U.S. patent application number 13/645422 was filed with the patent office on 2013-01-31 for rapid establishment and/or termination of substantial steady-state drug delivery.
This patent application is currently assigned to INTARCIA THERAPEUTICS, INC.. The applicant listed for this patent is Thomas R. Alessi, Kenneth L. Luskey. Invention is credited to Thomas R. Alessi, Kenneth L. Luskey.
Application Number | 20130030417 13/645422 |
Document ID | / |
Family ID | 43780643 |
Filed Date | 2013-01-31 |
United States Patent
Application |
20130030417 |
Kind Code |
A1 |
Alessi; Thomas R. ; et
al. |
January 31, 2013 |
Rapid Establishment and/or Termination of Substantial Steady-State
Drug Delivery
Abstract
The present invention is directed to treatment methods for a
disease or condition, in a subject in need of such treatment, that
provide alternatives to treatment by injection that give, relative
to treatment by injection, improved treatment outcomes, 100%
treatment compliance, reduced side effects, and rapid establishment
and/or termination of substantial steady-state drug delivery. The
method typically includes providing continuous delivery of a drug
from an implanted osmotic delivery device, wherein substantial
steady-state delivery of the drug at therapeutic concentrations is
typically achieved within about 7 days or less after implantation
of the osmotic delivery device in the subject and the substantial
steady-state delivery of the drug from the osmotic delivery device
is continuous over a period of at least about 3 months. In one
embodiment, the present invention is directed to treatment of type
2 diabetes mellitus using incretin mimetics.
Inventors: |
Alessi; Thomas R.; (Hayward,
CA) ; Luskey; Kenneth L.; (Saratoga, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alessi; Thomas R.
Luskey; Kenneth L. |
Hayward
Saratoga |
CA
CA |
US
US |
|
|
Assignee: |
INTARCIA THERAPEUTICS, INC.
Hayward
CA
|
Family ID: |
43780643 |
Appl. No.: |
13/645422 |
Filed: |
October 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12924175 |
Sep 21, 2010 |
8298561 |
|
|
13645422 |
|
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61358112 |
Jun 24, 2010 |
|
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61277724 |
Sep 28, 2009 |
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Current U.S.
Class: |
604/891.1 |
Current CPC
Class: |
A61F 5/0013 20130101;
A61K 9/0004 20130101; A61P 1/00 20180101; A61P 43/00 20180101; A61K
38/26 20130101; A61M 5/14276 20130101; A61P 3/06 20180101; A61P
3/04 20180101; A61M 2205/04 20130101; A61P 3/08 20180101; A61P 9/12
20180101; A61P 1/08 20180101; A61P 5/48 20180101; A61K 9/0024
20130101; A61K 38/00 20130101; A61L 27/54 20130101; A61P 35/00
20180101; A61P 3/10 20180101; A61M 2005/14513 20130101 |
Class at
Publication: |
604/891.1 |
International
Class: |
A61M 5/168 20060101
A61M005/168 |
Claims
1. A method of weight loss in a subject in need thereof,
comprising: providing continuous delivery of exenatide from an
osmotic delivery device, the osmotic delivery device comprising an
impermeable reservoir comprising interior and exterior surfaces and
first and second open ends, a semi-permeable membrane in sealing
relationship with the first open end of the reservoir, an osmotic
engine within the reservoir, the osmotic engine adjacent the
semi-permeable membrane, a piston adjacent the osmotic engine,
wherein the piston forms a movable seal with the interior surface
of the reservoir, the piston divides the reservoir into a first
chamber and a second chamber, the first chamber containing the
osmotic engine, a suspension formulation contained in the second
chamber, the suspension formulation comprising a particle
formulation and a vehicle formulation, wherein the particle
formulation comprises particles comprising exenatide in particles
of less than 10 microns in diameter, and the vehicle formulation
comprises a solvent and a polymer, wherein the solvent is selected
from the group consisting of benzyl benzoate, lauryl lactate, and
lauryl alcohol, and the polymer is polyvinylpyrrolidone, the
vehicle formulation having a viscosity between about 10,000 poise
and about 20,000 poise at 37.degree. C., and a diffusion moderator
that defines a delivery orifice inserted in the second open end of
the reservoir, the diffusion moderator adjacent the suspension
formulation; wherein (i) substantial steady-state delivery of
exenatide at a therapeutic concentration is achieved within a time
period of 5 days or less after implantation of the osmotic delivery
device in the subject, and (ii) the substantial steady-state
delivery of exenatide from the osmotic delivery device is
continuous over an administration period of at least about 3 months
at a mcg/day dose of exenatide selected from the group consisting
of about 10 mcg/day, about 20 mcg/day, about 30 mcg/day, about 40
mcg/day, about 60 mcg/day, and about 80 mcg/day.
2. The method of claim 1, wherein substantial steady-state delivery
of exenatide at therapeutic concentrations is achieved after
implantation of the osmotic delivery device in the subject within a
time period selected from the group consisting of about 4 days or
less, about 3 days or less, about 2 days or less, and about 1 day
or less.
3. The method of claim 1, wherein the substantial steady-state
delivery of exenatide from the osmotic delivery device is
continuous over an administration period selected from the group
consisting of at least about 3 months to about a year, at least
about 4 months to about a year, at least about 5 months to about a
year, at least about 6 months to about a year, at least about 8
months to about a year, and at least about 9 months to about a
year.
4. The method of claim 1, further comprising providing a
significant decrease in the subject's fasting plasma glucose
concentration after implantation of the osmotic delivery device in
the subject, relative to the subject's fasting plasma glucose
concentration before implantation of the osmotic delivery device,
within a number of days selected from the group consisting of about
7 days or less, about 6 days or less, about 5 days or less, about 4
days or less, about 3 days or less, about 2 days or less, and about
1 day or less.
5. The method of claim 4, wherein the significant decrease in the
subject's fasting plasma glucose concentration is achieved,
relative to the subject's fasting plasma glucose concentration
before implantation of the osmotic device, within about 1 day of
implantation of the osmotic delivery device in the subject.
6. The method of claim 4, wherein the significant decrease in
fasting plasma glucose is maintained over the administration
period.
7-8. (canceled)
9. The method of claim 16, wherein exenatide is detected by a
radioimmunoassay.
10. (canceled)
11. The method of 1, wherein the reservoir comprises titanium or a
titanium alloy.
12-15. (canceled)
16. The method of claim 1, further comprising termination of
continuous delivery by removal of the osmotic delivery device from
the subject such that the concentration of exenatide is
substantially undetectable in a blood sample from the subject after
termination of continuous delivery in a number of hours selected
from the group consisting of less than about 72 hours, less than
about 48 hours, less than about 24 hours, and less than about 12
hours.
17. The method of claim 1, wherein the method further comprises a
first continuous administration period of exenatide at a first
mcg/day dose that is followed by a second continuous administration
period providing a dose escalation of exenatide to a second mcg/day
dose, wherein the second mcg/day dose is greater than the first
mcg/day dose.
18. The method of claim 17, wherein the first mcg/day dose is
delivered by the osmotic delivery device and the second mcg/day
dose is delivered by a second osmotic delivery device.
19. (canceled)
20. The method of claim 17, wherein the method further comprises at
least one more continuous administration period providing a dose
escalation of exenatide to a higher mcg/day dose relative to the
second mcg/day dose.
21. The method of claim 17, wherein the first mcg/day dose followed
by the second mcg/day dose for continuous delivery are selected
from the group consisting of: about 10 mcg/day followed by about 20
mcg/day; about 10 mcg/day followed by about 40 mcg/day; about 10
mcg/day followed by about 60 mcg/day; about 10 mcg/day followed by
about 80 mcg/day; about 20 mcg/day followed by about 40 mcg/day;
about 20 mcg/day followed by about 60 mcg/day; about 20 mcg/day
followed by about 80 mcg/day; about 40 mcg/day followed by about 60
mcg/day; about 40 mcg/day followed by about 80 mcg/day; and about
60 mcg/day followed by about 80 mcg/day.
22-26. (canceled)
27. The method of claim 1, wherein the subject is a human.
28-39. (canceled)
40. A method of treating obesity in a subject in need thereof,
comprising: providing continuous delivery of exenatide from an
osmotic delivery device, the osmotic delivery device comprising an
impermeable reservoir comprising interior and exterior surfaces and
first and second open ends, a semi-permeable membrane in sealing
relationship with the first open end of the reservoir, an osmotic
engine within the reservoir, the osmotic engine adjacent the
semi-permeable membrane, a piston adjacent the osmotic engine,
wherein the piston forms a movable seal with the interior surface
of the reservoir, the piston divides the reservoir into a first
chamber and a second chamber, the first chamber containing the
osmotic engine, a suspension formulation contained in the second
chamber, the suspension formulation comprising a particle
formulation and a vehicle formulation, wherein the particle
formulation comprises particles comprising exenatide in particles
of less than 10 microns in diameter, and the vehicle formulation
comprises a solvent and a polymer, wherein the solvent is selected
from the group consisting of benzyl benzoate, lauryl lactate, and
lauryl alcohol, and the polymer is polyvinylpyrrolidone, the
vehicle formulation having a viscosity between about 10,000 poise
and about 20,000 poise at 37.degree. C., and a diffusion moderator
that defines a delivery orifice inserted in the second open end of
the reservoir, the diffusion moderator adjacent the suspension
formulation; wherein (i) substantial steady-state delivery of
exenatide at a therapeutic concentration is achieved within a time
period of 5 days or less after implantation of the osmotic delivery
device in the subject, and (ii) the substantial steady-state
delivery of exenatide from the osmotic delivery device is
continuous over an administration period of at least about 3 months
at a mcg/day dose of exenatide selected from the group consisting
of about 10 mcg/day, about 20 mcg/day, about 30 mcg/day, about 40
mcg/day, about 60 mcg/day, and about 80 mcg/day.
41. A method of suppressing appetite in a subject in need thereof,
comprising: providing continuous delivery of exenatide from an
osmotic delivery device, the osmotic delivery device comprising an
impermeable reservoir comprising interior and exterior surfaces and
first and second open ends, a semi-permeable membrane in sealing
relationship with the first open end of the reservoir, an osmotic
engine within the reservoir, the osmotic engine adjacent the
semi-permeable membrane, a piston adjacent the osmotic engine,
wherein the piston forms a movable seal with the interior surface
of the reservoir, the piston divides the reservoir into a first
chamber and a second chamber, the first chamber containing the
osmotic engine, a suspension formulation contained in the second
chamber, the suspension formulation comprising a particle
formulation and a vehicle formulation, wherein the particle
formulation comprises particles comprising exenatide in particles
of less than 10 microns in diameter, and the vehicle formulation
comprises a solvent and a polymer, wherein the solvent is selected
from the group consisting of benzyl benzoate, lauryl lactate, and
lauryl alcohol, and the polymer is polyvinylpyrrolidone, the
vehicle formulation having a viscosity between about 10,000 poise
and about 20,000 poise at 37.degree. C., and a diffusion moderator
that defines a delivery orifice inserted in the second open end of
the reservoir, the diffusion moderator adjacent the suspension
formulation; wherein (i) substantial steady-state delivery of
exenatide at a therapeutic concentration is achieved within a time
period of 5 days or less after implantation of the osmotic delivery
device in the subject, and (ii) the substantial steady-state
delivery of exenatide from the osmotic delivery device is
continuous over an administration period of at least about 3 months
at a mcg/day dose of exenatide selected from the group consisting
of about 10 mcg/day, about 20 mcg/day, about 30 mcg/day, about 40
mcg/day, about 60 mcg/day, and about 80 mcg/day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. 61/277,724, filed 28 Sep. 2009, now pending, and
U.S. Provisional Application Ser. No. 61/358,112, filed 24 Jun.
2010, now pending, which applications are herein incorporated by
reference in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to organic chemistry,
formulation chemistry, and peptide chemistry applied to
pharmaceutical research and development. Aspects of the present
invention include, but are not limited to, methods of treatment for
a disease or condition in a subject in need of such treatment. In
one embodiment the disease is type 2 diabetes mellitus.
BACKGROUND OF THE INVENTION
[0003] A variety of drug dosage forms and methods of drug
administration have been developed for delivery of drugs to
mammals, in particular, for delivery of drugs to humans (see, e.g.,
the Merck Manual of Diagnosis and Therapy, 18th edition, Published
by Merck Sharp & Dohme Corp., Whitehouse Station, N.J.). Such
dosage forms include, for example, use of the following routes of
administration: oral; injection (e.g., intravenously,
intramuscularly, intrathecally, or subcutaneously); implantation
(e.g., subcutaneous); and across a skin or mucosal barrier (e.g.,
sublingual, rectal, vaginal, ocular, nasal, inhalation into the
lungs, topical, or transdermal). Each route of administration has
specific purposes, advantages, and disadvantages.
[0004] The oral route of administration is the most common and
generally considered to be the most convenient. Oral
administration, however, poses some limitations because drugs
administered by this route are exposed to the harsh conditions of
the digestive system. Other routes of administration may be
required when the oral route cannot be used.
[0005] When drugs are prepared for administration by injection
(e.g., subcutaneous, intramuscular, intravenous, or intrathecal
administration), the drug can be formulated in a variety of ways
including formulations that prolong drug absorption from the
injection site for hours, days, or longer. Such formulations are
typically used for subcutaneous injection. Injectable products
formulated for prolonged delivery typically are not administered as
often as injectable drug products having more rapid absorption.
Subcutaneous administration is used for many protein or peptide
drugs because such drugs are typically broken down by the digestive
system to inactive forms if taken orally. Subcutaneous
administration of a drug typically requires frequent
self-injection, for example, one or more times daily or once-weekly
injections.
[0006] When a large volume of a drug product is required,
intramuscular administration is generally the preferred route of
administration. Typically, intramuscular administration of drugs is
by injection into the muscle of the upper arm, thigh, or buttock.
The rate of drug absorption into the bloodstream in large part
depends on the blood supply to the muscle, that is, the more blood
supply the faster the drug is absorbed.
[0007] Intravenous drug administration requires that a needle be
inserted directly into a vein. A drug may be given in a single dose
or continuously infused. For infusion, a drug solution is either
delivered using gravity (e.g., from a collapsible plastic bag) or
using an infusion pump through a tube inserted in a vein, usually
in the forearm. An intravenous injection can be more difficult to
administer than a subcutaneous or intramuscular injection, for
example, because inserting a needle or catheter into a vein may be
difficult, drugs typically must be mixed within a relatively short
time before beginning administration, there is an increased chance
of infection (e.g., abscessed infections of injection sites caused
by lack of hygiene and/or a lack of correct aseptic technique), and
over time there is scarring damage to the peripheral veins.
[0008] When drugs are administered by intravenous injection it is
often desirable for health care practitioners to closely monitor
subjects for signs that the drug is working and that the drug is
not causing undesired side effects. Typically, the effect of
intravenously administered drugs tends to last for a shorter
periods of time than drugs administered by subcutaneous injection
or intramuscular injection. Therefore, some drugs must be
administered by continuous infusion to provide appropriate
therapeutic effect. Because of the difficulties associated with
intravenous drug administration it is most typically used in
hospital or skilled care settings; it is rarely used for long-term
self-administered treatment.
[0009] A number of complications negatively impact compliance with
injection treatment regimens, including, but not limited to, the
following. A subject being needle phobic, which is particularly
troublesome to a subject when a drug must be self-injected over
extended periods of time. Compliance can also be complicated by the
inconvenience of administration of a drug by injection, for
example, when subjects are in public or busy with daily activities.
Also, frequent self-administration of a drug reminds subjects of
their disease state and carries a stigma associated with the
disease and/or treatment.
[0010] The implantable osmotic drug delivery devices of the present
invention, and use of these osmotic delivery devices in methods for
the treatment of diseases or conditions in subjects in need of
treatment, uniquely address unmet needs of previously described
drug dosage forms and methods of treatment. For example, the
present invention provides treatment of subjects at a target drug
dose that is continuously administered over time with the ability
to rapidly establish and sustain over time substantial steady-state
drug delivery while also providing the ability to rapidly terminate
administration of the drug. Heretofore, drug administration via
injection has not typically been able to provide rapid
establishment and long-term maintenance (e.g., three months or
more) of steady-state drug delivery and, even if that were
possible, treatment using drugs administered by injection (e.g.,
drugs formulated for prolonged delivery) has not been able to be
rapidly terminated. The present invention also provides for
enhanced tolerization of subjects to drug dose escalation relative
to dose escalation performed by administration of drug by
injection.
SUMMARY OF THE INVENTION
[0011] The present invention generally relates to improved methods
of treating diseases or conditions in subjects in need of
treatment, wherein the methods of the invention provide rapid
establishment and/or rapid termination of substantial steady-state
drug delivery. Further, the present invention relates to methods of
escalating drug dose that provide improved tolerization of subjects
to increased drug dose levels relative to dose escalation by
standard drug injection methods. Preferred subjects for the methods
of the present invention are humans.
[0012] In a first aspect, the present invention relates to methods
of treating type 2 diabetes mellitus in a subject in need of
treatment. The method comprises providing continuous delivery of an
incretin mimetic from an osmotic delivery device, wherein
substantial steady-state delivery of the incretin mimetic at a
therapeutic concentration is achieved within a time period of about
7 days or less after implantation of the osmotic delivery device in
the subject. The substantial steady-state delivery of the incretin
mimetic from the osmotic delivery device is typically continuous
over an administration period of at least about 3 months. In some
embodiments of the invention, the substantial steady-state delivery
of the incretin mimetic at therapeutic concentrations is achieved
after implantation of the osmotic delivery device in the subject
within a time period selected from the group consisting of about 5
days or less, about 4 days or less, about 3 days or less, about 2
days or less, or about 1 day or less.
[0013] The substantial steady-state delivery of the incretin
mimetic from the osmotic delivery device is continuous over an
administration period of, for example at least about 3 months to
about a year, at least about 4 months to about a year, at least
about 5 months to about a year, at least about 6 months to about a
year, at least about 8 months to about a year, or at least about 9
months to about a year.
[0014] The method can further comprise providing a significant
decrease in the subject's fasting plasma glucose concentration
after implantation of the osmotic delivery device in the subject,
relative to the subject's fasting plasma glucose concentration
before implantation of the osmotic delivery device. The decrease is
typically obtained within, for example, about 7 days or less, about
6 days or less, about 5 days or less, about 4 days or less, about 3
days or less, about 2 days or less, or about 1 day or less.
Normally, a significant decrease in fasting plasma glucose is
maintained over the administration period.
[0015] Also, the method can further comprising the capability to
terminate the continuous delivery of the incretin mimetic such that
the concentration of the incretin mimetic is substantially
undetectable in a blood sample from the subject within about 6
half-lives or less, about 5 half-lives or less, about 4 half-lives
or less, or about 3 half-lives or less of the incretin mimetic
after termination of continuous delivery. When exenatide is the
incretin mimetic, the method can further comprise the capability to
terminate the continuous delivery such that the concentration of
exenatide is substantially undetectable in a blood sample from the
subject after termination of continuous delivery in a number of
hours selected from the group consisting of less than about 72
hours, less than about 48 hours, less than about 24, and less than
about 12 hours. In one embodiment, termination of continuous
delivery is accomplished by removal of the osmotic delivery device
from the subject. The incretin mimetic is, for example, detected by
a radioimmunoassay.
[0016] Osmotic delivery devices for use in the methods of the
present invention can comprise the components described herein
including, but note limited to, a reservoir, a semi-permeable
membrane, an osmotic engine, a piston, a suspension formulation,
and a diffusion moderator.
[0017] Suspension formulations for use in the present invention
typically comprise a particle formulation comprising an incretin
mimetic, and a vehicle formulation. Examples of incretin mimetics
useful in the practice of the present invention include, but are
not limited to, exenatide peptides, exenatide peptide analogs,
exenatide peptide derivatives, GLP-1 peptides, GLP-1 peptide
analogs, or GLP-1 peptide derivatives. Examples of preferred
incretin mimetics useful in the practice of the present invention
include exenatide having the amino acid sequence of exendin-4,
lixisenatide, GLP-1(7-36), liraglutide, albiglutide, and
taspoglutide. In some embodiments, the vehicle formulation
comprises a solvent (e.g., benzyl benzoate, lauryl lactate, and/or
lauryl alcohol) and a polymer (e.g., polyvinylpyrrolidone).
[0018] In some embodiments of the present invention, the continuous
delivery provides to the subject a mcg/day dose of exenatide
selected from the group consisting of about 10 mcg/day, about 20
mcg/day, about 30 mcg/day, about 40 mcg/day, about 60 mcg/day, and
about 80 mcg/day.
[0019] In another embodiment of the present invention, the method
further comprises a first continuous administration period of the
incretin mimetic at a first mcg/day dose that is followed by a
second continuous administration period providing a dose escalation
of the incretin mimetic to a second mcg/day dose, wherein the
second mcg/day dose is greater than the first mcg/day dose. The
first mcg/day dose is, for example, delivered by a first osmotic
delivery device and the second mcg/day dose is delivered by a
second osmotic delivery device, and delivery of the incretin
mimetic from at least the first or the second osmotic delivery
device is continuous over the administration period of at least
about 3 months. In one embodiment, the second mcg/day dose is at
least two times greater than the first mcg/day dose. The method can
further comprise at least one more continuous administration period
providing a dose escalation of the incretin mimetic to a higher
mcg/day dose relative to the second mcg/day dose.
[0020] Exemplary dose escalations for exenatide are as follows:
about 10 mcg/day followed by about 20 mcg/day; about 10 mcg/day
followed by about 40 mcg/day; about 10 mcg/day followed by about 60
mcg/day; about 10 mcg/day followed by about 80 mcg/day; about 20
mcg/day followed by about 40 mcg/day; about 20 mcg/day followed by
about 60 mcg/day; about 20 mcg/day followed by about 80 mcg/day;
about 40 mcg/day followed by about 60 mcg/day; about 40 mcg/day
followed by about 80 mcg/day; or about 60 mcg/day followed by about
80 mcg/day.
[0021] In a second aspect, the present invention relates to a
method of treating a disease or condition in a subject in need of
treatment. The method typically comprises providing continuous
delivery of a drug from an osmotic delivery device, wherein
substantial steady-state delivery of the drug at therapeutic
concentrations is achieved within a time period of about 7 days or
less after implantation of the osmotic delivery device in the
subject. The substantial steady-state delivery of the drug from the
osmotic delivery device is usually continuous over an
administration period of at least about 3 months, wherein the drug
has a half-life. In one embodiment, the method comprises the
proviso that the disease or condition is not prostate cancer.
[0022] The method can further comprise the capability to terminate
the continuous delivery such that the concentration of the drug is
substantially undetectable in a blood sample from the within about
6 half-lives or less, about 5 half-lives or less, about 4
half-lives or less, or about 3 half-lives or less of the drug after
termination of continuous delivery. In one embodiment, termination
of continuous delivery is accomplished by removal of the osmotic
delivery device from the subject. The drug is, for example,
detected by a radioimmunoassay or chromatography.
[0023] In another embodiment of the present invention, the method
further comprises a first continuous administration period of the
drug at a first dose/day that is followed by a second continuous
administration period providing a dose escalation of the drug to a
second dose/day, wherein the second dose/day is greater than the
first dose/day. The first dose/day is, for example, delivered by a
first osmotic delivery device and the second dose/day dose is
delivered by a second osmotic delivery device, and delivery of the
drug from at least the first or the second osmotic delivery device
is continuous over the administration period of at least about 3
months. The method can further comprise at least one more
continuous administration period providing a dose escalation of the
drug to a higher dose/day relative to the second dose/day.
