchored on one end by
"not at all" and on the other end by "an awful lot". The "drug
effect" question was assessed just prior to each blood sample
during the study. The following adverse effects were elicited just
prior to blood sampling using the VAS: nausea; dizziness; and
sleepiness. Asymmetric blood sampling was used in this study due to
the number of sampling times.
[0164] The pharmacokinetic results (concentration in pg/ml vs.
hours) for Comparative Examples A-C are depicted in FIGS. 3-5,
respectively. FIG. 4 depicts the plasma concentration obtained
divided by 100. The pharmacodynamic results (PD variables (VAS))
for Comparative Examples C, B, A are depicted in FIGS. 6, 7, 8,
respectively.
Comparative Examples D-F
[0165] The bioequivalence between a buprenorphine transdermal
delivery system in accordance with Example 1 is compared to
identically prepared patches having different sizes and therefore
different amounts of buprenorphine contained therein.
[0166] Comparative Example D utilized a patch identical in size and
containing the same amount of buprenorphine as Example 1. The total
of buprenorphine included in the transdermal patch is 10 mg, the
active surface area is 12.5 cm.sup.2 and the patch size is 30.6
cm.sup.2. In Comparative Example E, two patches are utilized, each
patch including total of buprenorphine of about 5 mg, and having an
active surface area of 6.25 cm.sup.2 and a patch size of 19.4
cm.sup.2. Comparative Example F allows for the determination of the
dose proportionality of a buprenorphine transdermal delivery system
(patch) having twice the dose as compared to Example 1. In
Comparative Example F, the total of buprenorphine included in the
transdermal patch is 20 mg, the active surface area is 25 cm.sup.2
and the patch size is 51.8 cm.sup.2. The study was conducted via a
3-way cross-over design. The patches were left in place for 72
hours and then removed.
[0167] Table 11 provides a summary of mean plasma buprenorphine
concentrations (pg/ml) at each sampling time for Comparative
Example D:
TABLE-US-00011 TABLE 11 MEAN PLASMA HOURS CONC. (pg ml) STD. DEV.
CV % 3 1.92 8.82 458.26 6 22.69 30.98 136.54 9 38.54 48.79 126.62
12 59.22 62.92 106.24 16 89.85 78.93 87.84 24 128.70 72.79 56.55 30
125.99 84.68 67.21 36 143.07 78.40 54.80 48 196.72 101.50 51.59 60
182.72 82.61 45.21 72 169.95 65.04 38.27 84 122.19 41.69 34.12 96
83.30 35.56 42.69 108 55.09 30.82 55.94 120 41.63 20.74 49.82 132
27.14 25.47 93.84 144 17.54 20.09 114.51
[0168] Table 12 provides a summary of the pharmacokinetic
parameters for Comparative Example D:
TABLE-US-00012 TABLE 12 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 16278.05 15255.84 (1246.6) (1272.5) AUC
(0-Last) 14446.10 13162.96 (1292.0) (1340.6) Cmax (pg/ml) 229.87
214.47 (19.29) (17.92) T1/2 Elim. (hrs) 30.53 (2.80) Tmax (hrs)
67.02 (3.14)
[0169] Table 13 provides a summary of mean plasma buprenorphine
concentrations for Comparative Example E:
TABLE-US-00013 TABLE 13 MEAN PLASMA HOURS CONC. (pg/ml) STD. DEV CV
% 3 1.63 7.29 447.21 6 19.61 33.28 169.70 9 29.09 44.04 151.40 12
44.43 56.91 128.09 16 59.77 66.25 110.86 24 110.49 98.86 89.48 30
107.58 86.83 80.71 36 116.36 83.01 71.34 48 154.35 83.40 54.03 60
151.22 90.70 59.98 72 145.20 62.84 43.28 84 106.91 38.86 36.35 96
82.61 34.87 42.21 108 44.83 26.74 59.65 120 29.68 24.26 81.73 132
22.52 24.42 108.44 144 9.24 17.28 186.93
[0170] Table 14 provides a summary of the pharmacokinetic
parameters for Comparative Example E:
TABLE-US-00014 TABLE 14 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 13450.96 12315.56 (1326.8) (1142.0) AUC
(0-Last) 12026.65 10796.23 (1318.7) (1110.3) Cmax (pg/ml) 199.10
186.49 (17.50) (14.69) T1/2 Elim. (hrs) 25.82 (1.51) Tmax (hrs)
68.26 (3.18)
[0171] Table 15 provides a summary of mean plasma buprenorphine
concentrations for Comparative Example F:
TABLE-US-00015 TABLE 15 MEAN PLASMA HOURS CONC. (pg/ml) STD. DEV.