[0024] Osmotic delivery devices for use in the methods of the
present invention can comprise the components described herein
including, but not limited to, a reservoir, a semi-permeable
membrane, an osmotic engine, a piston, a drug formulation or a
suspension formulation, and a diffusion moderator. Drug
formulations typically comprise a drug and a vehicle
formulation.
[0025] Suspension formulations for use in the present invention
typically comprise a particle formulation comprising a drug, and a
vehicle formulation. In some embodiments, the drug is a
polypeptide, for example, a recombinant antibody, antibody
fragment, humanized antibody, single chain antibody, monoclonal
antibody, avimer, human growth hormone, epidermal growth factor,
fibroblast growth factor, platelet-derived growth factor,
transforming growth factor, nerve growth factor, a cytokine, or an
interferon. In some embodiments, the vehicle formulation comprises
a solvent (e.g., benzyl benzoate, lauryl lactate, and/or lauryl
alcohol) and a polymer (e.g., polyvinylpyrrolidone).
[0026] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein.
BRIEF DESCRIPTION OF THE FIGURES
[0027] FIG. 1 presents the data from a randomized, open-label
29-day study of continuous subcutaneous delivery of exenatide using
an osmotic delivery device. The figure shows fasting plasma glucose
concentration versus time over 28 days of treatment. In the figure,
the vertical axis is the Mean Fasting Plasma Glucose (mg/dL) and
the horizontal axis is Treatment Days. Closed circles show data
points for an osmotic device delivering 10 mcg/day. Closed
triangles show data points for an osmotic device delivering 20
mcg/day. Closed diamonds show data points for an osmotic device
delivering 40 mcg/day. Closed squares show data points for an
osmotic device delivering 80 mcg/day.
[0028] FIG. 2 presents the data from a randomized, open-label
29-day study of continuous subcutaneous delivery of exenatide using
an osmotic delivery device. The figure shows pharmacokinetic data
related to plasma exenatide concentration versus time over 28 days
of treatment ending on day 29 and at 7 days following removal. In
the figure, the vertical axis is the Exenatide Concentration
(pg/ml) and the horizontal axis is Time (days). Closed diamonds
show data points for an osmotic device delivering 10 mcg/day.
Closed squares show data points for an osmotic device delivering 20
mcg/day. Closed triangles show data points for an osmotic device
delivering 40 mcg/day. "X"s show data points for an osmotic device
delivering 80 mcg/day. On day 29, removal of the osmotic delivery
device and the accompanying drop in plasma exenatide concentration
is indicated with a vertical arrow.
[0029] FIG. 3 presents the data from a randomized, open-label
29-day study of continuous subcutaneous delivery of exenatide using
an osmotic delivery device. The figure shows nausea versus time in
individual subjects for osmotic devices delivering 10 mcg/day, 20
mcg/day, 40 mcg/day, and 80 mcg/day. The vertical axis is the
Number of Patients (subjects) Experiencing Nausea, the horizontal
axis for each concentration of exenatide being delivered is
presented in Weeks. The degree of nausea is given below the figure
as no nausea (clear box), mild nausea (vertical lines), moderate
nausea (horizontal lines), and severe nausea (cross-hatching).
[0030] FIG. 4 presents a partial cross-sectional view of one
embodiment of an osmotic delivery device useful in the practice of
the present invention.
[0031] FIG. 5 presents an overview of a Phase 2 clinical study
design. In the figure, the top line shows a timeline of the Phase 2
study (12 weeks) and the 12-week extension phase. The extension
phase is weeks 13-24 and the groups were randomized 1:1 to
continuous delivery of exenatide as indicated in the figure. Group
3, exenatide administered via injection, is the second line. The
split in the line indicates the randomization of the group and the
switch to continuous delivery at 40 mcg/day and 60 mcg/day. Group
1, exenatide administered using an osmotic delivery device to
provide continuous delivery at 20 mcg/day, is the third line. The
split in the line indicates the randomization of the group to
continue 20 mcg/day or escalate to the elevated dosage of 60
mcg/day. Group 2, exenatide administered using an osmotic delivery
device to provide continuous delivery at 40 mcg/day, is the fourth
line. The split in the line indicates the randomization of the
group to continue 40 mcg/day or escalate to the elevated dosage of
80 mcg/day.
[0032] FIG. 6 presents the data for incidence of nausea over time
for treatment by continuous delivery of exenatide (Groups 1 and 2)
versus treatment by twice-daily injection with exenatide (Group 3).
The vertical axis is the Weekly Incidence of Nausea (%) and the
horizontal axis is the time of treatment in Weeks. In the figure,
Group 1, treatment by continuous delivery of 20 mcg/day of
exenatide, is represented by diamonds; Group 2, treatment by
continuous delivery of 40 mcg/day of exenatide, is represented by
squares; and Group 3, treatment by injection with 5 mcg BID
(twice-daily injection) for 4 weeks (arrow approximately
illustrates starting time point) followed by 10 mcg BID for 8 weeks
(arrow approximately illustrates starting time point), is
represented by triangles.
[0033] FIG. 7 presents data showing the percent change from
baseline in overall Quality of Life (QOL) assessment at week 8. In
the figure the numbers over the bar graphs represent the following:
n with improved QOL score/n with stable QOL score/n with decreased
QOL score, respectively; for Group 3, 36/0/15; for Group 1, 35/3/9;
and for Group 2, 40/1/7. The vertical axis is the Change from
Baseline in Score (%; the overall QOL score). The groups are
arranged along the horizontal axis and the group sizes are provided
under each group: Group 3, n=51; Group 1, n=47; and Group 2,
n=48.
[0034] FIG. 8 presents data from a subscale analysis of QOL
performed at week 8. The vertical axis is the percent Change from
Baseline in Score for each of the four QOL subscales: Well-Being,
Medical Control, Lifestyle, and Convenience. The four QOL subscales
are arranged along the horizontal axis. In the figure, each bar of
the graph is labeled with the Group number. Within each subscale,
the bar graphs are arrayed in the following order: Group 3, Group
1, and Group 2.
[0035] FIG. 9 presents an overview of the extension phase for
subject status at week 20. In the figure, continuous delivery of
exenatide at the indicated dosages is shown as "CD." The group
sizes are presented next to the extension phase dosage. In the
extension phase for weeks 13-24, subjects from each treatment group
were randomized to receive continuous delivery of exenatide at 20,
40, 60 or 80 mcg/day. In the figure, Group 1 is treatment by
continuous delivery of 20 mcg/day of exenatide for the first 12
weeks; Group 2 is treatment by continuous delivery of 40 mcg/day of
exenatide for the first 12 weeks; and Group 3 is treatment by
injection with 5 mcg BID (twice-daily) injection for 4 weeks
followed by 10 mcg BID for 8 weeks for the first 12 weeks. The
split in the group indicates the randomization of the group at week
12 and the boxes show the dosages for the dose escalation after
week 12. The number in each group at week 20 is shown as "n."
[0036] FIG. 10 presents the extension phase (weeks 13-24) data for
incidence of nausea over time. The first point (-1 Week) shows the
incidence of nausea the week prior to randomization and the
beginning of the extension phase treatment protocol. The vertical
axis is the Weekly Incidence of Nausea percent (%) and the
horizontal axis is the time of treatment in Weeks. In the figure,
the data for continuous delivery using implantable osmotic devices
delivering 20 mcg/day of exenatide is presented as closed
triangles; the data for continuous delivery using implantable
osmotic devices delivering 20 mcg/day of exenatide wherein subjects
were subsequently switched in the extension phase to continuous
delivery using implantable osmotic devices delivering 60 mcg/day of
exenatide is presented as squares; and, the data for twice-daily
injection of exenatide wherein subjects were switched in the
extension phase to continuous delivery using implantable osmotic
devices delivering 60 mcg/day of exenatide is presented as closed
circles.
[0037] FIG. 11 presents extension phase data showing the percent
change from baseline in overall QOL assessment at week 20. In the
figure the numbers in each bar graph represent which week (week 8
or week 20) the QOL assessment was performed. The groups are
arranged along the horizontal axis from the left as follows: Group
3 (at Week 8) switched to continuous delivery of exenatide at 40
mcg/day (CD 40 mcg/day); and Group 3 (at Week 8) switched to
continuous delivery of exenatide at 60 mcg/day (CD 60 mcg/day). The
vertical axis is the % Change from Baseline for the overall QOL
score.
[0038] FIG. 12 presents further extension phase data showing the
percent change from baseline in overall QOL assessment at week 20.
In the figure the numbers in each bar graph represent which week
(week 8 or week 20) the QOL assessment was performed. The groups
are arranged along the horizontal axis from the left as follows:
Group 1 (at Week 8) switched to continuous delivery of exenatide at
60 mcg/day (CD 60 mcg/day); and Group 2 (at Week 8) switched to
continuous delivery of exenatide at 80 mcg/day (CD 80 mcg/day). The
vertical axis is the % Change from Baseline for the overall QOL
score.
[0039] FIG. 13 presents a competitive profile among subjects on
metformin-only background treatment combined with a variety of type
2 diabetes mellitus treatments. The vertical axis is HbAlc %. The
treatments are displayed on the horizontal axis, as follows:
exenatide administered by twice-daily injection (Treatment A);
exenatide administered by once-weekly injection (Treatment B);
liraglutide administered by once-daily injection (Treatment C);
taspoglutide administered by once-weekly injection (Treatment D);
and treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide at 20
mcg/day and 60 mcg/day (Treatment E). The number within and near
the top of the bar graph (vertical lines) associated with each
treatment provides the baseline HbAlc % (e.g., Treatment A, 8.2).
The number within and near the top of the bar graph (diagonal
lines) associated with each treatment provides the endpoint HbAlc %
for the study (e.g., Treatment A, 7.4). The number within and near
the horizontal axis of the bar graph (diagonal lines) associated
with each treatment provides the change of HbAlc for the study
(e.g., Treatment A, -0.8).
[0040] FIG. 14 presents a competitive profile among subjects on
metformin-only background treatment combined with a variety of type
2 diabetes mellitus treatments. The vertical axis is HbAlc %. The
treatments are displayed on the horizontal axis, as follows:
treatment using sitagliptin (Treatment F); and treatment using
pioglitazone (Treatment G); exenatide administered by once-weekly
injection (Treatment B); treatment using the methods and osmotic
delivery devices of the present invention for continuous delivery
of exenatide at 20 mcg/day and 60 mcg/day (Treatment E). The number
within and near the top of the bar graph (vertical lines)
associated with each treatment provides the baseline HbAlc % (e.g.,
Treatment F, 8.5). The number within and near the top of the bar
graph (diagonal lines) associated with each treatment provides the
endpoint HbAlc % for the study (e.g., Treatment F, 7.6). The number
within and near the horizontal axis of the bar graph (diagonal
lines) associated with each treatment provides the change of HbAlc
for the study (e.g., Treatment F, -0.9).
[0041] FIG. 15 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with once-weekly injection of exenatide.
The vertical axis is HbAlc %. The treatments are displayed toward
the top of the figure, as follows: treatment using the methods and
osmotic delivery devices of the present invention for continuous
delivery of exenatide at 20 mcg/day and 60 mcg/day (Treatment E),
which includes the first three sets of bar graphs; and treatment
using exenatide administered by once-weekly injection (Treatment
B), which is set off by a dotted-line box. On the horizontal axis,
the subjects for Treatment E are broken down into groups based on
baseline HbAlc as follows: All Subjects; Baseline HbAlc greater
than 7.0; and Baseline HbAlc of greater than or equal to 7.5. The
number within and near the top of the bar graph (vertical lines)
associated with each treatment provides the baseline HbAlc % (e.g.,
Treatment B, 8.6). The percent marked with an asterisk within the
bar graph (vertical lines) associated with each treatment provides
the percentage of subjects who achieved an HbAlc of 7% or less
(e.g., Treatment B, 58%*). The number within and near the top of
the bar graph (diagonal lines) associated with each treatment
provides the endpoint HbAlc % for the study (e.g., Treatment B,
7.1). The number within and near the horizontal axis of the bar
graph (diagonal lines) associated with each treatment provides the
change of HbAlc for the study (e.g., Treatment B, -1.5).
[0042] FIG. 16 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with once-weekly injection of exenatide,
wherein the baselines have been normalized. The vertical axis is
HbAlc %. The treatments are displayed toward the top of the figure,
as follows: treatment using exenatide administered by once-weekly
injection (Treatment B); and treatment using the methods and
osmotic delivery devices of the present invention for continuous
delivery of exenatide at 20 mcg/day and 60 mcg/day (Treatment E).
The figure is divided by a vertical line into two panels as
follows: on the left side and labeled on the horizontal axis is
data for subjects with a baseline HbAlc of less than 9.0; and on
the right side and labeled on the horizontal axis is data for
subjects with a baseline HbAlc of greater than or equal to 9.0. The
asterisk following "Subjects with Baseline HbAlc .gtoreq.9.0*"
signifies that approximately one-third of subjects in Treatment B
had baseline HbAlc of greater than or equal to 9.0; but only one
subject of Treatment E had a baseline HbAlc of greater than or
equal to 9.0. The number within and near the top of the bar graph
(vertical lines) associated with each treatment provides the
baseline HbAlc % (e.g., Treatment B, left panel, 7.8). The number
within and near the top of the bar graph (diagonal lines)
associated with each treatment provides the endpoint HbAlc % for
the study (e.g., Treatment B, left panel, 6.7). The number within
and near the horizontal axis of the bar graph (diagonal lines)
associated with each treatment provides the change of HbAlc for the
study (e.g., Treatment B, left panel, -1.1).
[0043] FIG. 17 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with sitagliptin. The vertical axis is
HbAlc %. The treatments are displayed toward the top of the figure,
as follows: treatment using the methods and osmotic delivery
devices of the present invention for continuous delivery of
exenatide at 20 mcg/day and 60 mcg/day (Treatment E), which
includes the first three sets of bar graphs; and treatment using
sitagliptin (Treatment F), which is set off by a dotted-line box.
On the horizontal axis, the subjects for Treatment E are broken
down into groups based on baseline HbAlc as follows: All Subjects;
Baseline HbAlc greater than 7.0; and Baseline HbAlc of greater than
or equal to 7.5. The number within and near the top of the bar
graph (vertical lines) associated with each treatment provides the
baseline HbAlc % (e.g., Treatment F, 8.5). The percent marked with
an asterisk within the bar graph (vertical lines) associated with
each treatment provides the percentage of subjects who achieved an
HbAlc of 7% or less (e.g., Treatment F, 31%*). The number within
and near the top of the bar graph (diagonal lines) associated with
each treatment provides the endpoint HbAlc % for the study (e.g.,
Treatment F, 7.6). The number within and near the horizontal axis
of the bar graph (diagonal lines) associated with each treatment
provides the change of HbAlc for the study (e.g., Treatment F,
-0.9).
[0044] FIG. 18 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with sitagliptin, wherein the baselines
have been normalized. The vertical axis is HbAlc %. The treatments
are displayed toward the top of the figure, as follows: treatment
using sitagliptin (Treatment F); and treatment using the methods
and osmotic delivery devices of the present invention for
continuous delivery of exenatide at 20 mcg/day and 60 mcg/day
(Treatment E). The figure is divided by a vertical line into two
panels as follows: on the left side and labeled on the horizontal
axis is data for subjects with a baseline HbAlc of less than 9.0;
and on the right side and labeled on the horizontal axis is data
for subjects with a baseline HbAlc of greater than or equal to 9.0.
The asterisk following "Subjects with Baseline HbAlc .gtoreq.9.0*"
signifies that approximately one-third of subjects in Treatment F
had baseline HbAlc of greater than or equal to 9.0; but only one
subject of Treatment E had a baseline HbAlc of greater than or
equal to 9.0. The number within and near the top of the bar graph
(vertical lines) associated with each treatment provides the
baseline HbAlc % (e.g., Treatment F, left panel, 7.7). The number
within and near the top of the bar graph (diagonal lines)
associated with each treatment provides the endpoint HbAlc % for
the study (e.g., Treatment F, left panel, 7.2). The number within
and near the horizontal axis of the bar graph (diagonal lines)
associated with each treatment provides the change of HbAlc for the
study (e.g., Treatment F, left panel, -0.5).
[0045] FIG. 19 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with pioglitazone. The vertical axis is
HbAlc %. The treatments are displayed toward the top of the figure,
as follows: treatment using the methods and osmotic delivery
devices of the present invention for continuous delivery of
exenatide at 20 mcg/day and 60 mcg/day (Treatment E), which
includes the first three sets of bar graphs; and treatment using
pioglitazone (Treatment G), which is set off by a dotted-line box.
On the horizontal axis, the subjects for Treatment E are broken
down into groups based on baseline HbAlc as follows: All Subjects;
Baseline HbAlc greater than 7.0; and Baseline HbAlc of greater than
or equal to 7.5. The number within and near the top of the bar
graph (vertical lines) associated with each treatment provides the
baseline HbAlc % (e.g., Treatment G, 8.5). The percent marked with
an asterisk within the bar graph (vertical lines) associated with
each treatment provides the percentage of subjects who achieved an
HbAlc of 7% or less (e.g., Treatment G, 43%*). The number within
and near the top of the bar graph (diagonal lines) associated with
each treatment provides the endpoint HbAlc % for the study (e.g.,
Treatment G, 7.3). The number within and near the horizontal axis
of the bar graph (diagonal lines) associated with each treatment
provides the change of HbAlc for the study (e.g., Treatment G,
-1.2).
[0046] FIG. 20 presents a competitive profile among subjects on
metformin-only background treatment combined either with continuous
delivery of exenatide or with pioglitazone, wherein the baselines
have been normalized. The vertical axis is HbAlc %. The treatments
are displayed toward the top of the figure, as follows: treatment
using pioglitazone (Treatment G); and treatment using the methods
and osmotic delivery devices of the present invention for
continuous delivery of exenatide at 20 mcg/day and 60 mcg/day
(Treatment E). The figure is divided by a vertical line into two
panels as follows: on the left side and labeled on the horizontal
axis is data for subjects with a baseline HbAlc of less than 9.0;
and on the right side and labeled on the horizontal axis is data
for subjects with a baseline HbAlc of greater than or equal to 9.0.
The asterisk following "Subjects with Baseline HbAlc .gtoreq.9.0*"
signifies that approximately one-third of subjects in Treatment G
had baseline HbAlc of greater than or equal to 9.0; but only one
subject of Treatment E had a baseline HbAlc of greater than or
equal to 9.0. The number within and near the top of the bar graph
(vertical lines) associated with each treatment provides the
baseline HbAlc % (e.g., Treatment G, left panel, 7.8). The number
within and near the top of the bar graph (diagonal lines)
associated with each treatment provides the endpoint HbAlc % for
the study (e.g., Treatment G, left panel, 6.9). The number within
and near the horizontal axis of the bar graph (diagonal lines)
associated with each treatment provides the change of HbAlc for the
study (e.g., Treatment G, left panel, -0.9).
[0047] FIG. 21 presents comparative weight loss data among subjects
on metformin-only background treatment combined with a variety of
type 2 diabetes mellitus treatments. The vertical axis is % Weight
Loss. The treatments are displayed on the horizontal axis, as
follows: treatment using pioglitazone (Treatment G); treatment
using sitagliptin (Treatment F); exenatide administered by
once-weekly injection (Treatment B); and treatment using the
methods and osmotic delivery devices of the present invention for
continuous delivery of exenatide at 20 mcg/day and 60 mcg/day
(Treatment E). The number within the bar graph associated with each
treatment provides the weight gain or loss for the study (e.g.,
Treatment G, +2.8 kg).
DETAILED DESCRIPTION OF THE INVENTION
[0048] All patents, publications, and patent applications cited in
this specification are herein incorporated by reference as if each
individual patent, publication, or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety for all purposes.
[0049] 1.0.0 Definitions
[0050] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only, and is
not intended to be limiting. As used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a solvent" includes a combination
of two or more such solvents, reference to "a peptide" includes one
or more peptides, or mixtures of peptides, reference to "a drug"
includes one or more drugs, reference to "an osmotic device"
includes one or more osmotic devices, and the like.
[0051] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
other methods and materials similar, or equivalent, to those
described herein can be used in the practice of the present
invention, the preferred materials and methods are described
herein.
[0052] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0053] The terms "drug," "therapeutic agent," and "beneficial
agent" are used interchangeably to refer to any therapeutically
active substance that is delivered to a subject to produce a
desired beneficial effect. In one embodiment of the present
invention, the drug is a polypeptide. In another embodiment of the
present invention, the drug is a small molecule, for example,
hormones such as androgens or estrogens. The devices and methods of
the present invention are well suited for the delivery of proteins,
small molecules and combinations thereof
[0054] The terms "peptide," "polypeptide," and "protein" are used
interchangeably herein and typically refer to a molecule comprising
a chain of two or more amino acids (e.g., most typically L-amino
acids, but also including, e.g., D-amino acids, modified amino
acids, amino acid analogs, and/or amino acid mimetic). Peptides may
be naturally occurring, synthetically produced, or recombinantly
expressed. Peptides may also comprise additional groups modifying
the amino acid chain, for example, functional groups added via
post-translational modification. Examples of post-translation
modifications include, but are not limited to, acetylation,
alkylation (including, methylation), biotinylation, glutamylation,
glycylation, glycosylation, isoprenylation, lipoylation,
phosphopantetheinylation, phosphorylation, selenation, and
C-terminal amidation. The term peptide also includes peptides
comprising modifications of the amino terminus and/or the carboxy
terminus. Modifications of the terminal amino group include, but
are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and
N-acyl modifications. Modifications of the terminal carboxy group
include, but are not limited to, amide, lower alkyl amide, dialkyl
amide, and lower alkyl ester modifications (e.g., wherein lower
alkyl is C.sub.1 -C.sub.4 alkyl). The term peptide also includes
modifications, such as but not limited to those described above, of
amino acids falling between the amino and carboxy termini. In one
embodiment, a peptide may be modified by addition of a
small-molecule drug.
[0055] The terminal amino acid at one end of the peptide chain
typically has a free amino group (i.e., the amino terminus). The
terminal amino acid at the other end of the chain typically has a
free carboxyl group (i.e., the carboxy terminus). Typically, the
amino acids making up a peptide are numbered in order, starting at
the amino terminus and increasing in the direction of the carboxy
terminus of the peptide.
[0056] The phrase "amino acid residue" as used herein refers to an
amino acid that is incorporated into a peptide by an amide bond or
an amide bond mimetic.
[0057] The phrase "incretin mimetics" as used herein includes, but
is not limited to, glucagon-like peptide 1 (GLP-1), as well as
peptide derivatives and peptide analogs thereof; and exenatide, as
well as peptide derivatives and peptide analogs thereof Incretin
mimetics are also known in the literature as "insulinotropic
peptides" or "GLP-1 receptor agonists."
[0058] The term "insulinotropic" as used herein typically refers to
the ability of a compound, e.g., a peptide, to stimulate or affect
the production and/or activity of insulin (e.g., an insulinotropic
hormone). Such compounds typically stimulate the secretion or
biosynthesis of insulin in a subject.
[0059] The term "vehicle" as used herein refers to a medium used to
carry a compound, e.g., a drug. Vehicles of the present invention
typically comprise components such as polymers and solvents. The
suspension vehicles of the present invention typically comprise
solvents and polymers that are used to prepare suspension
formulations further comprising drug particle formulations.
[0060] The phrase "phase separation" as used herein refers to the
formation of multiple phases (e.g., liquid or gel phases) in the
suspension vehicle, such as when the suspension vehicle contacts
the aqueous environment. In some embodiments of the present
invention, the suspension vehicle is formulated to exhibit phase
separation upon contact with an aqueous environment having less
than approximately 10% water.
[0061] The phrase "single-phase" as used herein refers to a solid,
semisolid, or liquid homogeneous system that is physically and
chemically uniform throughout.
[0062] The term "dispersed" as used herein refers to dissolving,
dispersing, suspending, or otherwise distributing a compound, for
example, a drug particle formulation, in a suspension vehicle.
[0063] The phrase "chemically stable" as used herein refers to
formation in a formulation of an acceptable percentage of
degradation products produced over a defined period of time by
chemical pathways, such as deamidation (usually by hydrolysis),
aggregation, or oxidation.
[0064] The phrase "physically stable" as used herein refers to
formation in a formulation of an acceptable percentage of
aggregates (e.g., dimers and other higher molecular weight
products). Further, a physically stable formulation does not change
its physical state as, for example, from liquid to solid, or from
amorphous to crystal form.
[0065] The term "viscosity" as used herein typically refers to a
value determined from the ratio of shear stress to shear rate (see,
e.g., Considine, D. M. & Considine, G. D., Encyclopedia of
Chemistry, 4th Edition, Van Nostrand, Reinhold, N.Y., 1984)
essentially as follows:
F/A=.mu.*V/L (Equation 1)
where F/A=shear stress (force per unit area), .mu.=a
proportionality constant (viscosity), and V/L =the velocity per
layer thickness (shear rate).
[0066] From this relationship, the ratio of shear stress to shear
rate defines viscosity. Measurements of shear stress and shear rate
are typically determined using parallel plate rheometery performed
under selected conditions (for example, a temperature of about
37.degree. C.). Other methods for the determination of viscosity
include, measurement of a kinematic viscosity using viscometers,
for example, a Cannon-Fenske viscometer, a Ubbelohde viscometer for
the Cannon-Fenske opaque solution, or a Ostwald viscometer.
Generally, suspension vehicles of the present invention have a
viscosity sufficient to prevent a particle formulation suspended
therein from settling during storage and use in a method of
delivery, for example, in an implantable, drug delivery device.
[0067] The term "non-aqueous" as used herein refers to an overall
moisture content, for example, of a suspension formulation,
typically of less than or equal to about 10 wt %, preferably less
than or equal to about 7 wt %, more preferably less than or equal
to about 5 wt %, and more preferably less than about 4 wt %.
[0068] The term "subject" as used herein refers to any member of
the subphylum Chordata, including, without limitation, humans and
other primates, including non-human primates such as rhesus
macaques and other monkey species and chimpanzees and other ape
species; farm animals such as cattle, sheep, pigs, goats and
horses; domestic mammals such as dogs and cats; laboratory animals
including rodents such as mice, rats and guinea pigs; birds,
including domestic, wild and game birds such as chickens, turkeys
and other gallinaceous birds, ducks, geese, and the like. The term
does not denote a particular age or gender. Thus, both adult and
newborn individuals are intended to be covered.
[0069] The term "osmotic delivery device" as used herein typically
refers to a device used for delivery of a drug (e.g., an incretin
mimetic) to a subject, wherein the device comprises, for example, a
reservoir (made, e.g., from a titanium alloy) having a lumen that
contains a suspension formulation comprising a drug (e.g., an
incretin mimetic) and an osmotic agent formulation. A piston
assembly positioned in the lumen isolates the suspension
formulation from the osmotic agent formulation. A semi-permeable
membrane is positioned at a first distal end of the reservoir
adjacent the osmotic agent formulation and a diffusion moderator
(which defines a delivery orifice through which the suspension
formulation exits the device) is positioned at a second distal end
of the reservoir adjacent the suspension formulation. Typically,
the osmotic delivery device is implanted within the subject, for
example, subcutaneously (e.g., in the inside, outside, or back of
the upper arm; or in the abdominal area). An exemplary osmotic
delivery device is the DUROS.RTM. (ALZA Corporation, Mountain View,
Calif.) delivery device.
[0070] The term "continuous delivery" as used herein typically
refers to a substantially continuous release of drug from an
osmotic delivery device. For example, the DUROS.RTM. delivery
device releases drug essentially at a predetermined rate based on
the principle of osmosis. Extracellular fluid enters the DUROS.RTM.
device through the semi-permeable membrane directly into the
osmotic engine that expands to drive the piston at a slow and
consistent rate of travel. Movement of the piston forces the drug
formulation to be released through the orifice of the diffusion
moderator. Thus release of the drug from the osmotic delivery
device is at a slow, controlled, consistent rate.
[0071] The term "substantial steady-state delivery" as used herein
typically refers to delivery of a drug at or near a target
concentration over a defined period of time, wherein the amount of
the drug being delivered from an osmotic device is substantially
zero-order delivery. Substantial zero-order delivery of an active
agent (e.g., exenatide) means that the rate of drug delivered is
constant and is independent of the drug available in the delivery
system; for example, for zero-order delivery, if the rate of drug
delivered is graphed against time and a line is fitted to the data
the line has a slope of approximately zero, as determined by
standard methods (e.g., linear regression).
[0072] The phrase "drug half-life" as used herein refers how long
it takes a drug to be eliminated from blood plasma by one half of
its concentration. A drug's half-life is usually measured by
monitoring how a drug degrades when it is administered via
injection or intravenously. A drug is usually detected using, for
example, a radioimmunoassay or chromatographic method.
[0073] 2.0.0 General Overview of the Invention
[0074] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
types of drug delivery devices, particular sources of drugs,
particular solvents, particular polymers, and the like, as use of
such particulars may be selected in view of the teachings of the
present specification. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments of the invention only, and is not intended to be
limiting.
[0075] In a first aspect, the present invention relates to a method
of treating type 2 diabetes mellitus in a subject in need of
treatment. The method comprises providing continuous delivery of an
incretin mimetic from an osmotic delivery device, wherein
substantial steady-state delivery of the incretin mimetic at a
therapeutic concentration is achieved within a time period of about
7 days or less after implantation of the osmotic delivery device in
the subject. The substantial steady-state delivery of the incretin
mimetic from the osmotic delivery device is continuous over an
administration period. Humans are preferred subjects for the
practice of the present invention. The present invention includes
an incretin mimetic (e.g., exenatide), as well as an osmotic device
comprising an incretin mimetic (e.g., exenatide) for use in the
present methods of treating type 2 diabetes mellitus in a subject
in need of treatment.
[0076] In some embodiments of the present invention, the
administration period is, for example, at least about 3 months, at
least about 3 months to about a year, at least about 4 months to
about a year, at least about 5 months to about a year, at least
about 6 months to about a year, at least about 8 months to about a
year, at least about 9 months to about a year, or at least about 10
months to about a year.
[0077] In some embodiments of the present invention, the
substantial steady-state delivery of an incretin mimetic at
therapeutic concentrations is achieved within about 5 days or less
after implantation of the osmotic delivery device in the subject,
within about 4 days or less after implantation of the osmotic
delivery device in the subject, within about 3 days or less after
implantation of the osmotic delivery device in the subject, within
about 2 days or less after implantation of the osmotic delivery
device in the subject, or within about 1 day or less after
implantation of the osmotic delivery device in the subject. In
preferred embodiments of the present invention, the substantial
steady-state delivery of the incretin mimetic at therapeutic
concentrations is achieved within about 2 days or less, more
preferably within about 1 day or less after implantation of the
osmotic delivery device in the subject.
[0078] In further embodiments, the treatment methods of the present
invention provide significant decrease in the subject's fasting
plasma glucose concentration after implantation of the osmotic
delivery device in the subject (relative to the subject's fasting
plasma glucose concentration before implantation of the osmotic
delivery device) that is achieved within about 7 days or less after
implantation of the osmotic delivery device in the subject, within
about 6 days or less after implantation of the osmotic delivery
device in the subject, within about 5 days or less after
implantation of the osmotic delivery device in the subject, within
about 4 days or less after implantation of the osmotic delivery
device in the subject, within about 3 days or less after
implantation of the osmotic delivery device in the subject, within
about 2 days or less after implantation of the osmotic delivery
device in the subject, or within about 1 day or less after
implantation of the osmotic delivery device in the subject. In
preferred embodiments of the present invention, the significant
decrease in the subject's fasting plasma glucose concentration
after implantation of the osmotic device, relative to the subject's
fasting plasma glucose concentration before implantation, is
achieved within about 2 days or less, preferably within about 1 day
or less after implantation of the osmotic delivery device in the
subject, or more preferably within about 1 day after implantation
of the osmotic delivery device in the subject. The significant
decrease in fasting plasma glucose is typically statistically
significant as demonstrated by application of an appropriate
statistical test or is considered significant for the subject by a
medical practitioner. A significant decrease in fasting plasma
glucose relative to the baseline before implantation is typically
maintained over the administration period.
[0079] In yet further embodiments of the first aspect of the
present invention, the treatment methods further comprise the
capability to terminate the continuous delivery of the incretin
mimetic such that the concentration of the incretin mimetic is
substantially undetectable in a blood sample from the subject
within about 6 half-lives or less of the incretin mimetic after
termination of continuous delivery, within about 5 half-lives or
less of the incretin mimetic after termination of continuous
delivery, within about 4 half-lives or less of the incretin mimetic
after termination of continuous delivery, or within about 3
half-lives or less of the incretin mimetic after termination of
continuous delivery. Examples of incretin mimetic half-lives are
exenatide, approximately 2.5 hours, and GLP-1, approximately 2
minutes. The incretin mimetic may be detected, for example, by a
radioimmunoassay. Termination of the continuous delivery can be
accomplished, for example, by removal of the osmotic delivery
device from the subject.
[0080] In related embodiments of the present invention, the
treatment methods further comprise the capability to terminate the
continuous delivery of exenatide such that the concentration of
exenatide is substantially undetectable in a blood sample from the
subject in less than about 72 hours after termination of continuous
delivery, in less than about 48 hours after termination of
continuous delivery, in less than about 24 hours after termination
of continuous delivery, in less than about 18 hours after
termination of continuous delivery, in less than about 14 hours
after termination of continuous delivery, in less than about 12
hours after termination of continuous delivery, in less than about
6 hours after termination of continuous delivery, or in less than
about 4 hours after termination of continuous delivery. In
preferred embodiments, exenatide is substantially undetectable in a
blood sample from the subject in less than about 24 hours after
termination of continuous delivery, in less than about 18 hours
after termination of continuous delivery, or more preferably in
less than about 14 hours after termination of continuous
delivery.
[0081] In preferred embodiments of the first aspect of the present
invention, the incretin mimetic comprises an exenatide peptide, a
peptide analog thereof, or a peptide derivative thereof; a GLP-1
peptide (e.g., GLP-1(7-36)amide peptide), a peptide analog thereof,
or a peptide derivative thereof. Specific examples of preferred
incretin mimetics useful in the practice of the present invention
include exenatide having the amino acid sequence of exendin-4,
lixisenatide, GLP-1(7-36), liraglutide, albiglutide, and
taspoglutide.
[0082] In some embodiments of the first aspect of the present
invention, wherein the incretin mimetic is exenatide, the
continuous delivery can provide to the subject a mcg/day dose of
exenatide, for example, of about 10 mcg/day, about 20 mcg/day,
about 30 mcg/day, about 40 mcg/day, about 60 mcg/day, or about 80
mcg/day.
[0083] In some embodiments of the first aspect of the present
invention, wherein the incretin mimetic is exenatide, the method of
treating type 2 diabetes mellitus further comprises the capability
to terminate the continuous delivery such that the concentration of
the exenatide is substantially undetectable in a blood sample from
the subject after termination of continuous delivery, for example,
in less than about 72 hours, in less than about 48 hours, in less
than about 24, or in less than about 12 hours.
[0084] In additional embodiments of the first aspect of the present
invention, the method of treating type 2 diabetes mellitus further
comprises a first continuous administration period of the incretin
mimetic at a first mcg/day dose that is followed by a second
continuous administration period providing a dose escalation of the
incretin mimetic to a second mcg/day dose, wherein the second
mcg/day dose is greater than the first mcg/day dose. In some
embodiments, the first mcg/day dose is delivered by a first osmotic
delivery device and the second mcg/day dose is delivered by a
second osmotic delivery device, and delivery of the incretin
mimetic from at least the first or the second osmotic delivery
device is continuous over the administration period of at least
about 3 months. In one embodiment, the second mcg/day dose is at
least two times greater than the first mcg/day dose. Further, the
method can comprise at least one more continuous administration
period providing a dose escalation of the incretin mimetic to a
higher mcg/day dose relative to the second mcg/day dose. Dose
escalation can be accomplished, for example, by removal of the
first osmotic delivery device and implantation of a second osmotic
delivery device, or by implantation of a second or further osmotic
delivery device where the total dose delivered by the first and
second osmotic delivery devices results in the desired dose
escalation.
[0085] In a preferred embodiment of the present invention
comprising dose escalation, the incretin mimetic is an exenatide,
and the first mcg/day dose followed by the second mcg/day dose for
continuous delivery are selected from the group consisting of:
about 10 mcg/day followed by about 20 mcg/day; about 10 mcg/day
followed by about 40 mcg/day; about 10 mcg/day followed by about 60
mcg/day; about 10 mcg/day followed by about 80 mcg/day; about 20
mcg/day followed by about 40 mcg/day; about 20 mcg/day followed by
about 60 mcg/day; about 20 mcg/day followed by about 80 mcg/day;
about 40 mcg/day followed by about 60 mcg/day; about 40 mcg/day
followed by about 80 mcg/day; and about 60 mcg/day followed by
about 80 mcg/day.
[0086] In a second aspect, the present invention relates to a
method of treating type 2 diabetes mellitus in a subject in need of
treatment. The method comprises providing continuous delivery of an
incretin mimetic (e.g., exenatide) from an implanted osmotic
delivery device, wherein (i) a significant decrease in fasting
plasma glucose concentration is achieved after implantation of the
osmotic device in the subject, relative to the fasting plasma
glucose concentration before implantation, within about 7 days of
implantation of the osmotic delivery device in the subject, (ii)
the delivery of the incretin mimetic is continuous over an
administration period, and (iii) a significant decrease in fasting
plasma glucose is maintained over the period. The significant
decrease in fasting plasma glucose is typically statistically
significant as demonstrated by application of an appropriate
statistical test or is considered significant for the subject by a
medical practitioner.
[0087] In a third aspect, the present invention relates to a method
of treating type 2 diabetes mellitus in a subject in need of
treatment comprising the capability to terminate continuous
delivery of an incretin mimetic such that the concentration of the
incretin mimetic is substantially undetectable in a blood sample
from the subject within about 6 half-lives or less of the incretin
mimetic after termination of continuous delivery, within about 5
half-lives or less of the incretin mimetic after termination of
continuous delivery, within about 4 half-lives or less of the
incretin mimetic after termination of continuous delivery, or
within about 3 half-lives or less of the incretin mimetic after
termination of continuous delivery. Examples of incretin mimetic
half-lives include exenatide, approximately 2.5 hours, and GLP-1,
approximately 2 minutes.
[0088] In a fourth aspect, the present invention relates to a
method of treating type 2 diabetes mellitus, comprising a first
continuous administration period of an incretin mimetic at a first
mcg/day dose that is followed by a second continuous administration
period providing a dose escalation of the incretin mimetic to a
second mcg/day dose, wherein the second mcg/day dose is greater
than the first mcg/day dose. In some embodiments, the first mcg/day
dose is delivered by a first osmotic delivery device and the second
mcg/day dose is delivered by a second osmotic delivery device, and
delivery of the incretin mimetic from at least the first or the
second osmotic delivery device is continuous over the
administration period of at least about 3 months. In one
embodiment, the second mcg/day dose is at least two times greater
than the first mcg/day dose. Further, the method can comprise at
least one additional continuous administration period providing a
dose escalation of the incretin mimetic to a higher mcg/day dose
relative to the second mcg/day dose. Dose escalation can be
accomplished, for example, by removal of the first osmotic delivery
device and implantation of a second osmotic delivery device, or by
implantation of a second or further osmotic delivery device where
the total dose delivered by the first and second (or further)
osmotic delivery devices results in the desired dose escalation.
This aspect of the present invention (which comprises multiple,
sequential continuous administration periods of escalating doses of
the incretin mimetic) provides improved tolerization to dose
escalation of the incretin mimetic relative to dose escalation
based on injection of the incretin mimetic.
[0089] In embodiments of all aspects of the present invention
relating to methods of treating type 2 diabetes mellitus, an
exemplary osmotic delivery device comprises the following: an
impermeable reservoir comprising interior and exterior surfaces and
first and second open ends; a semi-permeable membrane in sealing
relationship with the first open end of the reservoir; an osmotic
engine within the reservoir and adjacent the semi-permeable
membrane; a piston adjacent the osmotic engine, wherein the piston
forms a movable seal with the interior surface of the reservoir,
the piston divides the reservoir into a first chamber and a second
chamber, the first chamber comprising the osmotic engine; a
suspension formulation, wherein the second chamber comprises the
suspension formulation and the suspension formulation is flowable
and comprises the incretin mimetic; and a diffusion moderator
inserted in the second open end of the reservoir, the diffusion
moderator adjacent the suspension formulation. In preferred
embodiments, the reservoir comprises titanium or a titanium
alloy.
[0090] In embodiments of all aspects of the present invention
relating to methods of treating type 2 diabetes mellitus,
suspension formulations for use in the methods can, for example,
comprise a particle formulation comprising an incretin mimetic, and
a vehicle formulation. Examples of incretin mimetics include, but
are not limited to, an exenatide peptide, a peptide analog thereof,
or a peptide derivative thereof; a GLP-1 peptide, a peptide analog
thereof, or a peptide derivative thereof. Specific examples of
preferred incretin mimetics include exenatide having the amino acid
sequence of exendin-4, lixisenatide, GLP-1(7-36), liraglutide,
albiglutide, and taspoglutide. Vehicle formulations for use in
forming the suspension formulations of the present invention can,
for example, comprise a solvent and a polymer. Examples of solvents
include, but are not limited to benzyl benzoate, lauryl lactate,
lauryl alcohol, or combinations thereof. An example of a polymer is
a polyvinvylpyrrolidone. In a preferred embodiment, the suspension
vehicle consists essentially of one solvent and one polymer, for
example, the solvent benzyl benzoate and the polymer
polyvinvylpyrrolidone.
[0091] The reservoir of the osmotic delivery devices may, for
example, comprise titanium or a titanium alloy.
[0092] In a fifth aspect, the present invention relates to a method
of treating a disease or condition in a subject in need of
treatment. The method comprises providing continuous delivery of a
drug from an osmotic delivery device, wherein substantial
steady-state delivery of the drug at therapeutic concentrations is
achieved within a time period of about 7 days or less after
implantation of the osmotic delivery device in the subject. The
substantial steady-state delivery of the drug from the osmotic
delivery device is continuous over an administration period of at
least about 3 months. The drug has a known or determined half-life
in a typical subject. Humans are preferred subjects for the
practice of the present invention. The present invention includes a
drug effective for treatment of the disease or condition, as well
as an osmotic device comprising the drug for use in the present
methods of treating the disease or condition in a subject in need
of treatment. Advantages of the present invention include
mitigation of peak-associated drug toxicities and attenuation of
sub-optimal drug therapy associated with troughs.
[0093] In some embodiments of the present invention, the
administration period is, for example, at least about 3 months, at
least about 3 months to about a year, at least about 4 months to
about a year, at least about 5 months to about a year, at least
about 6 months to about a year, at least about 8 months to about a
year, at least about 9 months to about a year, or at least about 10
months to about a year.
[0094] In one embodiment of this aspect of the present invention,
the method of treating a disease or condition includes the proviso
that the disease or condition is not prostate cancer.
[0095] In some embodiments of this aspect of the present invention,
the substantial steady-state delivery of a drug at therapeutic
concentrations is achieved within a period of about 7 days or less
after implantation of the osmotic delivery device in the subject,
about 5 days or less after implantation of the osmotic delivery
device in the subject, about 4 days or less after implantation of
the osmotic delivery device in the subject, about 3 days or less
after implantation of the osmotic delivery device in the subject,
about 2 days or less after implantation of the osmotic delivery
device in the subject, or about 1 day or less after implantation of
the osmotic delivery device in the subject.
[0096] In some embodiments of this aspect of the present invention,
establishment of the substantial steady-state delivery of the drug
at therapeutic concentrations, after implantation of the osmotic
delivery device in the subject, may take a longer period of time,
for example, a period of about 2 weeks or less, or within less than
about 6 half-lives of the drug within the subject after
implantation of the device.
[0097] In yet further embodiments of the fifth aspect of the
present invention, the methods of treating a disease or condition
further comprise the capability to terminate the continuous
delivery of the drug such that the concentration of the drug is
substantially undetectable in a blood sample from the subject
within about 6 half-lives or less of the drug after termination of
continuous delivery, within about 5 half-lives or less of the drug
after termination of continuous delivery, within about 4 half-lives
or less after termination of continuous delivery, or within about 3
half-lives or less of the drug after termination of continuous
delivery. Some examples of drug half-lives are as follows:
exenatide, approximately 2.5 hours; GLP-1, approximately 2 minutes;
GIP, approximately 5 minutes; PYY, approximately 8 minutes;
glucagon, approximately 6 minutes; oxynotomodulin, approximately 6
minutes; and GLP-2, approximately 6 minutes. In the situation where
more than one drug is administered, the capability to terminate the
continuous delivery of the more than one drug is such that the
concentration of the more than one drug is substantially
undetectable in a blood sample from the subject within about 6
half-lives or less of the more than one drug having the longest
half-life after termination of continuous delivery. Termination of
the continuous delivery can be accomplished, for example, by
removal of the osmotic delivery device from the subject. In some
embodiments, the drug is detected in a blood sample by a
radioimmunoassay or chromatography.
[0098] In preferred embodiments of the fifth aspect of the present
invention, the drug comprises a polypeptide, for example, selected
from the following: recombinant antibodies, antibody fragments,
humanized antibodies, single chain antibodies, monoclonal
antibodies, and avimers; human growth hormone, epidermal growth
factor, fibroblast growth factor, platelet-derived growth factor,
transforming growth factor, and nerve growth factor; cytokines; and
interferons. In other embodiments, the drug comprises a small
molecule.
[0099] In additional embodiments of the fifth aspect of the present
invention, the method of treating a disease or condition further
comprises a first continuous administration period of the drug at a
first dose/day that is followed by a second continuous
administration period providing a dose escalation of the drug to a
second dose/day, wherein the second dose/day is greater than the
first dose/day. In some embodiments, the first dose/day is
delivered by a first osmotic delivery device and the second
dose/day is delivered by a second osmotic delivery device, and
delivery of the drug from at least the first or the second osmotic
delivery device is continuous over the administration period of at
least about 3 months. In one embodiment, the second dose/day is at
least two times greater than the first dose/day. Further, the
method can comprise at least one more continuous administration
period providing a dose escalation of the drug to a higher dose/day
relative to the second dose/day. Dose escalation can be
accomplished, for example, by removal of the first osmotic delivery
device and implantation of a second osmotic delivery device, or by
implantation of a second or further osmotic delivery device where
the total dose delivered by the first and second osmotic delivery
devices results in the desired dose escalation.