CV % 3 5.23 13.21 252.44 6 34.49 55.11 159.80 9 58.67 91.17 155.40
12 94.52 111.07 117.51 16 137.07 118.65 86.56 24 195.58 148.53
75.94 30 201.51 142.24 70.59 36 229.52 154.25 67.20 48 283.35
124.06 43.78 60 314.17 173.81 55.32 72 306.60 124.57 40.63 84
209.66 62.84 29.97 96 143.30 43.88 30.62 108 113.53 70.33 61.95 120
78.71 37.46 47.59 132 75.29 47.92 63.64 144 44.45 32.26 72.57
[0172] Table 16 provides a summary of the dose-corrected
pharmacokinetic parameters for Comparative Example F. The values
are calculated based on a Cmax value which is one-half the actual
reported value:
TABLE-US-00016 TABLE 16 ARITHMETIC GEOMETRIC PARAMETER MEAN (SE)
MEAN (SE) AUC (0-Infinity) 14761.59 13540.78 (1469.7) (1228.3) AUC
(0-Last) 12558.04 11456.76 (1313.9) (1067.0) Cmax (pg/ml) 191.84
179.60 (16.93) (14.23) T1/2 Elim. (hrs) 26.59 (1.52) Tmax (hrs)
72.37 (1.89)
[0173] Table 17 provides a summary of the buprenorphine patch
residuals for each of Comparative Examples D-F:
TABLE-US-00017 TABLE 17 SUMMARY OF BUPRENORPHINE PATCH RESIDUALS
Ex. D Ex. F Ex. E AMOUNT LEFT IN PATCH (mg) N 27 27 52 MEAN 8.76
18.31 4.75 SE 0.07 0.15 0.03 % RELEASED (ASSAY) N 27 27 52 MEAN
12.31 10.84 8.43 SE 0.67 0.73 0.53
[0174] The pharmacokinetic results (concentration in pg/ml vs.
hours) for Comparative Examples D-F are depicted in FIGS. 9-11,
respectively. The pharmacodynamic results (PD variables (VAS)) for
Comparative Examples D-F are depicted in FIGS. 12-14,
respectively.
CONCLUSIONS
[0175] In order to readily consider the results obtained comparing
the method of the present invention to the Comparative Examples,
the following tables are provided.