[0100] In a sixth aspect, the present invention relates to a method
of treating a disease or condition in a subject in need of
treatment comprising the capability to terminate continuous
delivery of a drug such that the concentration of the drug is
substantially undetectable in a blood sample from the subject
within about 6 half-lives or less of the drug after termination of
continuous delivery, within about 5 half-lives or less of the drug
after termination of continuous delivery, within about 4 half-lives
or less of the drug after termination of continuous delivery, or
within about 3 half-lives or less of the drug after termination of
continuous delivery. Some examples of drug half-lives are as
follows: exenatide, approximately 2.5 hours; GLP-1, approximately 2
minutes; GIP, approximately 5 minutes; PYY, approximately 8
minutes; glucagon, approximately 6 minutes; oxyntomodulin,
approximately 6 minutes; and GLP-2, approximately 6 minutes. In
some embodiments, termination of continuous delivery comprises
removal of the osmotic delivery device from the subject. In some
embodiments, the drug is detected in a blood sample by a
radioimmunoassay or chromatography.
[0101] In a seventh aspect, the present invention relates to a
method of treating a disease or condition in a subject in need of
treatment, comprising a first continuous administration period of a
drug at a first dose/day that is followed by a second continuous
administration period providing a dose escalation of the drug to a
second dose/day, wherein the second dose/day is greater than the
first dose/day. In some embodiments, the first dose/day is
delivered by a first osmotic delivery device and the second
dose/day is delivered by a second osmotic delivery device, and
delivery of the drug from at least the first or the second osmotic
delivery device is continuous over the administration period of at
least about 3 months. In one embodiment, the second dose/day is at
least two times greater than the first dose/day. Further, the
method can comprise at least one additional continuous
administration period providing a dose escalation of the drug to a
higher dose/day relative to the second dose/day. Dose escalation
can be accomplished, for example, by removal of the first osmotic
delivery device and implantation of a second osmotic delivery
device, or by implantation of a second or further osmotic delivery
device where the total dose delivered by the first and second (or
further) osmotic delivery devices results in the desired dose
escalation. This aspect of the present invention (which comprises
multiple, sequential continuous administration periods of
escalating doses of the drug) provides improved tolerization to
dose escalation of the drug relative to, for example, dose
escalation based on injection of the drug.
[0102] In embodiments of all aspects of the present invention
relating to methods of treating a disease or condition in a
subject, an exemplary osmotic delivery device comprises the
following: an impermeable reservoir comprising interior and
exterior surfaces and first and second open ends; a semi-permeable
membrane in sealing relationship with the first open end of the
reservoir; an osmotic engine within the reservoir and adjacent the
semi-permeable membrane; a piston adjacent the osmotic engine,
wherein the piston forms a movable seal with the interior surface
of the reservoir, the piston divides the reservoir into a first
chamber and a second chamber, the first chamber comprising the
osmotic engine; a drug formulation or suspension formulation
comprising the drug, wherein the second chamber comprises the drug
formulation or suspension formulation and the drug formulation or
suspension formulation is flowable; and a diffusion moderator
inserted in the second open end of the reservoir, the diffusion
moderator adjacent the suspension formulation. In preferred
embodiments, the reservoir comprises titanium or a titanium
alloy.
[0103] In embodiments of all aspects of the present invention
relating to methods of treating a disease or condition in a
subject, the drug formulation can comprise the drug and a vehicle
formulation. Alternatively, suspension formulations are used in the
methods and can, for example, comprise a particle formulation
comprising the drug and a vehicle formulation. Vehicle formulations
for use in forming the suspension formulations of the present
invention can, for example, comprise a solvent and a polymer.
Examples of solvents include, but are not limited to benzyl
benzoate, lauryl lactate, lauryl alcohol, or combinations thereof.
An example of a polymer is a polyvinvylpyrrolidone. In a preferred
embodiment, the suspension vehicle consists essentially of one
solvent and one polymer, for example, the solvent benzyl benzoate
and the polymer polyvinvylpyrrolidone.
[0104] The reservoir of the osmotic delivery devices may, for
example, comprise titanium or a titanium alloy.
[0105] In embodiments of all aspects of the present invention the
implanted osmotic delivery device can be used to provide
subcutaneous delivery.
[0106] In embodiments of all aspects of the present invention the
continuous delivery can, for example, be zero-order, controlled
continuous delivery.
[0107] 3.0.0 Formulations and Compositions
[0108] Drugs for use in the practice of the present invention are
typically uniformly suspended, dissolved or dispersed in a
suspension vehicle to form a suspension formulation.
[0109] 3.1.0 Drug Particle Formulations
[0110] In one aspect, the present invention provides drug particle
formulations for pharmaceutical use. The particle formulation
typically comprises a drug and includes one or more stabilizing
component. Examples of stabilizing components include, but are not
limited to, carbohydrates, antioxidants, amino acids, buffers,
inorganic compounds, and surfactants.
[0111] 3.1.1 Exemplary Drugs
[0112] The drug particle formulations comprise a drug. The drug may
be any physiologically or pharmacologically active substance,
particularly those known to be delivered to the body of a human or
an animal. Drugs that may be delivered by the osmotic delivery
system of the present invention include, but are not limited to,
drugs that act on the peripheral nerves, adrenergic receptors,
cholinergic receptors, the skeletal muscles, the cardiovascular
system, smooth muscles, the blood circulatory system, synoptic
sites, neuroeffector junctional sites, endocrine and hormone
systems, the immunological system, the reproductive system, the
skeletal system, autacoid systems, the alimentary and excretory
systems, the histamine system or the central nervous system.
Further, drugs that may be delivered by the osmotic delivery system
of the present invention include, but are not limited to, drugs
used for the treatment of infectious diseases, chronic pain,
diabetes, autoimmune disorders, endocrine disorders, metabolic
disorders, and rheumatologic disorders.
[0113] Suitable drugs include, but are not limited to, the
following: peptides, proteins, polypeptides (e.g., enzymes,
hormones, cytokines), polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, steroids, analgesics,
local anesthetics, antibiotic agents, anti-inflammatory
corticosteroids, ocular drugs, other small molecules for
pharmaceutical use (e.g., ribavirin), or synthetic analogs of these
species, as well as mixtures thereof
[0114] In one embodiment, preferred drugs include macromolecules.
Such macromolecules include, but are not limited to,
pharmacologically active peptides proteins, polypeptides, genes,
gene products, other gene therapy agents, or other small molecules.
In a preferred embodiment the macromolecules are peptides,
polypeptides or proteins. Numerous peptides, proteins, or
polypeptides that are useful in the practice of the present
invention are described herein. In addition to the peptides,
proteins, or polypeptides described, modifications of these
peptides, proteins, or polypeptides are also known to one of skill
in the art and can be used in the practice of the present invention
following the guidance presented herein. Such modifications
include, but are not limited to, amino acid analogs, amino acid
mimetics, analog polypeptides, or derivative polypeptides. Further,
the drugs disclosed herein may be formulated or administered singly
or in combination (e.g., using mixtures of drugs or multiple
devices; U.S. Patent Publication No. 2009/0202608).
[0115] Examples of proteins that can be formulated into drug
particle formulations of the present invention include, but are not
limited to, the following: human growth hormone; somatostatin;
somatropin, somatotropin, somatotropin analogs, somatomedin-C,
somatotropin plus an amino acid, somatotropin plus a protein;
follicle stimulating hormone; luteinizing hormone, luteinizing
hormone-releasing hormone (LHRH), LHRH analogs such as leuprolide
or leuprolide acetate, nafarelin and goserelin, LHRH agonists or
antagonists; growth hormone releasing factor; calcitonin;
colchicine; gonadotropic releasing hormone; gonadotropins such as
chorionic gonadotropin; oxytocin, octreotide; vasopressin;
adrenocorticotrophic hormone; epidermal growth factor; fibroblast
growth factor; platelet-derived growth factor; transforming growth
factor; nerve growth factor; prolactin; cosyntropin; lypressin
polypeptides such as thyrotropin releasing hormone; thyroid
stimulation hormone; secretin; pancreozymin; enkephalin; glucagon;
incretin mimetics; endocrine agents secreted internally and
distributed by way of the bloodstream; or the like.
[0116] Further proteins that may be formulated into drug particle
formulations include, but are not limited to, the following: alpha
antitrypsin; factor VII; factor VIII; factor IX and other
coagulation factors; insulin and insulin related compounds (for
example, isophane insulin suspension, protamine zinc insulin
suspension, globin zinc insulin, extended insulin zinc suspension);
peptide hormones; adrenal cortical stimulating hormone, thyroid
stimulating hormone and other pituitary hormones; erythropoietin;
growth factors such as granulocyte-colony stimulating factor,
granulocyte-macrophage colony stimulating factor, insulin-like
growth factor 1; tissue plasminogen activator; CD4;
1-deamino-8-D-arginine vasopressin; interleukin-1 receptor
antagonist; tumor necrosis factor, tumor necrosis factor receptor;
tumor suppresser proteins; pancreatic enzymes; lactase; cytokines,
including lymphokines, chemokines or interleukins such as
interleukin-1, interleukin-2; cytotoxic proteins; superoxide
dismutase; endocrine agents secreted internally and distributed in
an animal by way of the bloodstream; recombinant antibodies,
antibody fragments, humanized antibodies, single chain antibodies,
monoclonal antibodies; avimers; or the like.
[0117] Some embodiments of the present invention comprise use of
peptide hormones, for example, incretin mimetics (e.g., GLP-1 or
exenatide), as well as peptide analogs and peptide derivatives
thereof; PYY (also known as peptide YY, peptide tyrosine tyrosine),
as well as peptide analogs and peptide derivatives thereof, for
example, PYY(3-36); oxyntomodulin, as well as peptide analogs and
peptide derivatives thereof); and gastric inhibitory peptide (GIP),
as well as peptide analogs and peptide derivatives thereof.
[0118] Other embodiments comprise use of interferon peptides (e.g.,
alpha, beta, gamma, lambda, omega, tau, consensus, and variant
interferons, as well as peptide analogs or peptide derivatives
thereof such as pegylated forms, as well as mixtures thereof; see,
for example, The Interferons: Characterization and Application, by
Anthony Meager (Editor), Wiley-VCH (May 1, 2006)).
[0119] GLP-1, including three forms of the peptide, GLP-1(1-37),
GLP-1(7-37) and GLP-1(7-36)amide, as well as peptide analogs of
GLP-1 have been shown to stimulate insulin secretion (i.e., is
insulinotropic), which induces glucose uptake by cells and results
in decreases in serum glucose concentrations (see, e g., Mojsov,
S., Int. J. Peptide Protein Research, 40:333-343 (1992)).
[0120] Numerous GLP-1 peptide derivatives and peptide analogs
demonstrating insulinotropic action are known in the art (see,
e.g., U.S. Pat. Nos. 5,118,666; 5,120,712; 5,512,549; 5,545,618;
5,574,008; 5,574,008; 5,614,492; 5,958,909; 6,191,102; 6,268,343;
6,329,336; 6,451,974; 6,458,924; 6,514,500; 6,593,295; 6,703,359;
6,706,689; 6,720,407; 6,821,949; 6,849,708; 6,849,714; 6,887,470;
6,887,849; 6,903,186; 7,022,674; 7,041,646; 7,084,243; 7,101,843;
7,138,486; 7,141,547; 7,144,863; and 7,199,217), as well as in
clinical trials (e.g., taspoglutide and albiglutide). One example
of a GLP-1 peptide derivative useful in the practice of the present
invention is Victoza.RTM. (Novo Nordisk A/S, Bagsvaerd DK)
(liraglutide; U.S. Pat. Nos. 6,268,343, 6,458,924, 7,235,627).
Once-daily injectable Victoza.RTM. (liraglutide) is commercially
available in the United States, Europe, and Japan. For ease of
reference herein, the family of GLP-1 peptides, GLP-1 peptide
derivatives and GLP-1 peptide analogs having insulinotropic
activity is referred to collectively as "GLP-1."
[0121] The molecule exenatide has the amino acid sequence of
exendin-4 (Kolterman O. G., et al., J. Clin. Endocrinol. Metab.
88(7):3082-9 (2003)) and is produced by chemical synthesis or
recombinant expression. Twice-daily injectable exenatide is
commercially available in the United States and Europe, and sold
under the tradename of Byetta.RTM. (Amylin Pharmaceuticals, Inc.,
San Diego Calif.). Exendin-3 and exendin-4 are known in the art and
were originally isolated from Heloderma spp. (Eng, J., et al., J.
Biol. Chem., 265:20259-62 (1990); Eng., J., et al., J. Biol. Chem.,
267:7402-05 (1992)). Use of exendin-3 and exendin-4 for the
treatment of type 2 diabetes mellitus and the prevention of
hyperglycemia has been proposed (see, e.g., U.S. Pat. No.
5,424,286). Numerous exenatide peptide derivatives and peptide
analogs (including, e.g., exendin-4 agonists) are known in the art
(see, e.g., U.S. Pat. Nos. 5,424,286; 6,268,343; 6,329,336;
6,506,724; 6,514,500; 6,528,486; 6,593,295; 6,703,359; 6,706,689;
6,767,887; 6,821,949; 6,849,714; 6,858,576; 6,872,700; 6,887,470;
6,887,849; 6,924,264; 6,956,026; 6,989,366; 7,022,674; 7,041,646;
7,115,569; 7,138,375; 7,141,547; 7,153,825; and 7,157,555). One
example of an exenatide derivative useful in the practice of the
present invention is lixisenatide (also known as ZP10, AVE0010)
(see, e.g., U.S. Pat. No. 6,528,486), which is in clinical trials.
For ease of reference herein, the family of exenatide peptides
(e.g., including exendin-3, exendin-4, and exendin-4-amide),
exenatide peptide derivatives, and exenatide peptide analogs is
referred to collectively as "exenatide."
[0122] PYY is a 36 amino acid residue peptide amide. PYY inhibits
gut motility and blood flow (Laburthe, M., Trends Endocrinol Metab.
1(3):168-74 (1990), mediates intestinal secretion (Cox, H. M., et
al., Br J Pharmacol 101(2):247-52 (1990); Playford, R. J., et al.,
Lancet 335(8705):1555-7 (1990)), and stimulate net absorption
(MacFayden, R. J., et al., Neuropeptides 7(3):219-27 (1986)). Two
major in vivo variants, PYY(1-36) and PYY(3-36), have been
identified (e.g., Eberlein, G. A., et al., Peptides 10(4), 797-803
(1989)). The sequence of PYY, as well as peptide analogs and
peptide derivatives thereof, are known in the art (e.g., U.S. Pat.
Nos. 5,574,010 and 5,552,520).
[0123] Oxyntomodulin is a naturally occurring 37 amino acid peptide
hormone found in the colon that has been found to suppress appetite
and facilitate weight loss (Wynne K, et al., Int J Obes (Lond)
30(12):1729-36(2006)). The sequence of oxyntomodulin, as well as
peptide analogs and peptide derivatives thereof, are known in the
art (e.g., Bataille D, et al., Peptides 2(Suppl 2):41-44 (1981);
and U.S. Patent Publication Nos. 2005/0070469 and
2006/0094652).
[0124] GIP is an insulinotropic peptide hormone (Efendic, S., et
al., Horm Metab Res. 36:742-6 (2004)) and is secreted by the mucosa
of the duodenum and jejunum in response to absorbed fat and
carbohydrate that stimulate the pancreas to secrete insulin. GIP
circulates as a biologically active 42-amino acid peptide. GIP is
also known as glucose-dependent insulinotropic protein. GIP is a
42-amino acid gastrointestinal regulatory peptide that stimulates
insulin secretion from pancreatic beta cells in the presence of
glucose (Tseng, C., et al., PNAS 90:1992-1996 (1993)). The sequence
of GIP, as well as peptide analogs and peptide derivatives thereof,
are known in the art (e.g., Meier J. J., Diabetes Metab Res Rev.
21(2):91-117 (2005); Efendic S., Horm Metab Res. 36(11-12):742-6
(2004)).
[0125] Examples of half-lives of some of the peptides are as
follows: exenatide, approximately 2.5 hours; GLP-1, approximately 2
minutes; GIP, approximately 5 minutes; PYY, approximately 8
minutes; glucagon, approximately 6 minutes; oxyntomodulin,
approximately 6 minutes; and GLP-2, approximately 6 minutes.
[0126] Drug particle formulations for use in the practice of the
present invention are exemplified using exenatide. The examples are
not intended to be limiting.
[0127] In another embodiment, preferred drugs include small
molecules. Examples of drugs that may be used in the practice of
the present invention include, but are not limited to, the
following: chemotherapeutics; hypnotics and sedatives such as
pentobarbital sodium, phenobarbital, secobarbital, thiopental,
amides and ureas exemplified by diethylisovaleramide and
alpha-bromo-isovaleryl urea, urethanes, or disulfanes; heterocyclic
hypnotics such as dioxopiperidines, and glutarimides;
antidepressants such as isocarboxazid, nialamide, phenelzine,
imipramine, tranylcypromine, pargyline); tranquilizers such as
chloropromazine, promazine, fluphenazine reserpine, deserpidine,
meprobamate, benzodiazepines such as chlordiazepoxide;
anticonvulsants such as primidone, diphenylhydantoin, ethltoin,
pheneturide, ethosuximide; muscle relaxants and anti-parkinson
agents such as mephenesin, methocarbomal, trihexylphenidyl,
biperiden, levo-dopa, also known as L-dopa and
L-beta-3-4-dihydroxyphenylalanine; analgesics such as morphine,
codeine, meperidine, nalorphine; antipyretics and anti-inflammatory
agents such as aspirin, salicylamide, sodium salicylamide,
naproxin, ibuprofen; local anesthetics such as procaine, lidocaine,
naepaine, piperocaine, tetracaine, dibucane; antispasmodics and
anti-ulcer agents such as atropine, scopolamine, methscopolamine,
oxyphenonium, papaverine, prostaglandins such as PGE.sub.1,
PGE.sub.2, PGF.sub.1alpha, PGF.sub.2alpha, PGA; anti-microbials
such as penicillin, tetracycline, oxytetracycline,
chlorotetracycline, chloramphenicol, sulfonamides, tetracycline,
bacitracin, chlorotetracycline, erythromycin, isoniazid, rifampin,
ethambutol, pyrazinamide, rifabutin, rifapentine, cycloserine,
ethionamide, streptomycin, amikacin/kanamycin, capreomycin,
p-aminosalicyclic acid, levofloxacin, moxifloxacin and
gatifloxacin; anti-malarials such as 4-aminoquinolines,
8-aminoquinolines, pyrimethamine, chloroquine,
sulfadoxine-pyrimethamine; mefloquine; atovaquone-proguanil;
quinine; doxycycline; artemisinin (a sesquiterpene lactone) and
derivatives; anti-leishmaniasis agents (e.g., meglumine
antimoniate, sodium stibogluconate, amphotericin, miltefosine, and
paromomycin); anti-trypanosomiasis agents (e.g., benznidazole and
nifurtimox); anti-amoebiasis agents (e.g., metronidazole,
tinidazole, and diloxanide furoate); anti-protozoal diseases agents
(e.g., eflornithine, furazolidone, melarsoprol, metronidazole,
ornidazole, paromomycin sulfate, pentamidine, pyrimethamine and
tinidazole); hormonal agents such as prednisolone, cortisone,
cortisol and triamcinolone, androgenic steroids (for example,
methyltestosterone, fluoxmesterone), estrogenic steroids (for
example, 17-beta-estradoil and thinyl estradiol), progestational
steroids (for example, 17-alpha-hydroxyprogesterone acetate,
19-nor-progesterone, norethindrone); sympathomimetic drugs such as
epinephrine, amphetamine, ephedrine, norepinephrine; cardiovascular
drugs such as procainamide, amyl nitrate, nitroglycerin,
dipyridamole, sodium nitrate, mannitol nitrate; diuretics such as
acetazolamide, chlorothiazide, flumethiazide; antiparasitic agents
such as bephenium hydroxynaphthoate, dichlorophen, enitabas,
dapsone; neoplastic agents such as mechloroethamine, uracil
mustard, 5-fluorouracil, 6-thioguanine and procarbazine;
hypoglycemic drugs such as tolbutamide, acetohexamide, tolazamide,
chlorpropamide; nutritional agents such as vitamins, essential
amino acids, and essential fats; eye drugs such as pilocarpine
base, pilocarpine hydrochloride, pilocarpine nitrate; antiviral
drugs such as disoproxil fumarate, aciclovir, cidofovir, docosanol,
famciclovir, fomivirsen, foscarnet, ganciclovir, idoxuridine,
penciclovir, trifluridine, tromantadine, valaciclovir,
valganciclovir, vidarabine, amantadine, arbidol, oseltamivir,
peramivir, rimantadine, zanamivir, abacavir, didanosine,
emtricitabine, lamivudine, stavudine, zalcitabine, zidovudine,
tenofovir, efavirenz, delavirdine, nevirapine, loviride,
amprenavir, atazanavir, darunavir, fosamprenavir, indinavir,
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir,
enfuvirtide, adefovir, fomivirsen, imiquimod, inosine,
podophyllotoxin, ribavirin, viramidine, fusion blockers
specifically targeting viral surface proteins or viral receptors
(for example, gp-41 inhibitor (T-20), CCR-5 inhibitor); anti-nausea
such as scopolamine, dimenhydrinate); iodoxuridine, hydrocortisone,
eserine, phospholine, iodide, as well as other beneficial
drugs.
[0128] The drugs can also be in various forms including, but not
limited to, the following: uncharged molecules; components of
molecular complexes; and pharmacologically acceptable salts such as
hydrochloride, hydrobromide, sulfate, laurates, palmatates,
phosphate, nitrate, borate, acetate, maleate, tartrate, oleates, or
salicylates. For acidic drugs, salts of metals, amines or organic
cations, for example, quaternary ammonium, can be employed.
Furthermore, simple derivatives of the drug such as esters, ethers,
amides and the like that have solubility characteristics suitable
for the purpose of the invention can also be used herein.
[0129] The above drugs and other drugs known to those of skill in
the art are useful in methods of treatment for a variety of
conditions including but not limited to the following: chronic
pain, hemophilia and other blood disorders, endocrine disorders,
metabolic disorders, rheumatologic disorders, diabetes (including
type 1 and type 2 diabetes mellitus), leukemia, hepatitis, renal
failure, infectious diseases (including bacterial infection, viral
infection (e.g., infection by human immunodeficiency virus,
hepatitis C virus, hepatitis B virus, yellow fever virus, West Nile
virus, Dengue virus, Marburg virus, Ebola virus, etc.), and
parasitic infection), hereditary diseases (such as cerbrosidase
deficiency and adenosine deaminase deficiency), hypertension,
septic shock, autoimmune diseases (e.g., Grave's disease, systemic
lupus erythematosus, multiple sclerosis, and rheumatoid arthritis),
shock and wasting disorders, cystic fibrosis, lactose intolerance,
Crohn's diseases, inflammatory bowel disease, gastrointestinal
cancers (including colon cancer and rectal cancer), breast cancer,
leukemia, lung cancer, bladder cancer, kidney cancer, non-Hodgkin
lymphoma, pancreatic cancer, thyroid cancer, endometrial cancer,
and other cancers. Further, some of the above agents are useful for
the treatment of infectious diseases requiring chronic treatments
including, but not limited to, tuberculosis, malaria,
leishmaniasis, trypanosomiasis (sleeping sickness and Chagas
disease), and parasitic worms.
[0130] The amount of drug in drug particle formulations is that
amount necessary to deliver a therapeutically effective amount of
the agent to achieve the desired therapeutic result in the subject
to which the drug is being delivered. In practice, this will vary
depending upon such variables, for example, as the particular
agent, the severity of the condition, and the desired therapeutic
effect. Beneficial agents and their dosage unit amounts are known
to the prior art in Goodman & Gilman's The Pharmacological
Basis of Therapeutics, 11th Ed., (2005), McGraw Hill; Remington's
Pharmaceutical Sciences, 18th Ed., (1995), Mack Publishing Co.; and
Martin's Physical Pharmacy and Pharmaceutical Sciences, 1.00
edition (2005), Lippincott Williams & Wilkins. Further, highly
concentrated drug particles are described in U.S. Patent
Publication No. 2010/0092566. Typically, for an osmotic delivery
system, the volume of the chamber comprising the drug formulation
is between about 100 .mu.l to about 1000 .mu.l, more preferably
between about 140 .mu.l and about 200 .mu.l. In one embodiment, the
volume of the chamber comprising the drug formulation is about 150
.mu.l.
[0131] Drug particle formulations of the invention are preferably
chemically and physically stable for at least 1 month, preferably
at least 3 months, more preferably at least 6 months, more
preferably at least 12 months at delivery temperature. The delivery
temperature is typically normal human body temperature, for
example, about 37.degree. C., or slightly higher, for example,
about 40.degree. C. Further, drug particle formulations of the
present invention are preferably chemically and physically stable
for at least 3 months, preferably at least 6 months, more
preferably at least 12 months, at storage temperature. Examples of
storage temperatures include refrigeration temperature, for
example, about 5.degree. C.; or room temperature, for example,
about 25.degree. C.
[0132] A drug particle formulation may be considered chemically
stable if less than about 25%, preferably less than about 20%, more
preferably less than about 15%, more preferably less than about
10%, and more preferably less than about 5% breakdown products of
the drug particles are formed after about 3 months, preferably
after about 6 months, preferably after about 12 months at delivery
temperature and after about 6 months, after about 12 months, and
preferably after about 24 months at storage temperature.
[0133] A drug particle formulation may be considered physically
stable if less than about 10%, preferably less than about 5%, more
preferably less than about 3%, more preferably less than 1%
aggregates of the drug are formed after about 3 months, preferably
after about 6 months, at delivery temperature and about 6 months,
preferably about 12 months, at storage temperature.
[0134] When the drug in the drug particle formulation is a protein,
the protein solution is kept in a frozen condition and lyophilized
or spray dried to a solid state. Tg (glass transition temperature)
may be one factor to consider in achieving stable compositions of
protein. While not intending to be bound by any particular theory,
the theory of formation of a high Tg amorphous solid to stabilize
peptides, polypeptides, or proteins has been utilized in
pharmaceutical industry. Generally, if an amorphous solid has a
higher Tg, such as 100.degree. C., peptide products will not have
mobility when stored at room temp or even at 40.degree. C. because
the storage temperature is below the Tg. Calculations using
molecular information have shown that if a glass transition
temperature is above a storage temperature of 50.degree. C. that
there is zero mobility for molecules. Zero mobility of molecules
correlates with better stability. Tg is also dependent on the
moisture concentration in the product formulation. Generally, the
more moisture, the lower the Tg of the composition.
[0135] Accordingly, in some aspects of the present invention,
excipients with higher Tg may be included in the protein
formulation to improve stability, for example, sucrose
(Tg=75.degree. C.) and trehalose (Tg=110.degree. C.). Preferably,
particle formulations are formable into particles using processes
such as spray drying, lyophilization, desiccation, freeze-drying,
milling, granulation, ultrasonic drop creation, crystallization,
precipitation, or other techniques available in the art for forming
particles from a mixture of components. In one embodiment of the
invention the particles are spray dried. The particles are
preferably substantially uniform in shape and size.
[0136] The particles are typically sized such that they can be
delivered via an implantable osmotic drug delivery device. Uniform
shape and size of the particles typically helps to provide a
consistent and uniform rate of release from such a delivery device;
however, a particle preparation having a non-normal particle size
distribution profile may also be used. For example, in a typical
implantable osmotic delivery device having a delivery orifice, the
size of the particles is less than about 30%, more preferably is
less than about 20%, more preferably is less than about than 10%,
of the diameter of the delivery orifice. In an embodiment of the
particle formulation for use with an osmotic delivery system,
wherein the delivery orifice diameter of the implant is about 0.5
mm, particle sizes may be, for example, less than about 150 microns
to about 50 microns. In an embodiment of the particle formulation
for use with an osmotic delivery system, wherein the delivery
orifice diameter of the implant is about 0.1 mm, particle sizes may
be, for example, less than about 30 microns to about 10 microns. In
one embodiment, the orifice is about 0.25 mm (250 microns) and the
particle size is about 2 microns to about 5 microns.
[0137] Typically, the particles of the particle formulations, when
incorporated in a suspension vehicle, do not settle in less than
about 3 months, preferably do not settle in less than about 6
months, more preferably do not settle in less than about 12 months,
more preferably do not settle in less than about 24 months at
delivery temperature, and most preferably do not settle in less
than about 36 months at delivery temperature. The suspension
vehicles typically have a viscosity of between about 5,000 to about
30,000 poise, preferably between about 8,000 to about 25,000 poise,
more preferably between about 10,000 to about 20,000 poise. In one
embodiment, the suspension vehicle has a viscosity of about 15,000
poise, plus or minus about 3,000 poise. Generally speaking, smaller
particles tend to have a lower settling rate in viscous suspension
vehicles than larger particles. Accordingly, micron-to nano-sized
particles are typically desirable. In viscous suspension
formulation, particles of about 2 microns to about 7 microns of the
present invention will not settle for at least 20 years at room
temperature based on simulation modeling studies. In an embodiment
of the particle formulation of the present invention, for use in an
implantable osmotic delivery device, comprises particles of sizes
less than about 50 microns, more preferably less than about 10
microns, more preferably in a range from about 2 microns to about 7
microns.
[0138] In one embodiment, a drug particle formulation comprises a
drug, as described above, one or more stabilizers, and optionally a
buffer. The stabilizers may be, for example, carbohydrate,
antioxidant, amino acid, buffer, inorganic compound, or surfactant.
The amounts of stabilizers and buffer in the particle formulation
can be determined experimentally based on the activities of the
stabilizers and buffers and the desired characteristics of the
formulation, in view of the teachings of the present specification.
Typically, the amount of carbohydrate in the formulation is
determined by aggregation concerns. In general, the carbohydrate
amount should not be too high so as to avoid promoting crystal
growth in the presence of water due to excess carbohydrate unbound
to drug. Typically, the amount of antioxidant in the formulation is
determined by oxidation concerns, while the amount of amino acid in
the formulation is determined by oxidation concerns and/or
formability of particles during spray drying. Typically, the amount
of buffer in the formulation is determined by pre-processing
concerns, stability concerns, and formability of particles during
spray drying. Buffer may be required to stabilize drug during
processing, e.g., solution preparation and spray drying, when all
excipients are solubilized.
[0139] Examples of carbohydrates that may be included in the
particle formulation include, but are not limited to,
monosaccharides (e.g., fructose, maltose, galactose, glucose,
D-mannose, and sorbose), disaccharides (e.g., lactose, sucrose,
trehalose, and cellobiose), polysaccharides (e.g., raffinose,
melezitose, maltodextrins, dextrans, and starches), and alditols
(acyclic polyols; e.g., mannitol, xylitol, maltitol, lactitol,
xylitol sorbitol, pyranosyl sorbitol, and myoinsitol). Preferred
carbohydrates include disaccharides and/or non-reducing sugars,
such as sucrose, trehalose, and raffinose.
[0140] Examples of antioxidants that may be included in the
particle formulation include, but are not limited to, methionine,
ascorbic acid, sodium thiosulfate, catalase, platinum,
ethylenediaminetetraacetic acid (EDTA), citric acid, cysteins,
thioglycerol, thioglycolic acid, thiosorbitol, butylated
hydroxanisol, butylated hydroxyltoluene, and propyl gallate.
Further, amino acids that readily oxidize can be used as
antioxidants, for example, cysteine, methionine, and tryptophan. A
preferred antioxidant is methionine.
[0141] Examples of amino acids that may be included in the particle
formulation include, but are not limited to, arginine, methionine,
glycine, histidine, alanine, L-leucine, glutamic acid, iso-leucine,
L-threonine, 2-phenylamine, valine, norvaline, praline,
phenylalanine, trytophan, serine, asparagines, cysteine, tyrosine,
lysine, and norleucine. Preferred amino acids include those that
readily oxidize, e.g., cysteine, methionine, and trytophan.
[0142] Examples of buffers that may be included in the particle
formulation include, but are not limited to, citrate, histidine,
succinate, phosphate, maleate, tris, acetate, carbohydrate, and
gly-gly. Preferred buffers include citrate, histidine, succinate,
and tris.
[0143] Examples of inorganic compounds that may be included in the
particle formulation include, but are not limited to, NaCl,
Na.sub.2SO4, NaHCO.sub.3, KCl, KH.sub.2PO4, CaCl.sub.2, and
MgCl.sub.2.
[0144] In addition, the particle formulation may include other
excipients, such as surfactants, and salts. Examples of surfactants
include, but are not limited to, Polysorbate 20, Polysorbate 80,
PLURONIC.RTM. (BASF Corporation, Mount Olive, N.J.) F68, and sodium
docecyl sulfate (SDS). Examples of salts include, but are not
limited to, sodium chloride, calcium chloride, and magnesium
chloride.
[0145] All components included in the particle formulation are
typically acceptable for pharmaceutical use in mammals, in
particular, in humans.
[0146] In summary, a selected drug or combination of drugs is
formulated into dried powders in solid state, which preserve
maximum chemical and biological stability of the drug. The particle
formulation offers long-term storage stability at high temperature,
and therefore, allows delivery to a subject of stable and
biologically effective drug for extended periods of time.
[0147] 3.2.0 Vehicle Formulations and Suspension Formulations
[0148] In one aspect, the suspension vehicle provides a stable
environment in which the drug particle formulation is dispersed.
The drug particle formulations are chemically and physically stable
(as described above) in the suspension vehicle. The suspension
vehicle typically comprises one or more polymer and one or more
solvent that form a solution of sufficient viscosity to uniformly
suspend the particles comprising the drug. The suspension vehicle
may comprise further components, including, but not limited to,
surfactants, antioxidants, and/or other compounds soluble in the
vehicle.
[0149] The viscosity of the suspension vehicle is typically
sufficient to prevent the drug particle formulation from settling
during storage and use in a method of delivery, for example, in an
implantable, osmotic delivery device. The suspension vehicle is
biodegradable in that the suspension vehicle disintegrates or
breaks down over a period of time in response to a biological
environment, while the drug particle is dissolved in the biological
environment and the active pharmaceutical ingredient (i.e., the
drug) in the particle is absorbed.
[0150] The solvent in which the polymer is dissolved may affect
characteristics of the suspension formulation, such as the behavior
of drug particle formulation during storage. A solvent may be
selected in combination with a polymer so that the resulting
suspension vehicle exhibits phase separation upon contact with the
aqueous environment. In some embodiments of the invention, the
solvent may be selected in combination with the polymer so that the
resulting suspension vehicle exhibits phase separation upon contact
with the aqueous environment having less than approximately about
10% water.
[0151] The solvent may be an acceptable solvent that is not
miscible with water. The solvent may also be selected so that the
polymer is soluble in the solvent at high concentrations, such as
at a polymer concentration of greater than about 30%. Examples of
solvents useful in the practice of the present invention include,
but are not limited to, lauryl alcohol, benzyl benzoate, benzyl
alcohol, lauryl lactate, decanol (also called decyl alcohol), ethyl
hexyl lactate, and long chain (C.sub.8 to C.sub.24) aliphatic
alcohols, esters, or mixtures thereof. The solvent used in the
suspension vehicle may be "dry," in that it has a low moisture
content. Preferred solvents for use in formulation of the
suspension vehicle include lauryl lactate, lauryl alcohol, benzyl
benzoate, and mixtures thereof
[0152] Examples of polymers for formulation of the suspension
vehicles of the present invention include, but are not limited to,
a polyester (e.g., polylactic acid or polylacticpolyglycolic acid),
a polymer comprising pyrrolidones (e.g., polyvinylpyrrolidone
having a molecular weight ranging from approximately 2,000 to
approximately 1,000,000), ester or ether of an unsaturated alcohol
(e.g., vinyl acetate), polyoxyethylenepolyoxypropylene block
copolymer, or mixtures thereof. Polyvinylpyrrolidone can be
characterized by its K-value (e.g., K-17), which is a viscosity
index. In one embodiment, the polymer is polyvinylpyrrolidone
having a molecular weight of 2,000 to 1,000,000. In a preferred
embodiment the polymer is polyvinylpyrrolidone K-17 (typically
having an approximate average molecular weight range of
7,900-10,800). The polymer used in the suspension vehicle may
include one or more different polymers or may include different
grades of a single polymer. The polymer used in the suspension
vehicle may also be dry or have a low moisture content.
[0153] Generally speaking, a suspension vehicle for use in the
present invention may vary in composition based on the desired
performance characteristics. In one embodiment, the suspension
vehicle may comprise about 40 wt % to about 80 wt % polymer(s) and
about 20 wt % to about 60 wt % solvent(s). Preferred embodiments of
a suspension vehicle include vehicles formed of polymer(s) and
solvent(s) combined at the following ratios: about 25 wt % solvent
and about 75 wt % polymer; about 50 wt % solvent and about 50 wt %
polymer; about 75 wt % solvent and about 25 wt % polymer.
Accordingly, in some embodiments the suspension vehicle may
comprise selected components and in other embodiments consist
essentially of selected components.
[0154] The suspension vehicle may exhibit Newtonian behavior. The
suspension vehicle is typically formulated to provide a viscosity
that maintains a uniform dispersion of the particle formulation for
a predetermined period of time. This helps facilitate making a
suspension formulation tailored to provide controlled delivery of
the drug contained in the drug particle formulation. The viscosity
of the suspension vehicle may vary depending on the desired
application, the size and type of the particle formulation, and the
loading of the particle formulation in the suspension vehicle. The
viscosity of the suspension vehicle may be varied by altering the
type or relative amount of the solvent or polymer used.
[0155] The suspension vehicle may have a viscosity ranging from
about 100 poise to about 1,000,000 poise, preferably from about
1,000 poise to about 100,000 poise. In preferred embodiments, the
suspension vehicles typically have a viscosity, at 33.degree. C.,
of between about 5,000 to about 30,000 poise, preferably between
about 8,000 to about 25,000 poise, more preferably between about
10,000 to about 20,000 poise. In one embodiment, the suspension
vehicle has a viscosity of about 15,000 poise, plus or minus about
3,000 poise, at 33.degree. C. The viscosity may be measured at
33.degree. C., at a shear rate of 10.sup.-4/sec, using a parallel
plate rheometer.
[0156] The suspension vehicle may exhibit phase separation when
contacted with the aqueous environment; however, typically the
suspension vehicle exhibits substantially no phase separation as a
function of temperature. For example, at a temperature ranging from
approximately 0.degree. C. to approximately 70.degree. C. and upon
temperature cycling, such as cycling from 4.degree. C. to
37.degree. C. to 4.degree. C., the suspension vehicle typically
exhibits no phase separation.
[0157] The suspension vehicle may be prepared by combining the
polymer and the solvent under dry conditions, such as in a dry box.
The polymer and solvent may be combined at an elevated temperature,
such as from approximately 40.degree. C. to approximately
70.degree. C., and allowed to liquefy and form the single phase.
The ingredients may be blended under vacuum to remove air bubbles
produced from the dry ingredients. The ingredients may be combined
using a conventional mixer, such as a dual helix blade or similar
mixer, set at a speed of approximately 40 rpm. However, higher
speeds may also be used to mix the ingredients. Once a liquid
solution of the ingredients is achieved, the suspension vehicle may
be cooled to room temperature. Differential scanning calorimetry
(DSC) may be used to verify that the suspension vehicle is a single
phase. Further, the components of the vehicle (e.g., the solvent
and/or the polymer) may be treated to substantially reduce or
substantially remove peroxides (e.g., by treatment with methionine;
see, e.g., U.S., Patent Application Publication No.
2007-0027105).
[0158] The drug particle formulation is added to the suspension
vehicle to form a suspension formulation. In some embodiments the
suspension formulation may comprise a drug particle formulation and
a suspension vehicle and in other embodiments consist essentially
of a drug particle formulation and a suspension vehicle.
[0159] The suspension formulation may be prepared by dispersing the
particle formulation in the suspension vehicle. The suspension
vehicle may be heated and the particle formulation added to the
suspension vehicle under dry conditions. The ingredients may be
mixed under vacuum at an elevated temperature, such as from about
40.degree. C. to about 70.degree. C. The ingredients may be mixed
at a sufficient speed, such as from about 40 rpm to about 120 rpm,
and for a sufficient amount of time, such as about 15 minutes, to
achieve a uniform dispersion of the particle formulation in the
suspension vehicle. The mixer may be a dual helix blade or other
suitable mixer. The resulting mixture may be removed from the
mixer, sealed in a dry container to prevent water from
contaminating the suspension formulation, and allowed to cool to
room temperature before further use, for example, loading into an
implantable, drug delivery device, unit dose container, or
multiple-dose container.
[0160] The suspension formulation typically has an overall moisture
content of less than about 10 wt %, preferably less than about 5 wt
%, and more preferably less than about 4 wt %.
[0161] In preferred embodiments, the suspension formulations of the
present invention are substantially homogeneous and flowable to
provide delivery of the drug particle formulation from the osmotic
delivery device to the subject.
[0162] In summary, the components of the suspension vehicle provide
biocompatibility. Components of the suspension vehicle offer
suitable chemico-physical properties to form stable suspensions of
drug particle formulations. These properties include, but are not
limited to, the following: viscosity of the suspension; purity of
the vehicle; residual moisture of the vehicle; density of the
vehicle; compatibility with the dry powders; compatibility with
implantable devices; molecular weight of the polymer; stability of
the vehicle; and hydrophobicity and hydrophilicity of the vehicle.
These properties can be manipulated and controlled, for example, by
variation of the vehicle composition and manipulation of the ratio
of components used in the suspension vehicle.
[0163] 4.0.0 Delivery of Suspension Formulations
[0164] The suspension formulations described herein may be used in
an implantable, osmotic drug delivery device to provide zero-order,
continuous, controlled, and sustained delivery of a compound over
an extended period of time, such as over weeks, months, or up to
about one year or more. Such an implantable osmotic drug delivery
device is typically capable of delivering the suspension
formulation, comprising the drug, at a desired flow rate over a
desired period of time. The suspension formulation may be loaded
into the implantable, osmotic drug delivery device by conventional
techniques.
[0165] A dose and delivery rate can be selected to achieve a
desired blood concentration of a drug generally within less than
about 6 half-lives of the drug within the subject after
implantation of the device. The blood concentration of the drug is
selected to give the optimal therapeutic effects of the drug while
avoiding undesirable side effects that may be induced by excess
concentration of the drug, while at the same time avoiding peaks
and troughs that may induce side effects associated with peak or
trough plasma concentrations of the drug.
[0166] The implantable, osmotic drug delivery device typically
includes a reservoir having at least one orifice through which the
suspension formulation is delivered. The suspension formulation may
be stored within the reservoir. In a preferred embodiment, the
implantable, drug delivery device is an osmotic delivery device,
wherein delivery of the drug is osmotically driven. Some osmotic
delivery devices and their component parts have been described, for
example, the DUROS.RTM. delivery device or similar devices (see,
e.g., U.S. Pat. Nos. 5,609,885; 5,728,396; 5,985,305; 5,997,527;
6,113,938; 6,132,420; 6,156,331; 6,217,906; 6,261,584; 6,270,787;
6,287,295; 6,375,978; 6,395,292; 6,508,808; 6,544,252; 6,635,268;
6,682,522; 6,923,800; 6,939,556; 6,976,981; 6,997,922; 7,014,636;
7,207,982; 7,112,335; 7,163,688; U.S. Patent Publication Nos.
2005/0175701, 2007/0281024, 2008/0091176, and 2009/0202608).
[0167] The DUROS.RTM. delivery device typically consists of a
cylindrical reservoir which contains the osmotic engine, piston,
and drug formulation. The reservoir is capped at one end by a
controlled-rate, semi-permeable membrane and capped at the other
end by a diffusion moderator through which suspension formulation,
comprising the drug, is released from the drug reservoir. The
piston separates the drug formulation from the osmotic engine and
utilizes a seal to prevent the water in the osmotic engine
compartment from entering the drug reservoir. The diffusion
moderator is designed, in conjunction with the drug formulation, to
prevent body fluid from entering the drug reservoir through the
orifice.
[0168] The DUROS.RTM. device releases a drug at a predetermined
rate based on the principle of osmosis. Extracellular fluid enters
the DUROS.RTM. device through a semi-permeable membrane directly
into a salt engine that expands to drive the piston at a slow and
even delivery rate. Movement of the piston forces the drug
formulation to be released through the orifice or exit port at a
predetermined sheer rate. In one embodiment of the present
invention, the reservoir of the DUROS.RTM. device is load with a
suspension formulation wherein the device is capable of delivering
the suspension formulation to a subject over an extended period of
time (e.g., about 1, about 3, about 6, about 9, about 10, or about
12 months) at a pre-determined, therapeutically effective delivery
rate.
[0169] The release rate of the drug from the osmotic delivery
device typically provides a subject with a predetermined target
dose of a drug, for example, a therapeutically effective daily dose
delivered over the course of a day; that is, the release rate of
the drug from the device, provides substantial steady-state
delivery of the drug at a therapeutic concentration to the
subject.
[0170] Typically, for an osmotic delivery device, the volume of a
beneficial agent chamber comprising the beneficial agent
formulation is between about 100 .mu.l to about 1000 .mu.l, more
preferably between about 120 .mu.l and about 500 .mu.l, more
preferably between about 150 .mu.l and about 200 .mu.l.
[0171] Typically, the osmotic delivery device is implanted within
the subject, for example, subcutaneously to provide subcutaneous
drug delivery. The device(s) can be implanted subcutaneously into
either or both arms (e.g., in the inside, outside, or back of the
upper arm) or the abdomen. Preferred locations in the abdominal
area are under the abdominal skin in the area extending below the
ribs and above the belt line. To provide a number of locations for
implantation of one or more osmotic delivery device within the
abdomen, the abdominal wall can be divided into 4 quadrants as
follows: the upper right quadrant extending 5-8 centimeters below
the right ribs and about 5-8 centimeters to the right of the
midline, the lower right quadrant extending 5-8 centimeters above
the belt line and 5-8 centimeters to the right of the midline, the
upper left quadrant extending 5-8 centimeters below the left ribs
and about 5-8 centimeters to the left of the midline, and the lower
left quadrant extending 5-8 centimeters above the belt line and 5-8
centimeters to the left of the midline. This provides multiple
available locations for implantation of one or more devices on one
or more occasions. Implantation and removal of osmotic delivery
devices are generally carried out by medical professionals using
local anesthesia (e.g., lidocaine).
[0172] Termination of treatment by removal of an osmotic delivery
device from a subject is straightforward, and provides the
important advantage of immediate cessation of delivery of the drug
to the subject.