[0176] Table 18 provides a direct comparison of the plasma
concentrations obtained from Example 1 (a 10 mg buprenorphine patch
maintained in contact with the subjects' skin for 7 days) to
Comparative Example A (20 mg buprenorphine patch left on the
subjects' skin for only 3 days, then removed) to Comparative
Example C (three sequential applications of a 20 mg buprenorphine
patch left on the subjects' skin for only 3 days, then removed). In
order to compare the plasma concentrations, the plasma
concentrations of Comparative Examples A and C are also presented
at 50% concentrations for each time interval:
TABLE-US-00018 TABLE 18 COMPARISON OF PLASMA CONCENTRATIONS
COMPARATIVE COMPARATIVE EXAMPLE C EXAMPLE A HOUR/ Ex. 1 MEAN MEAN
(DAY) MEAN MEAN (1/2 DOSE) MEAN (1/2 DOSE) 24 (1) 58.94 218.57
109.29 175.58 87.79 48 (2) 104.69 265.04 132.52 251.10 125.55 72
(3) 130.55 306.02 153.01 286.50 143.25 96 (4) 146.70 269.91 134.96
90.75 45.38 120 (5) 136.22 310.27 155.14 44.85 22.43 144 (6) 115.23
305.99 153.00 29.14 14.57 168 (7) 102.00 340.71 170.36 192 (8)
395.95 197.98
[0177] The data presented in Table 18 shows that plasma levels
effective to provide analgesia were present in Example 1 (patch
remained on skin for 7 days) even 7 days after application of the
patch; whereas in Comparative Example A (patch removed after 3
days), blood levels fell dramatically once the patch was removed,
such that plasma levels which would be indicative of ineffective
treatment for the dosage of buprenorphine occurred not long after
patch removal. On the other hand, turning to Comparative Example C,
it is apparent that the plasma levels obtained from 3-day
sequential administration of the buprenorphine patch resulted in
significant increases in Cmax levels during each day dosing
interval. This fact is confirmed by the graph of plasma
concentration over time for Comparative Example C provided in FIG.
3. In contrast, the plasma level for Example 1 remained
substantially level over the time-frame of 72 hours-168 hours after
patch application. Furthermore, comparing the VAS results
graphically depicted for Example 1 to Comparative Example C, it is
apparent that side effects were significantly reduced according to
the method of Example 1, during the 7-day dosage interval. Further
benefits are obtained from the invention with respect to modes of
administration other than transdermally where the large plasma
concentration peaks obtained in the prior art, e.g., through
intravenous dosing, can be avoided. For example in Comparative
Example B, a Cmax in excess of about 30,000 pg/ml was obtained.
[0178] Table 19 provides a direct comparison of the plasma
concentrations of Example 1 (a 10 mg buprenorphine patch maintained
in contact with the subjects' skin for 7 days) to Comparative
Example D (same 10 mg buprenorphine patch left on the subjects'
skin for only 3 days, then removed) to Comparative Example E (two 5
mg buprenorphine patches left on the subjects' skin for only 3
days, then removed):
TABLE-US-00019 TABLE 19 COMPARISON OF PLASMA CONCENTRATIONS (PG/ML)
Hours (Post- Ex. 1 Ex. D Ex. E Application) MEAN CONC. MEAN CONC.
MEAN CONC. 3 1.92 1.63 6 1.76 22.69 19.61 9 38.54 29.09 12 18.47
59.22 44.43 16 89.85 59.77 24 58.94 128.70 110.49 30 67.69 125.99
107.58 36 82.44 143.07 116.36 48 104.69 196.72 154.35 60 112.93
182.72 151.22 72 130.55 169.95 145.20 84 129.03 122.19 106.91 96
146.70 83.30 82.61 108 135.49 55.09 44.83 120 136.22 41.63 29.68
132 124.78 27.14 22.52 144 115.23 17.54 9.24
[0179] The results depicted in Table 19 confirm that the method
according to the present invention provides effective plasma levels
over the 7-day period; whereas if the patch (or patches) containing
the same dose is removed after 3 days, the buprenorphine plasma
levels fall precipitously over the next 24 hour interval to levels
which would be indicative of ineffective treatment for the dosage
of buprenorphine. (It must be noted that the absolute mean plasma
levels of Example 1 and the Comparative Examples are not directly
comparable because these results are taken from different studies
involving different subjects, etc.).