[0173] The suspension formulations may also be used in infusion
pumps, for example, the ALZET.RTM. (DURECT Corporation, Cupertino
Calif.) osmotic pumps which are miniature, infusion pumps for the
continuous dosing of laboratory animals (e.g., mice and rats).
[0174] 5.0.0 Exemplary Advantages of Certain Aspects of the Present
Invention
[0175] In one aspect, the present invention relates to methods of
treatment with continuous delivery of incretin mimetics (e.g.,
exenatide), for example, by use of an implantable osmotic delivery
device. Experiments described herein have demonstrated that
continuous delivery of exenatide using an implantable osmotic
delivery device, provided the following benefits for subjects in
need of treatment: treating type 2 diabetes mellitus, improving
glycemic control (as measured, e.g., by glucose levels, HbAlc,
and/or fructosamine), reducing HbAlc, reducing fasting plasma
glucose, reducing post-prandial blood glucose levels, reducing
adverse gastrointestinal events (e.g., nausea and vomiting)
relative to twice-daily injections, weight loss, reducing LDL-C,
reducing systolic blood pressure, treating hypertension, reducing
fructosamine levels, and improving of quality of life for subjects
undergoing treatment.
[0176] In addition, the continuous delivery of incretin mimetics
(e.g., exenatide) may be used in the practice of the following
methods: treating obesity, controlling appetite, reducing caloric
intake, reducing food intake, suppressing appetite, inducing
anorexia, treating impaired glucose tolerance, treating
post-prandial hyperglycemia, treating post-prandial dumping
syndrome, treating hyperglycemic conditions, reducing
triglycerides, reducing cholesterol, increasing urine flow,
decreasing potassium concentration in the urine, alleviating toxic
hypervolemia, inducing rapid diuresis, pre-surgical patient
preparation, post-surgical patient treatment, increasing renal
plasma flow and glomerular filtration rate, treating pre-eclampsia
or eclampsia during pregnancy, increasing cardiac contractility,
treating renal failure, treating congestive heart failure, treating
nephrotic syndrome, treating pulmonary edema, treating systemic
edema, treating cirrhosis, treating impaired glucose tolerance,
treating pre-diabetes (blood glucose levels that are higher than
normal but not yet high enough to be diagnosed as diabetes),
treating type 1 diabetes mellitus (e.g., in combination with
insulin), reducing risk of a cardiovascular event due to impaired
glucose tolerance, reducing risk of a cerebrovascular event due to
impaired glucose tolerance, delaying the progression of diabetes,
ameliorating diabetes, delaying diabetes onset, inducing 1 cell
regeneration, restoring normoglycemia, providing euglycemic
control, treating peripheral vascular disease, treating acute
coronary syndrome, treating cardiomyopathy, treating gestational
diabetes, treating polycystic ovary syndrome, treating or
preventing nephropathy, and treating diabetes induced by a variety
of diseases or conditions (for example, steroid induced diabetes,
human immunodeficiency virus treatment-induced diabetes, latent
autoimmune diabetes in adults, nonalcoholic steatohepatitis,
nonalcoholic fatty liver disease, hypoglycemia unawareness,
restrictive lung disease, chronic obstructive pulmonary disease,
lipoatrophy and metabolic syndrome).
[0177] The present invention also provides treatment methods for
delivery of an incretin mimetic having the following advantages.
The continuous delivery from, for example, an osmotic delivery
device, ensures 100% treatment compliance for subjects and avoids
the need for twice-daily, daily, weekly, or even monthly injections
because the devices described herein can deliver an incretin
mimetic for time periods of up to a about year or more. The
avoidance of self-injection is a particular advantage for a subject
who is needle phobic. Further, use of implantable devices for
continuous delivery provides treatment convenience and avoids
scheduling conflicts, for example, with meals, and also eliminates
the inconvenience of administration of a drug by injection, for
example, when subjects are in public or busy with daily activities.
Also, frequent self-administration of a drug reminds subjects of
their disease state and carries a stigma associated with the
disease and/or treatment; whereas continuous delivery of a drug
from an implanted osmotic device may offer subjects some respite
from such reminders and stigma.
[0178] The present invention also provides methods to treat
subjects at dosage levels of incretin mimetics previously thought
to be higher than tolerable dosage levels. For example, continuous
delivery of exenatide is described herein for dosages tolerated at
least up to 80 mcg/day.
[0179] In another aspect the present invention provides methods of
dosage escalation. In one embodiment, multiple devices for
continuous delivery of a drug, for example, an incretin mimetic,
are provided. Each device is capable of delivering a particular
drug dose per day. A low-dose device is initially implanted,
followed by removal and implantation of a higher daily dose device.
Alternatively, the first device may be kept in place and a second
device implanted to increase the daily dose. In another
alternative, a subject may be started by dosing with an injectable
form of the drug (e.g., twice-daily, once-daily, once-weekly, or
once- or twice-monthly injection) and transitioned to an
implantable device to provide continuous delivery after an initial
period. Such transitioning from injectable to implantable may, for
example, allow subjects or physicians to try a drug and perhaps be
observed for any immediate adverse effects before implantation of a
device. Injectable to implantable transitions may also be useful
for treatment of subjects who are particularly nervous about
possible drug side effects. Also, providing the drug by injection
or by continuous delivery at low dose may permit tolerization of
the drug at low dose before changing to higher and more efficacious
therapeutic doses.
[0180] Optimal time periods are determined for a drug concerning
how long an initial device remains in place before replacement with
a higher dose delivery device. Similarly optimal time periods are
determined for how long an initial phase of treatment by injection
goes on before implantation of an osmotic delivery device. For
example, treatment is commenced at a low dose with low incidence of
side effects (e.g., for about 2 weeks, about 3 months, about 6
months, about 9 months, about a year). The subject adjusts to that
dose and subsequently a higher dose delivery device is implanted
providing dose escalation. Alternatively, a subject who has been
treated with an injectable form dose escalates to an implantable
osmotic delivery device. Such dose escalations were shown from the
data presented herein to achieve additional benefits in glucose
regulation and weight loss. Examples of initial dosages include,
but are not limited to, delivery of about 1 mcg/day to about 20
mcg/day, followed by dose escalation to about 5 mcg/day to about
1,000 mcg/day. Preferably, escalation of incretin mimetic doses
include, but are not limited to, the following: about 10 mcg/day
followed by about 20 mcg/day; about 10 mcg/day followed by about 40
mcg/day; about 10 mcg/day followed by about 60 mcg/day; about 10
mcg/day followed by about 80 mcg/day; about 20 mcg/day followed by
about 40 mcg/day; about 20 mcg/day followed by about 60 mcg/day;
about 20 mcg/day followed by about 80 mcg/day; about 40 mcg/day
followed by about 60 mcg/day; about 40 mcg/day followed by about 80
mcg/day; and about 60 mcg/day followed by about 80 mcg/day. In one
embodiment, the present invention includes kits and methods for
manufacturing kits comprising one or more lower dose osmotic
delivery devices and one or more higher dose osmotic delivery
devices (the lower and higher dosages being relative to the other
devices in the kit). Such kits may optionally include an implanter,
lidocaine, and sterile field/supplies.
[0181] Generally, dose escalation is from a low dose of incretin
mimetic, for example, about 1 mcg/day to about 30 mcg/day, to a
high dose of greater than the low dose to about 80 mcg/day.
[0182] In another aspect, the present invention provides a method
of treating diabetes without a substantial increase in insulin
secretion using an incretin mimetic. In a preferred embodiment of
this aspect of the present invention the incretin mimetic is
exenatide. Data obtained in the course of the studies described
herein demonstrated that, at higher doses of continuous delivery of
exenatide (e.g., 20 mcg/day, 40 mcg/day, and 80 mcg/day), effective
treatment of diabetes was achieved in the absence of an increase in
insulin production. Insulin levels were measured by
radioimmunoassay.
[0183] In another aspect, the methods of the present invention
allow for the administration of a drug, e.g., an incretin mimetic,
without a substantial initial drug burst that typically occurs with
depot injections (e.g., initial drug burst of from about 5% of
total drug in depot formulation to about 1% of total drug in depot
formulation) that provide sustained delivery over a period of time
(e.g., depot injections formulated using poly(lactides),
poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s,
poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s and
blends and copolymers thereof).
[0184] In a further aspect the present invention is directed to
methods of providing greater reduction in plasma blood glucose in a
shorter time period (e.g. within 1-5 days) than can be achieved
using twice-daily daily injections, comprising providing continuous
delivery of an incretin mimetic, for example, exenatide. In one
embodiment, continuous delivery is achieved by use of an
implantable osmotic delivery device.
[0185] Another advantage of the present invention is the ability to
remove the delivery device providing continuous delivery of the
drug and provide rapid termination of drug delivery for any reason,
for example, in the case of myocardial infarction, pregnancy,
pancreatitis or suspected pancreatitis, emergency medical care
(e.g., termination of drug therapies), or adverse drug
reactions.
[0186] The present invention uniquely addresses unmet needs
relative to injectable incretin mimetics. For example, one
shortcoming of twice-daily injectable exenatide is that greater
than 65% of subjects are not treated to or maintained at HbAlc
treatment goals. Another disadvantage of twice-daily injectable
exenatide is that greater than 65% of these subjects become
noncompliant between 6-12 months when attempting to adhere to the
injection treatment schedule. Also, 65% of subjects treated with
twice-daily injectable exenatide are overweight and need sustained
weight loss.
[0187] Experiments described herein (e.g., Example 3) demonstrated
that the methods of and osmotic devices comprising an incretin
mimetic for use in methods of treating type 2 diabetes mellitus by
continuous delivery as set forth by the present invention provide
sustained treatment of subjects at target doses, complete subject
compliance with the treatment, and sustained weight loss. A target
dose typically provides substantial steady-state delivery of the
incretin mimetic at a therapeutic concentration to the subject.
[0188] The data presented in the Experimental section herein
demonstrate that the present invention provides methods of and
osmotic devices comprising incretin mimetics for use in methods of
treating type 2 diabetes mellitus by continuous delivery, wherein
substantial steady-state delivery of the incretin mimetic at
therapeutic concentrations is achieved within a time period of
about 7 days or less, about 6 days or less, about 5 days or less,
about 4 days or less, about 3 days or less, preferably about 2 days
or less, and more preferably about 1 day or less, after
implantation of the osmotic delivery device in the subject.
[0189] The data also demonstrate that the present invention
provides methods of and osmotic devices comprising incretin
mimetics for use in methods of treating type 2 diabetes mellitus by
continuous delivery, wherein a significant decrease in fasting
plasma glucose concentration, relative to the fasting plasma
glucose concentration before implantation, is achieved after
implantation of the osmotic delivery device in the subject within a
time period of about 7 days or less, about 6 days or less, about 5
days or less, about 4 days or less, about 3 days or less,
preferably about 2 days or less, and more preferably about 1 day or
less, after implantation of the osmotic delivery device in the
subject.
[0190] The data also demonstrate that the present invention
provides the capability to terminate the continuous delivery such
that the concentration of an incretin mimetic is substantially
undetectable in a blood sample from the subject, after termination
of continuous delivery, in less than about 6 half-lives of the drug
after termination of continuous delivery, in less than about 5
half-lives of the drug after termination of continuous delivery, in
less than about 4 half-lives of the drug after termination of
continuous delivery, or in less than about 3 half-lives of the drug
after termination of continuous delivery. Further, the data show
that treatment by continuous delivery of an incretin mimetic
provided better decreases in HbAlc than treatment by injection.
[0191] Also, the data illustrate that the methods of and osmotic
devices comprising an incretin mimetic for use in methods of
treating type 2 diabetes mellitus by continuous delivery as
described herein provide improved tolerization to dose escalation
of the incretin mimetic relative to injection of the incretin
mimetic.
[0192] In addition, these data presented herein demonstrate a
significant advantage of the implanted osmotic delivery device of
the present invention over incretin mimetic administration via
injection in terms of reported quality of life for treated
subjects.
[0193] The comparative data described below demonstrate the
superior treatment outcomes using the methods of and osmotic
devices comprising an incretin mimetic for use in methods of
treating type 2 diabetes mellitus by continuous delivery of the
present invention, in combination with metformin therapy, relative
to other treatment methods. Such other treatment methods include
twice-daily injection of exenatide, once-weekly injection of
exenatide, once-daily injection of liraglutide, once-weekly
injection of taspoglutide, once-daily orally administered
sitagliptin, and once-daily orally administered pioglitazone.
[0194] In summary, the methods of and osmotic devices comprising an
incretin mimetic, for example, exenatide, for use in methods of
treating type 2 diabetes mellitus by continuous delivery as
described herein provide a new standard of effective treatment. The
present invention provides superior HbAlc reduction, improved
weight loss, and complete compliance, as well as long-term glycemic
control relative to the use of dipeptidyl peptidase-4 (DPP-4)
inhibitors (e.g., sitagliptin), thiazolidinediones (TZDs) (e.g.,
pioglitazone), other injectable incretin mimetics (e.g.,
liraglutide and taspoglutide), and twice-daily or once-weekly
injection of exenatide. Further, the present invention provides
better incretin mimetic treatment tolerability because no
self-injections are required and the methods of and osmotic devices
comprising an incretin mimetic for use in methods of treating type
2 diabetes mellitus by continuous delivery provide improved
gastrointestinal tolerance.
Experimental
[0195] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to practice the present invention, and are not
intended to limit the scope of what the inventors regard as the
invention. Efforts have been made to ensure accuracy with respect
to numbers used (e.g., amounts, concentrations, percent changes,
etc.) but some experimental errors and deviations should be
accounted for. Unless indicated otherwise, temperature is in
degrees Centigrade and pressure is at or near atmospheric.
[0196] The compositions used to practice the methods of the present
invention meet the specifications for content and purity required
of pharmaceutical products. Further examples of suspension
formulations comprising incretin mimetics can be found in U.S.
Patent Publication Nos. 2006/0193918, 2008/0260840, and
2010/0092566.
EXAMPLE 1
Description of a Typical Osmotic Delivery Device
[0197] Suspension formulations comprising exenatide particles
suspended in solvent/polymer vehicles were developed for the
treatment of type 2 diabetes mellitus. Suspension formulations were
loaded into a DUROS.RTM. device for subcutaneous implantation to
deliver exenatide at a continuous and consistent rate.
[0198] FIG. 4 depicts an example of a DUROS.RTM. delivery system
useful in the practice of the present invention. In FIG. 4, the
osmotic delivery device 10 is shown comprising a reservoir 12. A
piston assembly 14 is positioned in the lumen of the reservoir and
divides the lumen into two chambers. In this example, the chamber
16 contains a beneficial agent formulation and the chamber 20
contains an osmotic agent formulation. A semi-permeable membrane 18
is positioned at a first distal end of the reservoir, adjacent the
chamber 20 containing the osmotic agent formulation. A diffusion
moderator 22 is positioned in mating relationship at a second
distal end of the reservoir 12, adjacent the chamber 16 containing
the suspension formulation, comprising the drug. The diffusion
moderator 22 includes a delivery orifice 24. The diffusion
moderator 22 may be any suitable flow device having a delivery
orifice. In this embodiment, the flow path 26 is formed between a
threaded diffusion moderator 22 and threads 28 formed on the
interior surface of the reservoir 12. In alternative embodiments,
the diffusion moderator can, for example, (i) be press-fit (or
friction fit) through an opening and contacting a smooth interior
surface of the reservoir, or (ii) comprise two pieces with an outer
shell constructed and arranged for positioning in an opening, an
inner core inserted in the outer shell, and a fluid channel having
a spiral shape defined between the outer shell and the inner core
(e.g., U.S. Patent Publication No. 2007/0281024).
[0199] Fluid is imbibed into the chamber 20 through the
semi-permeable membrane 18. The beneficial agent formulation is
dispensed from the chamber 16 through the delivery orifice 24 in
the diffusion moderator 22. The piston assembly 14 engages and
seals against the interior wall of the reservoir 12, thereby
isolating the osmotic agent formulation in chamber 20 and fluid
imbibed through the semi-permeable membrane 18 from the beneficial
agent formulation in chamber 16. At steady-state, the suspension
formulation is released through the delivery orifice 24 in the
diffusion moderator 22 at a rate corresponding to the rate at which
external fluid is imbibed into the chamber 20 through the
semi-permeable membrane 18. That is, the DUROS.RTM. delivery device
releases drug at a predetermined rate based on the principle of
osmosis. Extracellular fluid enters the DUROS.RTM. delivery device
through the semi-permeable membrane directly into the osmotic
engine that expands to drive the piston at a slow and consistent
rate of travel. Movement of the piston forces the drug formulation
to be released through the orifice of the diffusion moderator.
[0200] The semi-permeable membrane 18 may be in the form of a plug
that is resiliently engaged in sealing relationship with the
interior surface of the reservoir 12. In FIG. 4, it is shown to
have ridges that serve to frictionally engage the semi-permeable
membrane 18 with the interior surface of the reservoir 12.
[0201] These DUROS.RTM. delivery devices allow for zero-order,
continuous, and controlled subcutaneous delivery of exenatide at
consistent rate, which provides several advantages as a treatment
of type 2 diabetes mellitus; for example, relatively constant blood
therapeutic concentrations of exenatide allow for better control of
blood glucose concentrations and may moderate the risk of secondary
disease otherwise associated with poorly controlled type 2 diabetes
mellitus. These DUROS.RTM. delivery devices provide treatment
durations of about 3 to about 12 months over a broad range of
dosages with preserved stability of the exenatide.
[0202] Unlike daily or twice-daily injections of exenatide, the
DUROS.RTM. delivery devices maintain consistent blood
concentrations of exenatide. This is particularly important during
all meal periods and overnight. The DUROS.RTM. delivery device does
not require any action on the part of the subject to ensure
therapeutic compliance.
[0203] In addition, these DUROS.RTM. delivery devices may have
safety advantages compared to daily or twice-daily injections of
exenatide or depot formulations of exenatide. Zero-order delivery
eliminates the peak blood concentrations of exenatide typically
observed with daily or twice-daily injections that appear to be
associated with adverse reactions, e.g., frequent nausea, and the
trough concentrations that may be associated with reduced efficacy.
A further desirable feature of these DUROS.RTM. delivery devices is
that they can be quickly and easily removed in a doctor's office to
terminate drug administration in the event of adverse drug reaction
or any event requiring cessation of treatment.
EXAMPLE 2
Phase 1b Clinical Trial Data for Continuous Delivery of
Exenatide
[0204] A b 1b clinical trial was designed as a multi-center,
randomized, open-label study with three sites and a total of 44
subjects. The Phase 1b clinical trial was designed and conducted to
evaluate the safety and tolerability of continuous subcutaneous
delivery of unmodified, synthetic exenatide having the amino acid
sequence of exendin-4 via DUROS.RTM. delivery devices (ITCA 650) in
subjects with inadequately controlled type 2 diabetes mellitus. In
this study, osmotic delivery devices were implanted subcutaneously
in the abdominal area under the abdominal skin.
[0205] In the study, subjects were randomized to receive doses of
10 mcg/day, 20 mcg/day, 40 mcg/day, or 80 mcg/day of ITCA 650.
There were 10-12 subjects per group for each of four dose groups.
Treatment was for 28 days with a 7-day follow-up period. Thus, this
was a 29-day study that corresponded to a total of 28 days of
treatment.
[0206] A. Demographics of Study Group
[0207] Inclusion/exclusion criteria were as follows: subjects were
30-70 years of age and diagnosed as having type 2 diabetes mellitus
for greater than 6 months prior to screening. Subjects had
inadequately controlled type 2 diabetes mellitus but were on stable
treatment regimens of diet and exercise alone or in combination
with metformin monotherapy, TZD monotherapy, or metformin plus TZD
combination therapy. Subjects' hemoglobin Alc (HbAlc) levels were
greater than or equal to 6.5% and less than or equal to 10%.
Subjects had fasting plasma glucose of less than 270 mg/dL and
fasting C-peptide of greater than 0.8 ng/ml.
[0208] The following 4 dose groups were investigated: Group 1, 10
mcg/day exenatide delivered by DUROS.RTM. delivery devices; Group
2, 20 mcg/day exenatide delivered by DUROS.RTM. delivery devices;
Group 3, 40 mcg/day exenatide delivered by DUROS.RTM. delivery
devices; and Group 4, 80 mcg/day exenatide delivered by DUROS.RTM.
delivery devices.
[0209] The demographics of the study groups are presented in Table
1.
TABLE-US-00001 TABLE 1 Group 1 Group 2 Group 3 Group 4 Age (years)
Mean 56.4 57.4 52.1 56.7 Range 44-68 47-70 37-67 49-63 Sex (M/F)
8/4 7/4 4/6 7/4 Weight (kg) Mean 95.7 94.3 88.5 89.5 Range
75.5-130.2 55.7-120.4 56.1-125.8 58.1-130.3 HbA1c (%) Mean 7.7%
7.9% 7.4% 7.4% Range 6.5-10.2 6.7-9.8 6.5-9.4 6.6-9.4 Previous
Treatment: Diet & Exercise 8.3% .sup. 20.0% .sup. 36.4%
Metformin .sup. 91.7% .sup. 90.9% .sup. 80.0% .sup. 45.4% Metformin
+ 9.1% .sup. 18.2% TZD
[0210] The disposition of the subjects in the study is presented in
Table 2.
TABLE-US-00002 TABLE 2 Group 1 Group 2 Group 3 Group 4 n 12 11 10
11 Completed the Study 11 (92%) 11 (100%) 10 (100%) 7 (64%)
Subjects Discontinued 1 (8%) 0 (0%) 0 (0%) 4 (36%) Adverse Events 1
0 0 1 Withdrew Consent 0 0 0 3
[0211] B. Pharmacodynamic Data
[0212] The following pharmacodynamic measurement data were obtained
from the study of exenatide delivered by DUROS.RTM. delivery
devices.
[0213] Fasting plasma glucose (determined by standard methods)
decreased within 24 hours (FIG. 1) following initiation of
treatment (i.e., implantation of the DUROS.RTM. delivery devices)
and was significantly different from baseline to endpoint in the 20
mcg/day group, the 40 mcg/day group, and the 80 mcg/day group as
shown in Table 3. In Table 3 the data are shown from the
randomized, open-label 29-day study of continuous subcutaneous
delivery of exenatide using an osmotic delivery device. The table
shows the change in fasting plasma glucose concentrations at the
end of the 28-day treatment for osmotic devices delivering 10
mcg/day, 20 mcg/day, 40 mcg/day, and 80 mcg/day. Mean values in the
table are given in mg/dL units. The decreases in fasting plasma
glucose concentrations for the osmotic devices delivering 20
mcg/day, 40 mcg/day, and 80 mcg/day were statistically
significant.
[0214] Accordingly, in one embodiment, the present invention
relates to methods of and osmotic devices comprising exenatide for
use in methods of treating type 2 diabetes mellitus by continuous
delivery of exenatide wherein substantial steady-state delivery of
the exenatide at therapeutic concentrations is achieved within a
time period of about 7 days or less, preferably about 2 days or
less, and more preferably about 1 day or less, after implantation
of the osmotic delivery device in the subject. In a related
embodiment the invention provides a significant decrease in fasting
plasma glucose concentration, relative to the fasting plasma
glucose concentration before implantation, achieved after
implantation of the osmotic delivery device in the subject within a
time period of about 7 days or less, preferably about 2 days or
less, and more preferably about 1 day or less, after implantation
of the osmotic delivery device in the subject.
TABLE-US-00003 TABLE 3 Mean .+-. S.D. p-value 10 mcg/day -5.6 .+-.
34.33 0.5175 20 mcg/day -31.2 .+-. 24.20 0.0039 40 mcg/day -42.0
.+-. 33.16 0.0003 80 mcg/day -28.8 .+-. 32.25 0.0014
[0215] Treatment with exenatide delivered by DUROS.RTM. delivery
devices at 20 mcg/day, 40 mcg/day and 80 mcg/day resulted in
clinically and significant mean reductions in two-hour
post-prandial glucose from pre-treatment to endpoint as shown in
Table 4. An obvious dose-response relationship was observed.
Measurement of reductions in two-hour post-prandial glucose was
performed by standard methods. In Table 4 the data show the change
in 2-hour postprandial glucose concentrations at the end of the
28-day treatment for osmotic devices delivering 10 mcg/day, 20
mcg/day, 40 mcg/day, and 80 mcg/day. Mean values in the table are
given in mg/dL units. The decreases in 2 hour postprandial glucose
concentrations for the osmotic devices delivering 20 mcg/day, 40
mcg/day, and 80 mcg/day were statistically significant.
TABLE-US-00004 TABLE 4 Mean .+-. S.D. p-value 10 mcg/day -16.3 .+-.
24.78 0.1699 20 mcg/day -34.7 .+-. 32.39 0.0135 40 mcg/day -47.1
.+-. 70.45 0.0012 80 mcg/day -69.6 .+-. 44.35 <0.0001
[0216] Glucose AUC (area under the curve) and the ratio of endpoint
over pre-treatment was significantly different from baseline AUC in
the 20 mcg/day group, the 40 mcg/day group, and the 80 mcg/day
group; there was a trend toward reduction in these parameters at
the 10 mcg/day dose. AUC calculations were performed by standard
methods.
[0217] After implantation of the DUROS.RTM. delivery devices,
exenatide plasma concentrations rose to the steady-state exposure
concentration within 24-48 hours and were maintained throughout the
treatment period (FIG. 2). Following removal of the DUROS.RTM.
delivery devices, exenatide concentrations fell to undetectable
concentrations within 24 hours (FIG. 2). Exenatide was detected
using a radioimmunoassay. Accordingly, in one embodiment, the
present invention relates to methods of and osmotic devices
comprising exenatide for use in methods of treating type 2 diabetes
mellitus by continuous delivery of exenatide that provide the
capability to terminate the continuous delivery such that the
concentration of exenatide is substantially undetectable in a blood
sample from the subject after termination of continuous delivery in
less than about 72 hours, preferably less than about 24.
[0218] HbAlc (as shown in Table 5) and fructosamine levels were
significantly different from baseline to endpoint in the all
treatment groups. HblAc and fructosamine determinations were made
by standard methods. In Table 5 the data are shown from the
randomized, open-label 29-day study of continuous subcutaneous
delivery of exenatide using an osmotic delivery device. The table
shows the change in HbAlc at day 29 (relative to day 1 of the
study; i.e., the initiation of continuous delivery) for osmotic
devices delivering 10 mcg/day, 20 mcg/day, 40 mcg/day, and 80
mcg/day. Mean values in the table are change in HbAlc plus or minus
the standard deviation (S.D.). The decreases in HbAlc for all
osmotic devices (i.e., delivering 10 mcg/day, 20 mcg/day, 40
mcg/day, and 80 mcg/day) were statistically significant.
TABLE-US-00005 TABLE 5 Mean Change in Dose HbA1c .+-. S.D. p-value
10 mcg/day -0.54 .+-. 0.39 0.0010 20 mcg/day -0.62 .+-. 0.31
<0.0001 40 mcg/day -0.45 .+-. 0.31 0.0013 80 mcg/day -0.73 .+-.
0.36 0.0018
[0219] Body weight decreased in all treatment groups and was
significantly different from baseline to endpoint in the 80 mcg/day
group (Table 6). In Table 6 the data are shown from the randomized,
open-label 29-day study of continuous subcutaneous delivery of
exenatide using an osmotic delivery device. The table shows the
change in body weight at the end of the 28-day treatment for
osmotic devices delivering 10 mcg/day, 20 mcg/day, 40 mcg/day, and
80 mcg/day. Mean values in the table are given in kilograms
(kg).
TABLE-US-00006 TABLE 6 Dose Mean .+-. S.D. p-value 10 mcg/day -0.27
.+-. .91 0.3415 20 mcg/day -0.28 .+-. 1.51 0.5485 40 mcg/day -1.13
.+-. 1.60 0.0524 80 mcg/day -3.09 .+-. 2.13 0.0086
[0220] While there was an apparent dose-response relationship with
respect to gastrointestinal adverse events (nausea and vomiting),
these effects occurred early after implantation of the device(s)
and abated within the first week in most subjects. The data for
nausea versus time in individual subjects is presented in FIG.
3.
[0221] In summary, therapy with exenatide delivered using
DUROS.RTM. delivery devices at doses of 10, 20, and 40 mcg/day was
well tolerated for 28 days of treatment. Steady-state
concentrations of exenatide were rapidly achieved and maintained
throughout the course of treatment. Removal of the DUROS.RTM.
delivery devices provided rapid termination of treatment and
exenatide concentrations fell to undetectable concentrations within
24 hours. Significant decreases in fasting plasma glucose and
2-hour post-prandial glucose were observed within 1-5 days and were
maintained throughout the 28-day treatment period in the 20, 40, 80
mcg/day dose groups. Significant decreases in HbAlc were observed
in all treatment groups. Body weight decreased in all treatment
groups.
[0222] Treatment of subjects having type 2 diabetes mellitus with
the DUROS.RTM. delivery devices providing 10 mcg/day, 20 mcg/day,
40 mcg/day, and 80 mcg/day was safe and well-tolerated; no
clinically significant treatment-associated trends in safety, vital
signs, or physical examination findings were observed. While there
was an apparent dose-response relationship with respect to
gastrointestinal adverse events (nausea and vomiting), these
effects appeared to occur early (within the first week) after
implantation of the device(s) and tended to abate with time.
[0223] These data demonstrated that DUROS.RTM. delivery devices
providing continuous delivery of exenatide offered the following
benefits: highly effective control of glucose; reduction in
frequency, severity, and persistence of side effects; elimination
of need for self-injection; significant weight loss; and 100%
compliance with prescribed therapy. Further advantages for
treatment of type 2 diabetes mellitus with these devices were the
ability to rapidly achieve steady-state therapeutic concentrations
of exenatide in a subject after implantation; the ability to
provide long-term steady-state delivery of exenatide; the ability
to provide a significant decrease in fasting plasma glucose
concentration (relative to the fasting plasma glucose concentration
before implantation of the osmotic device); and the capability of
quickly terminating treatment if desirable.
EXAMPLE 3
Phase 2 Clinical Trial Data for Continuous Delivery of
Exenatide
[0224] A Phase 2 clinical trial was designed as a multi-center
randomized, open-label study with 50 sites and a total of 155
subjects. The Phase 2 study was designed and conducted to compare
the efficacy, safety and tolerability of treatment with continuous
subcutaneous delivery of unmodified, synthetic exenatide having the
amino acid sequence of exendin-4 via DUROS.RTM. delivery devices
(ITCA 650) versus twice-daily injections of unmodified, synthetic
exenatide having the amino acid sequence of exendin-4 in subjects
with inadequately controlled, metformin-treated type 2 diabetes
mellitus. In the study, subjects were initially randomized to
receive either 20 or 40 mcg/day of ITCA 650 for 12 weeks or
twice-daily (BID) exenatide injections at 5 mcg BID for 4 weeks
followed by 10 mcg BID for 8 weeks. Subsequently, subjects were
randomized to receive 20, 40, 60 or 80 mcg/day of ITCA 650 for an
additional 12 weeks. In this study, osmotic delivery devices (ITCA
650) were implanted subcutaneously in the abdominal area under the
abdominal skin.
[0225] There were approximately 50 subjects per group for each of
three groups as follows: Group 1, a group treated with implanted
osmotic delivery devices of the present invention that delivered 20
mcg/day; Group 2, a group treated with implanted osmotic delivery
devices of the present invention that delivered 40 mcg/day; and
Group 3, a group treated with twice-daily exenatide injections at 5
mcg BID for 4 weeks followed by 10 mcg BID for 8 weeks. An overview
of the study design is presented in FIG. 5. The extension phase was
weeks 13-24 and the groups were randomized 1:1 to continuous
delivery of exenatide as indicated in the figure. At the beginning
of the extension phase for each subject, any implanted osmotic
delivery device was removed and an osmotic delivery device
providing continuous delivery of exenatide at the assigned dose was
implanted. For example, if a subject was initially in Group 1 being
treated by continuous delivery of exenatide at 20 mcg/day and was
being increased to a dose of 60 mcg/day, then at the beginning of
the extension phase the osmotic device delivering 20 mcg/day was
removed and a new device delivering 60 mcg/day was implanted. For
subjects initially being treated by injection, the injections were
discontinued and osmotic delivery devices were implanted at the
beginning of the extension phase. The study was completed on 15
July 2010.
[0226] Accordingly, results of the Phase 2 study allow evaluation
of the safety and efficacy of treatment using continuous delivery
of exenatide versus exenatide twice-daily injections in type 2
diabetes mellitus over a 13-24 week treatment period. Further, the
study allows evaluation of treatment dose escalation by continuous
delivery of exenatide and the ability to transition subjects from
treatment with exenatide twice-daily injections to treatment by
continuous delivery.
[0227] A. Demographics of Study Group
[0228] Inclusion/exclusion criteria were as follows. Subjects were
18-70 years of age and diagnosed as having type 2 diabetes mellitus
for greater than 6 months prior to screening. Subjects had
inadequately controlled type 2 diabetes mellitus but were on stable
treatment regimens of diet and exercise alone or in combination
with metformin monotherapy. Subjects' HbAlc levels were greater
than or equal to 7.0% and less than or equal to 10%. Subjects had
fasting plasma glucose of less than 240 mg/dL and a body/mass index
(BMI) of less than or equal to 40 kg/m.sup.2.
[0229] The demographics of the study groups are presented in Table
7.
TABLE-US-00007 TABLE 7 Group 1 Group 2 Group 3 N (sample size) 51
51 53 Age (years) 54.0 53.3 53.8 Gender (M/F) 25/26 23/28 29/24
Duration of Diabetes 6.2 8.4 5.2 (years) HbA1c (%) 7.9 8.0 8.0
Weight (kg) 93.5 91.5 93.4 BMI (kg/m.sup.2) 33.5 31.8 33.0
[0230] The disposition of the subjects in the study at 12 weeks is
presented in Table 8.
TABLE-US-00008 TABLE 8 Group 1 Group 2 Group 3 Total N (%) N (%) N
(%) N (%) Randomized 51 51 53 155 and treated Completed 47 (92.2)
48 (94.1) 47 (88.7) 142 (91.6) treatment Early 4 (7.8) 3 (5.9) 6
(11.3) 13 (8.4) Withdrawal Withdrew 2 (3.9) 1 (2.0) 2 (3.8) 5 (3.2)
Consent Adverse 1 (2.0) 2 (3.9) 2 (3.8) 5 (3.2) Event Other 1 (2.0)
0 (0.0) 2 (3.8) 3 (1.9)
[0231] B. Pharmacodynamic Data
[0232] (i) Data at Week 12
[0233] The following pharmacodynamic measurement data were obtained
from this Phase 2 clinical study of exenatide.
[0234] The changes in HbAlc after 12 weeks of treatment are
presented in Table 9.
TABLE-US-00009 TABLE 9 Baseline Week 12 Change in Sample Size HbA1c
% HbA1c % HbA1c Group 1 n = 47 7.90 6.94 -0.96* Group 2 n = 47 8.00
6.96 -1.04* Group 3 n = 47 8.01 7.19 -0.82* *p < 0.001 relative
to baseline
[0235] The data demonstrated that after 12 weeks of treatment all
groups showed a reduction in HbAlc from baseline to endpoint.
Exenatide treatment by continuous delivery (Groups 1 and 2)
provided better decreases in HbAlc than exenatide treatment by
injection (Group 3). All decreases in HbAlc were statistically
different at 12 weeks compared to baseline; but not between each
other. The study was not powered to detect differences between
groups.
[0236] Further analysis of the data showed that a higher percentage
of subjects reached HbAlc less than or equal to 7% and less than or
equal to 6.5% at 12 weeks when treated following the methods of the
present invention using continuous delivery of exenatide from an
osmotic delivery device versus twice-daily injection (Table
10).
TABLE-US-00010 TABLE 10 Subjects Subjects (at or below 7% (at or
below 6.5% of Total) Percent of Total) Percent Group 1 30 of 47 64
15 of 47 32 Group 2 32 of 47 68 12 of 47 26 Group 3 24 of 47 51 8
of 47 17
[0237] Body weight decreased in all treatment groups and was
significantly different from baseline to endpoint after 12 weeks of
treatment in all groups (Table 11).
TABLE-US-00011 TABLE 11 Subjects Mean Weight Loss (in kg) Percent
Change (%) Group 1 n = 47 -0.8 .+-. 2.4** -0.9 .+-. 2.7 Group 2 n =
48 -2.0 .+-. 3.0* -2.6 .+-. 3.5 Group 3 n = 47 -1.3 .+-. 2.5* -1.5
.+-. 2.8 *p < 0.001 relative to baseline **p < 0.05 relative
to baseline
[0238] While there was an apparent dose-response relationship with
respect to gastrointestinal adverse events (nausea and vomiting),
these effects occurred early after implantation of the device(s)
and typically abated within the several weeks in most subjects
(FIG. 6). In FIG. 6 it can be seen that, when the dose of the
twice-daily injections was increased from 5 mcg/day to 10 mcg/day,
the incidence of nausea increased and remained higher than the with
the initial treatment dosage level. That result was in contrast to
the data seen with continuous delivery wherein the overall trend
was toward a decreased incidence of nausea over time.
[0239] Referring to FIG. 6, the initial frequency of nausea with
exenatide injections was above 20% at the starting dose of 5 mcg
BID. At four weeks when the dose was increased to 10 mcg BID, the
frequency of nausea increased again to greater than 20% and
persisted at that rate for the remainder of the 12-week period.
[0240] With treatment at 20 mcg/day by continuous delivery, the
initial frequency of nausea was about 25% and gradually decreased
every week. Over the first four weeks, the frequency of nausea was
similar to exenatide injections even though twice the amount of
exenatide was being delivered. From week 6 onward, the frequency of
nausea continued to fall and was less than 10% at the end of week
12. The duration of nausea was much less in the 20 mcg/day
continuous delivery group with a mean duration of nausea of 17 days
versus 47.7 days with exenatide injections.
[0241] At the higher dose of 40 mcg/day administered by continuous
delivery, the frequency of nausea was higher but fell to a similar
rate compared to exenatide injections from week six onward even
though the amount of exenatide that the subject received was twice
that of exenatide injections. Most of the nausea was mild to
moderate.
[0242] The data in FIG. 6 demonstrate that delivery of 20 mcg/day
by continuous delivery from an osmotic delivery device resulted in
continuing improvement of nausea symptoms over the 12-week
treatment period. Further, the data demonstrate that over time
delivery of 40 mcg/day by continuous delivery from an osmotic
delivery device resulted in no greater nausea than lower dose
exenatide twice-daily injection. These data show improved
tolerability of exenatide treatment using continuous delivery
versus twice-daily injections of exenatide. Accordingly, in one
embodiment, the present invention relates to methods of and osmotic
devices comprising exenatide for use in methods of treating type 2
diabetes mellitus by continuous delivery of exenatide that provide
improved tolerization to dose escalation of exenatide.
[0243] In addition, quality of life was assessed among study
subjects at baseline and week 8 using the validated DM-SAT Quality
of Life survey (Anderson, R T, et al., Diabetes Care 32:51 (2009)).
Sixteen criteria were examined and subjects self-scored on a scale
of 0-10. Comparisons of change were made from baseline across all
treatment arms (n-50 subjects/arm) and an aggregate total score
obtained from the 16 criteria. In addition, the 16 criteria were
grouped by four subscales of well-being, lifestyle, medical control
and convenience.
[0244] The data presented in FIG. 7 shows the percent change from
baseline in the overall QOL assessment at week 8. In the figure the
numbers over the bar graphs represent the following: n with
improved QOL score/n with stable QOL score/n with decreased QOL
score, respectively; for Group 3, 36/0/15; for Group 1, 35/3/9; and
for Group 2, 40/1/7. The data indicated that on average subjects
gave an overall higher QOL assessment to exenatide treatment when
the treatment was provided by continuous delivery at 20 mcg/day
(Group 1) and 40 mcg/day (Group 2) using an implanted osmotic
delivery device versus when exenatide was administered by
twice-daily injections (Group 3). For exenatide injections (Group
3), the QOL improvement was a little more than 10%. For Groups 1
and 2 the improvement in QOL was greater, from 20-30%. A greater
fraction of the subjects receiving exenatide injections (Group 3)
reported a decrease in QOL than either of the continuous delivery
groups (Groups 1 and 2). These data demonstrated a significant
advantage of the implanted osmotic delivery device over exenatide
administration via injection in terms of reported quality of life
for treated subjects.
[0245] Further, a subscale analysis of QOL was performed at week 8
and the percent changes from baseline are presented in FIG. 8. In
the figure, the bars are labeled with the Group number, that is,
Groups 3, 1, and 2, respectively. The data showed that subjects
rated continuous delivery of exenatide using an osmotic pump as
providing consistently higher QOL than exenatide administered by
injection by each of the four subscales of well-being, medical
control, lifestyle, and convenience. These data demonstrated a
significant advantage of the implanted osmotic delivery device over
exenatide administration via injection in terms of reported quality
of life in each of the four subscales for treated subjects.
[0246] Treatment with exenatide by continuous delivery resulted in
potential beneficial changes in other parameters relative to
treatment with exenatide injections at week 12. For example, the
change of low density lipoprotein cholesterol (LDL-C) values from
baseline to week 8 were as shown in Table 12.
TABLE-US-00012 TABLE 12 Change in LDL from Baseline Percent Change
Group 1 -4.8 mg/dL -1.63 Group 2 -5.4 mg/dL -4.33 Group 3 +1.2
mg/dL 15.26
[0247] LDL-C decreased 4.8 and 5.4 mg/dL with exenatide treatment
by continuous delivery at 20 and 40 mcg/day, respectively, whereas
it increased 1.2 mg/dL with exenatide treatment by injections.
These data demonstrated a more favorable effect on reduction of
LDL-C by treatment using continuous delivery of exenatide versus
twice-daily injection.
[0248] Further, the change of seated systolic blood pressure values
from baseline to week 8 were as shown in Table 13.
TABLE-US-00013 TABLE 13 Group 1 -3.6 mmHg Group 2 -6.8 mmHg Group 3
-4.2 mmHg
[0249] Systolic blood pressure decreased 3.6 and 6.8 mmHg with
exenatide treatment by continuous delivery at 20 and 40 mcg/day,
respectively, and decreased 4.2 mmHg with exenatide treatment by
injections. These data demonstrated that all treatment methods
provided similar, favorable effect on reduction of systolic blood
pressure by treatment using continuous delivery of exenatide and
twice-daily injection.
[0250] (ii) Data at Week 20
[0251] Extension phase data for subject status at week 20 is
presented in FIG. 9. In the extension phase for weeks 13-24,
subjects from each treatment group were randomized to receive
continuous delivery of exenatide at 20, 40, 60 or 80 mcg/day. The
changes in HbAlc percent at week 20 of treatment are presented in
Table 14.
TABLE-US-00014 TABLE 14 Dosage Delivered by Continuous Delivery
Sample Baseline Week 20 Change in to Randomized Groups Size HbA1c %
HbA1c % HbA1c 20 mcg/day n = 17 7.88 7.03 -0.85 40 mcg/day n = 39
7.83 6.77 -1.06 60 mcg/day n = 35 8.06 6.79 -1.27 80 mcg/day n = 17
8.07 6.68 -1.39
[0252] These data demonstrated that dose escalation to continuous
delivery at the higher doses of 60-80 mcg/day resulted in further
reduction in HbAlc relative to baseline. In addition, continued
weight loss was observed.
[0253] The data presented in Table 15 show subjects reaching HbAlc
treatment goals at 20 weeks. The data demonstrated continuing
reduction of HbAlc in the randomized groups. Further, the data
demonstrated that dose escalation resulted in more subjects
reaching HbAlc treatment goals.
TABLE-US-00015 TABLE 15 Subjects Subjects (at or below 7% (at or
below 6.5% of Total) Percent of Total) Percent 20 mcg/day 10 of 20
50% 4 of 20 20% 40 mcg/day 31 of 39 79% 18 of 39 46% 60 mcg/day 28
of 38 74% 18 of 38 47% 80 mcg/day 13 of 17 76% 9 of 17 53%
[0254] In summary, exenatide treatment by continuous delivery using
an implantable osmotic delivery device at doses of 20 and 40
mcg/day was well tolerated over 12 weeks with robust
glucose-lowering activity. HbAlc decreased by 0.96% and 1.04% with
exenatide treatment by continuous delivery at doses of 20 and 40
mcg/day, respectively, compared to a decrease of 0.82% with
exenatide injections. More subjects reached HbAlc treatment goals
of 7% or 6.5% with exenatide treatment by continuous delivery than
with exenatide injections. Weight loss was observed in all
treatment groups. Despite receiving twice as much exenatide during
the initial 4 weeks of treatment, nausea decreased progressively
over the first six weeks with exenatide treatment by continuous
delivery at 20 mcg/day compared to treatment with exenatide
injections where nausea persisted from weeks 4-12 with a weekly
incidence of >20%. Both doses of exenatide treatment by
continuous delivery performed better than exenatide injections
overall and in all four subscales (well-being, medical control,
lifestyle, convenience) of a QOL survey conducted after 8 weeks of
treatment.
[0255] In addition, dose escalation with exenatide treatment by
continuous delivery at week 13 resulted in further reduction of
HbAlc after 8 weeks of therapy. Subjects treated with exenatide
treatment by continuous delivery at 60 mcg/day from weeks 13-20 had
a decrease in HbAlc of 1.27% from baseline. Subjects treated with
exenatide treatment by continuous delivery at 80 mcg/day from weeks
13-20 had a decrease in HbAlc of 1.39% from baseline.
[0256] (iii) Final Data at Completion of Phase 2 Study
[0257] The overall disposition of the subjects at completion of the
study is presented in Table 16.
TABLE-US-00016 TABLE 16 Groups 1 and 2 Group 3 Weeks 1-12
Completion Rate 93% 89% Withdrawals due to nausea 3.9% 5.7%
Withdrawals prior to re-randomization 8.4% 6.4% Weeks 13-24
Completion Rate 95% NA* Withdrawals due to nausea <1% NA*
*NA--not applicable
[0258] In Table 16, "Weeks 1-12" presents the study disposition
over the first treatment period. There was a very high completion
rate, 93%, in the treatment groups providing continuous delivery
(Groups 1 and 2). Groups 1 and 2 each had two subjects withdraw due
to nausea, and Group 3 had three subjects withdraw due to nausea.
In the table, "Withdrawals prior to re-randomization" are subjects
that completed the first 12 weeks of treatment, but opted not to
continue through the 12-week extension phase treatment period. No
specific reasons were given for these withdrawals.