[0180] Table 20 below compares the amount of buprenorphine retained
in the transdermal delivery systems in Example 1 to certain
Comparative Examples, as well as their relative release rates:
TABLE-US-00020 TABLE 20 BUPRENORPHINE PATCH RELEASE RATES RR RR
cum. amt. [mg/patch/ [mg/patch/ RR.sub.norm Patch released day]
day] [mg/cm.sup.2/ strength Example [mg] 3 days appl. 7 days appl.
day] 5 MG E 0.44 mg 0.146 -- 0.0234 10 MG D 1.23 mg 0.410 -- 0.0328
20 MG F 2.52 mg 0.742 -- 0.0297 20 MG A, C 3.21 mg 1.090 -- 0.0437
10 MG 1 1.40 mg -- 0.200 0.0160 RR = relative release rate
[0181] The total amount of buprenorphine released for Example 1
(1.40 mg) may be expressed as 0.2 mg buprenorphine administered per
day, when averaged over the seven day dosing interval. In contrast,
Comparative Example D (same patch over 3 days) released a total of
1.23 mg, which may be expressed as 0.41 mg buprenorphine
administered per day.
[0182] Further, the results indicate that over the first 72 hours
the buprenorphine is released substantially according to first
order kinetics, whereas during the 72-168 hour time period after
administration, the buprenorphine is released substantially
according to zero order kinetics. This is confirmed from the plasma
concentration curve provided for Example 1 in FIG. 1.
Example 2
[0183] In Example 2, the method of the present invention is
accomplished via a different mode of administration, i.e.,
intravenous infusion. The pattern of plasma concentrations seen
through time in this invention can be achieved by using an
intravenous infusion using the injectable, parenteral form of,
e.g., buprenorphine hydrochloride suitably diluted in an
intravenous infusion solution. The infusion rate would be
controlled by a programmable infusion pump, to provide the desired
plasma concentration profile. The rate of infusion through time can
be determined and adjusted based upon pharmacodynamic parameters
such as pupil size (pupilometry) or pain relief (analgesia) or by
the results of a suitable bioassay to determine the plasma
buprenorphine concentrations at any particular point in time. In
addition, it is possible to model the desired curve using
pharmacokinetic modeling techniques; in this way the desired curve
can be approximated without need for pharmacokinetic or
pharmacodynamic monitoring. However, periodic plasma concentration
determinations would make the model more accurate and allow further
adjustment of the infusion rate.
[0184] Following the method set forth above, mean plasma
concentrations are obtained as follows: a mean plasma concentration
from about 1 to about 28 pg/ml at about 6 hours after initiation of
the dosing interval; a mean plasma concentration from about 14 to
about 74 pg/ml at about 12 hours after initiation of the dosing
interval; a mean plasma concentration from about 30 to about 161
pg/ml at about 24 hours after initiation of the dosing interval; a
mean plasma concentration from about 51 to about 188 pg/ml at about
36 hours after initiation of the dosing interval; a mean plasma
concentration from about 62 to about 246 pg/ml at about 48 hours
after initiation of the dosing interval; a mean plasma
concentration from about 79 to about 246 pg/ml at about 60 hours
after initiation of the dosing interval; a mean plasma
concentration from about 85 to about 263 pg/ml at about 72 hours
after initiation of the dosing interval; a mean plasma
concentration from about 92 to about 263 pg/ml at about 96 hours
after initiation of the dosing interval; a mean plasma
concentration from about 94 to about 263 pg/ml at about 120 hours
after initiation of the dosing interval; a mean plasma
concentration from about 86 to about 243 pg/ml at about 144 hours
after initiation of the dosing interval; and a mean plasma
concentration from about 77 to about 210 pg/ml at about 168 hours
after initiation of the dosing interval (for a seven day dosing
interval).
[0185] It will be readily apparent that various modifications to
the invention may be made by those skilled in the art without
departing from the scope of this invention. For example, many
different transdermal delivery systems may be utilized in order to
obtain the relative release rates and plasma levels described
herein. Further, it is possible that mean values for plasma
concentrations over a particular patient population for a
particular described time point along the dosing interval may vary
from the plasma concentration ranges described herein for that time
point. Such obvious modifications are considered to be within the
scope of the appended claims.
* * * * *