[0259] In Table 16, for "Weeks 13-24," all subjects were treated
using continuous delivery from implanted osmotic delivery devices.
This treatment period of the study had a very high completion rate.
Only one subject withdrew because of nausea. This subject had been
on exenatide injections and then received treatment by continuous
delivery at 60 mcg/day. The subject noted nausea for five days and
withdrew from study.
[0260] The changes in HbAlc percent for weeks 13-24 of treatment
are presented in Table 17.
TABLE-US-00017 TABLE 17 Dose Delivered by Percent of Continuous
Delivery Baseline Week 12 Week 24 Change Subjects who Weeks 13-24
Sample HbA1c HbA1c HbA1c in achieved HbA1c: (mcg/day) Size % % %
HbA1c .ltoreq.7% .ltoreq.6.5% 20 n = 20 7.96 7.10 7.07 -0.89* 60%
20% 40 n = 42 7.79 7.07 6.93 -0.86* 71% 43% 60 n = 41 8.05 7.08
6.67 -1.38* 73% 49% 80 n = 19 8.03 6.83 6.67 -1.36* 79% 63% *p <
0.0001 relative to baseline
[0261] In Table 17, the data given for Week 12 shows the average
change in HbAlc values from initiation of treatment (baseline) to
week 12 (the end of the first treatment period) for the subjects
after randomization and before entry into the extension phase
treatment period (weeks 13-24) (see FIG. 5). The data shown for
Week 24 show the changes in HbAlc associated with each dose at the
end of treatment by continuous delivery at the specified doses.
After treatment with exenatide by continuous delivery, at 24 weeks
further decreases in HbAlc were seen in all treatment groups. All
of these reductions in HbAlc are statistically significant relative
to the baseline and demonstrate that continued reduction of HbAlc
can be obtained using continuous delivery of exenatide. For the two
highest doses (i.e., 60 mcg/day and 80 mcg/day), both groups had a
change of greater than 1.3% demonstrating that increasing the dose
of exenatide administered by continuous delivery provided continued
reduction in HbAlc over the treatment period. The percentage of
subjects with HbAlc at 7% or less demonstrated good treatment
outcome for all groups, with the greatest improvements seen at the
higher doses (60 mcg/day, 73%; and 80 mcg/day, 79%). The study was
not powered to detect differences between groups.
[0262] The reductions in HbAlc and the percent of subjects who
achieved an HbAlc of less than 7% demonstrate the clinical value of
treatment of subjects having type 2 diabetes mellitus using
continuous delivery of exenatide over a range of different
doses.
[0263] Further analysis of the HbAlc data from weeks 13-24 for
subjects receiving continuous delivery of 60 mcg/day of exenatide
showed that the higher the initial HbAlc baseline at the beginning
of the extension phase treatment period the greater the reduction
in HbAlc that was seen at the end of the extension phase treatment
period (Table 18).
TABLE-US-00018 TABLE 18 Subjects Percent of treated by Subjects
continuous achieving delivery of Sample Baseline Week 24 Change in
HbA1c of 60 mcg/day Size HbA1c HbA1c HbA1c 7% or less All Subjects
n = 41 8.05 6.67 -1.38* 73% Subjects n = 36 8.22 6.73 -1.49* 69%
having a baseline HbA1c > 7.0 Subjects n = 27 8.54 6.77 -1.77*
63% having a baseline HbA1c .gtoreq. 7.5 *p < 0.0001 relative to
baseline
[0264] In Table 18, the "Baseline" is the mean HbAlc of the
subjects at initiation of treatment at the beginning of the
clinical study. For the 41 subjects who received treatment by
continuous delivery of 60 mcg/day of exenatide from weeks 13-24,
the mean HbAlc was 8.05% with a 1.38% drop after treatment. Of
these 41 subjects, 36 subjects who had a baseline HbAlc of greater
than 7 had a mean HbAlc of 8.22% with a 1.49% drop after treatment.
Of the 41 subjects, 27 subjects who had a baseline HbAlc of greater
than or equal to 7.5 had a mean HbAlc of 8.54% with an even bigger
drop of 1.77% after treatment. These results further demonstrate
that treatment of type 2 diabetes mellitus subjects using
continuous delivery of exenatide provides desirable treatment
outcome because continued improvement in HbAlc was seen over the
treatment period and subjects with higher baselines at the
beginning of the treatment period showed the desirable outcome of
greater reductions in HbAlc than subjects with lower baselines.
[0265] Body weight decreased in all treatment groups and was
significantly different from baseline to endpoint at 24 weeks of
treatment in all groups (Table 19).
TABLE-US-00019 TABLE 19 Dose Delivered by Continuous Delivery Weeks
13-24 Mean Weight Loss Percent Change (mcg/day) Sample Size (in kg)
(in %) 20 n = 20 -0.8 -0.85 40 n = 42 -3.6* -4.0 60 n = 41 -3.1*
-3.4 80 n = 19 -3.5** -3.8 *p < 0.0001 relative to baseline **p
< 0.01 relative to baseline
[0266] The lowest dose of 20 mcg/day had an average weight loss of
0.8 kg. All the higher doses had greater than 3 kg weight loss; the
values were also statistically significant.
[0267] The data presented in FIG. 10 show the incidence of nausea
over the treatment period of weeks 13-24. In the figure, the first
time point (-1 week) shows the incidence of nausea the week prior
to subject randomization for extension phase dosing. With
continuous delivery of 20 mcg/day of exenatide, the incidence of
nausea remained very low throughout the treatment period. With an
increase in the continuous delivery dose from 20 mcg/day to 60
mcg/day of exenatide, there was an increase in the incidence of
nausea; but treatment was well-tolerated as described below. When
subjects receiving 20 mcg/day of exenatide as twice-daily
injections were treated in the extension phase using continuous
delivery of 60 mcg/day of exenatide, the incidence of nausea was
much higher reaching 50% during the fourth week after dose
escalation. Thus, treatment with twice-daily exenatide injections
was not helpful in tolerization of subjects to the gastrointestinal
side effects of increased doses of exenatide, whereas treatment
using continuous delivery of exenatide did provide tolerization of
subjects to the gastrointestinal side effects of increased doses of
exenatide. Accordingly, in one embodiment, the present invention
relates to methods of and osmotic devices comprising exenatide for
use in methods of treating type 2 diabetes mellitus by continuous
delivery of exenatide that provide improved tolerization to dose
escalation of exenatide.
[0268] Regarding the treatment being well tolerated, for subjects
treated using continuous delivery of 20 to 60 mcg/day of exenatide,
there were no withdrawals from treatment, six subjects reported
nausea during weeks 13-24, and four reported nausea during weeks
1-12. There were no reports of vomiting. Four of these subjects
were at sites participating in a continuation phase allowing
treatment from weeks 25-48 and all four elected to continue
treatment using continuous delivery. Further, 85% of all eligible
subjects in all of the treatment groups elected to continue
treatment in the continuation phase.
[0269] In addition, changes in subjects' QOL score in the extension
phase of the study were evaluated essentially as described above.
With reference to FIG. 9, the data presented in FIG. 11 presents
changes from baseline for QOL scores based on subsequent
randomization to two treatment groups (i.e., continuous delivery of
either 40 mcg/day or 60 mcg/day exenatide) in the extension phase
of the original subjects in Group 3 (twice-daily injection of
exenatide). QOL for original subjects of Group 3 who were
randomized to continuous delivery of 40 mcg/day were compared using
their QOL data from week 8 and their QOL data obtained at week 20.
QOL data for original subjects of Group 3 who were randomized to
continuous delivery of 60 mcg/day were compared using their QOL
data from week 8 and their QOL data obtained at week 20. As can
been seen from the data in FIG. 11, subjects who switched from
twice-daily exenatide injections (Group 3) to continuous delivery
from an implanted osmotic device (at doses of 40 mcg/day or 60
mcg/day of exenatide) reported substantial increase in QOL
scores.
[0270] With reference to FIG. 9, the data presented in FIG. 12
presents changes from baseline for QOL scores based on the original
subjects of Group 1 (continuous delivery of 20 mcg/day of
exenatide) who were subsequently randomized to continuous delivery
at 60 mcg/day in the extension phase, and the original subjects of
Group 2 (continuous delivery of 40 mcg/day of exenatide) who were
subsequently randomized to continuous delivery of 80 mcg/day in the
extension phase. QOL data for these subjects were compared using
their QOL data from week 8 and their QOL data obtained at week 20.
As can be seen from the data presented in FIG. 12, the QOL scores
for subjects treated by continuous delivery who had their dose
increased 2-3 fold in the extension phase maintained higher QOL
scores (relative to those treated by twice-daily injection, compare
to FIG. 7 and FIG. 8) even at the higher doses. Thus, the present
invention provides methods of and osmotic devices comprising
exenatide for use in methods of treating type 2 diabetes mellitus
by continuous delivery of exenatide that provide improved QOL to
subjects being treated with exenatide.
[0271] In summary, treatment of type 2 diabetes mellitus using
continuous delivery of exenatide from implanted osmotic devices
provides glycemic control at all doses. Subjects started on
continuous delivery of 20 mcg/day followed by dose escalation to 60
mcg/day experienced superior tolerability and reductions in HbAlc
and weight. In addition, improvement in subject-reported QOL was
observed at all exenatide doses administered by continuous delivery
versus twice-daily injection of exenatide. A greater improvement in
QOL was observed in subjects treated by continuous delivery of
exenatide versus twice-daily exenatide injection. Also, marked QOL
improvement was seen in subjects switching from twice-daily
exenatide injection to continuous delivery using implanted osmotic
delivery devices.
[0272] The methods and implantable osmotic delivery devices of the
present invention provide unique potential for long-term optimal
treatment of type 2 diabetes mellitus because it is the first
incretin mimetic therapy that ensures subject adherence and
eliminates the need self injection.
[0273] C. Comparative Treatment Data
[0274] This example discusses comparisons of different therapeutic
approaches for the treatment of type 2 diabetes mellitus among
subjects on a metformin-only treatment background. The data from
the above-described Phase 2 clinical study of treatment using
continuous delivery from implanted osmotic delivery devices was
compared to treatment outcomes for twice-daily and once-weekly
exenatide injections, as well as oral anti-diabetic agents.
[0275] FIG. 13 to FIG. 21 present comparative treatment data for
the drugs and treatment methods set forth in Table 20.
TABLE-US-00020 TABLE 20 Treatment Designation Drug/Dosing in
Figures Schedule Source of Data/Studies Treatment A Exenatide,
twice-daily DeFronzo R A, et al., injection (5 mcg per injection)
Diabetes Care 28(5): 1092-1100 (2005) Treatment B Exenatide,
once-weekly Bergenstal R M, et al., injection (2 mg/week) Lancet
376(9739): 431-439 (2010) Treatment C Liraglutide, once-daily
Pratley R E, et al., injection (1.2 or 1.8 mg/day) Lancet
375(9724): 1447-1456 (2010) Treatment D Taspoglutide, once-weekly
Rosenstock J, et al., injection (10 or 20 mg/week) American
Diabetes Association (ADA) 70th Scientific Sessions, Orlando FL,
Abstract 62-OR (2010); Nauck M, et al., American Diabetes
Association (ADA) 70th Scientific Sessions, Orlando FL, Abstract
60-OR (2010); Bergenstal R, et al., American Diabetes Association
(ADA) 70th Scientific Sessions, Orlando FL, Abstract 58-OR (2010).
Treatment E Exenatide, continuous The Phase 2 clinical trial
delivery of 20 mcg/day described herein. or 60 mcg/day using an
implantable osmotic device (i.e., embodiments of the present
invention) Treatment F Sitagliptin, Bergenstal R M, et al., taken
orally once a day Lancet 376(9739): (100 mg/day) 431-439 (2010)
Treatment G Pioglitazone, Bergenstal R M, et al., taken orally once
a day Lancet 376 (9739): (15 mg, 30 mg, or 45 mg) 431-439
(2010)
[0276] Liraglutide and taspoglutide are both peptides and incretin
mimetics. Sitagliptin is a small molecule DPP-4 inhibitor.
Pioglitazone is a TZD and a potent agonist for peroxisome
proliferator-activated receptor-gamma.
[0277] The comparative data presented in FIG. 13 demonstrates that
treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide (Treatment
E) provided the best reduction in HbAlc over the treatment periods
of the studies. Accordingly, the continuous delivery of exenatide
as described herein provided superior HbAlc reductions relative to
exenatide administered by injection either twice-daily (Treatment
A) or once-weekly (Treatment B), as well as superior reductions in
HbAlc relative to treatment by two different incretin mimetics,
liraglutide (once-daily injection; Treatment C) and taspoglutide
(once-weekly injection; Treatment D).
[0278] The comparative data presented in FIG. 14 demonstrates that
treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide (Treatment
E) provided excellent HbAlc drop despite a lower baseline at study
initiation than treatment with sitagliptin (Treatment F),
pioglitazone (Treatment G), or once-weekly injections of exenatide
(Treatment B). In the Bergenstal R M, et al., study about one-third
of subjects had a HbAlc of greater than 9%; however, in the
experiments described herein using continuous delivery of 20
mcg/day or 60 mcg/day of exenatide, there was only one subject
above having a HbAlc above 9. This explains the difference in the
mean HbAlc baselines.
[0279] The comparative data presented in FIG. 15 demonstrates that
treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide (Treatment
E) provided an increased reduction in HbAlc despite lower baselines
when compared to once-weekly administration of exenatide. Unlike
the Phase 2 clinical trial described herein, which was conducted
entirely in the United States, the Bergenstal R M, et al., study
was conducted in the United States, Mexico and India. This
geographic distribution resulted in an enrollment of subjects who
were less well controlled on metformin monotherapy and who entered
the study with higher baseline HbAlc levels. The mean baseline
HbAlc in subjects treated with once-weekly injections of exenatide
(Treatment B) from the Bergenstal R M, et al., study, and one-third
of the subjects enrolled in the Bergenstal R M, et al., study had
baseline HbAlc levels higher than 9%. Analyzing only subjects from
Treatment E who had higher baseline HbAlc levels demonstrated that
the absolute drop in HbAlc is higher among subjects on treatment
using the methods and osmotic delivery devices of the present
invention for continuous delivery of exenatide (Treatment E). This
suggests that the continuous delivery of exenatide as described by
the present invention may outperform once-weekly injection of
exenatide in similar study populations who have high baseline
HbAlc.
[0280] The comparative data presented in FIG. 16 demonstrates that
treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide (Treatment
E) provided robust reductions of HbAlc relative to treatment with
once-weekly injections of exenatide (Treatment B). The HbAlc
changes from the Bergenstal R M, et al., study were further
analyzed between subjects with baseline HbAlc less than 9% and
subjects with baseline HbAlc greater than or equal to 9%. Comparing
the results of exenatide treatment by continuous delivery of the
present invention (Treatment E) to treatment using once-weekly
exenatide injection (Treatment B) following the same analysis
showed that HbAlc reductions following the treatment methods of the
present invention are as good or better than those seen using
once-weekly exenatide injection.
[0281] The same comparison of results of the treatment methods of
the present invention (Treatment E) with the results from subjects
on sitagliptin from the Bergenstal R M, et al., study suggested an
even greater advantage for the continuous delivery of exenatide to
provide better reductions in HbAlc relative to sitagliptin (FIG.
17). These results support use of the osmotic delivery devices of
the present invention for treatment providing continuous delivery
as a preferred add-on therapy to metformin relative to DPP-4
inhibitors (e.g., sitagliptin). Further, when comparing subjects
with HbAlc of less than or equal to 9% from the Bergenstal R M, et
al., study to similar subjects from the Phase 2 clinical study
described herein, it was seen that the treatment methods and
osmotic devices of the present invention provide much more
substantial reductions in HbAlc (FIG. 18).
[0282] Similarly, the same comparison of results of the treatment
methods of the present invention (Treatment E) with the results
from subjects on pioglitazone from the Bergenstal R M, et al.,
study suggested that the continuous delivery of exenatide provides
greater reductions in HbAlc relative to pioglitazone (FIG. 19).
These results support use of the osmotic delivery devices of the
present invention for treatment providing continuous delivery as a
preferred add-on therapy to metformin relative to TZDs (e.g.,
pioglitazone). Further, when comparing subjects with HbAlc of less
than or equal to 9% from the Bergenstal R M, et al., study to
similar subjects from the Phase 2 clinical study described herein,
it was seen that the treatment methods and osmotic devices of the
present invention provided much more substantial reductions in
HbAlc (FIG. 20).
[0283] Further, FIG. 21 presents a comparison of weight loss
obtained using sitagliptin (Treatment F), pioglitazone (Treatment
G), or once-weekly injections of exenatide (Treatment B) to
treatment using the methods and osmotic delivery devices of the
present invention for continuous delivery of exenatide (Treatment
E). The data presented in the figure demonstrate that, when
comparing the treatments, the methods and osmotic delivery devices
of the present invention provide the best weight loss.
[0284] Finally, all the subjects enrolled into the Phase 2 clinical
study were receiving only metformin therapy for treatment of their
type 2 diabetes mellitus before initiation of the study. The
metformin doses were not modified over the course of the Phase 2
clinical study. Subjects were treated using continuous delivery of
20 mcg/day or 40 mcg/day of exenatide for 12 weeks or were
randomized to a group that was treated by twice-daily,
self-injected exenatide (4 weeks at 5 mcg BID followed by 10 mcg
BID for 8 weeks).
[0285] Metformin is known to cause certain gastrointestinal adverse
events such as diarrhea, nausea and vomiting. Subjects treated by
continuous administration of 20 mcg/day of exenatide and whose dose
of exenatide was then escalated to higher doses of continuously
administered exenatide had fewer adverse gastrointestinal side
effects than those subjects who received exenatide injections at 20
mcg/day and were then escalated to higher doses of continuously
administered exenatide.
[0286] Thus, subjects who started on exenatide continuous delivery
therapy were better tolerized to the effects of the combination of
exenatide given with metformin than those who initially received
exenatide injections given with metformin. Accordingly, using
continuous administration of exenatide from an osmotic delivery
device is the best exenatide treatment option for combination with
metformin therapy relative to twice-daily injections of
exenatide.
[0287] The Phase 2 clinical trial data illustrates that exenatide
treatment by continuous delivery provided the following potential
benefits: highly effective control of glucose; reduction in the
gastrointestinal side effects relative to treatment by injection;
elimination of the need for self-injection; substantial
weight-loss; and 100% compliance to prescribed therapy.
EXAMPLE 4
Phase 3 Clinical Trial Study Designs for Continuous Delivery of
Exenatide
[0288] The following study designs are presented for illustrative
purposes only and other Phase 3 clinical trial designs are feasible
as will be understood by one of ordinary skill in the art.
[0289] A. First Study Design
[0290] One Phase 3 clinical trial study design is as follows. The
study is a randomized, double-blind, placebo-controlled study. The
study group includes subjects with type 2 diabetes mellitus treated
with metformin, TZD, sulfonylurea, and any combination of
metformin, TZD or sulfonylurea. Subjects have an HbAlc of greater
than 7%. Subjects are randomized 1:2 between placebo versus
continuous delivery of unmodified, synthetic exenatide having the
amino acid sequence of exendin-4 using implantable osmotic delivery
devices, respectively. There are a total of 300 subjects. The dose
of exenatide used for continuous delivery is selected based on the
results at completion of the Phase 2 study including tolerability,
glucose-lowering activity, and weight loss activity. The dose for
continuous delivery will likely include 3 months of treatment with
20 mcg/day and 3 months of treatment with 60 mcg/day. Randomization
is stratified based on sulfonylurea use and HbAlc (less than 9%
versus greater than or equal to 9%).
[0291] The data to be obtained and assessed includes the following:
HbAlc (primary endpoint), fasting plasma glucose, weight, lipids,
blood pressure, adiponectin, C-reactive protein (CRP), calcitonin,
and amylase/lipase. In addition QOL assessment will be
performed.
[0292] There will be either an open-label or a blinded 26-week
extension phase for long-term treatment using continuous delivery
from implanted osmotic delivery devices.
[0293] B. Second Study Design
[0294] A second Phase 3 clinical trial study design is as follows.
The study is a randomized, double-blind, placebo-controlled Phase 3
study having a 26-week blinded study and a mandatory 26-week
extension. The study group includes subjects with type 2 diabetes
mellitus treated with diet and exercise and/or an oral treatment
selected from the following: a TZD, a sulfonylurea, a TZD and
metformin, a sulfonylurea and metformin, or a TZD and a
sulfonylurea; with the exclusion of metformin-only treatment. The
exclusion of metformin-only treatment provides a larger
sulfonylurea subset for safety evaluation. Inclusion criteria for
subjects include stable maximum dose background therapy. There will
be no exclusion for cardiovascular risk.
[0295] Subjects have an HbAlc of greater than or equal to 7.5%.
Subjects are randomized 1:2 between placebo versus continuous
delivery of unmodified, synthetic exenatide having the amino acid
sequence of exendin-4 using implantable osmotic delivery devices,
respectively. There are a total of 375 subjects. The doses used for
continuous delivery of exenatide include: Group A (n=150), 13 weeks
of treatment with 20 mcg/day followed by 13 weeks of treatment with
60 mcg/day; Group B (n=150), 13 weeks of treatment with 20 mcg/day
followed by 13 weeks of treatment with 40 mcg/day; and, Group C
(n=75), the placebo control group, 13 weeks of treatment with
placebo followed by 13 weeks of treatment with placebo. The primary
endpoint of the study is week 26. There is a mandatory blinded
extension phase with treatment as follows: Group A, 26 weeks of
treatment with 60 mcg/day; Group B, 26 weeks of treatment with 40
mcg/day; and Group C, 26 weeks of treatment with 20 mcg/day.
[0296] The data to be obtained and assessed includes the following:
HbAlc (primary endpoint), fasting plasma glucose, weight, lipids,
blood pressure, adiponectin, C-reactive protein (CRP), calcitonin,
and amylase/lipase. In addition QOL assessment will be
performed.
[0297] Further modifications of this study may include the
following. Addition of a randomized, double-blind,
placebo-controlled phase 3 clinical trial, wherein the study group
includes subjects with type 2 diabetes mellitus treated with DPP-4
inhibitors or TZDs as add-ons to metformin treatment (i.e.,
subjects are treated with a DPP-4 inhibitor and metformin or a TZD
and metformin). The study is a 26-week blinded study with a
mandatory 26-week extension. The study is placebo-controlled with
placebos for both continuous delivery of exenatide and for orally
administered drugs. The total number of this group of subjects is
approximately 500. The treatment doses include: Group A (n=170), 13
weeks of treatment by continuous delivery of exenatide at 20
mcg/day followed by 13 weeks of treatment with 60 mcg/day; Group B
(n=170), 26 weeks of treatment with 45 mg/day pioglitazone (a TZD);
and, Group C (n=170), 26 weeks of treatment with 100 mg/day
sitagliptin (a DPP-4 inhibitor). The primary endpoint of the study
is week 26. There is a mandatory blinded extension phase with
treatment as follows: Group A, 26 weeks of treatment with
continuous delivery of exenatide at 60 mcg/day; Group B, 26 weeks
of treatment with 45 mg/day pioglitazone; and Group C, 26 weeks of
treatment with 100 mg/day sitagliptin.
[0298] The purpose of this study is to demonstrate superiority of
treatment with continuous delivery of exenatide using osmotic
delivery devices to treatment with DPP-4 inhibitors and TZDs.
[0299] As is apparent to one of skill in the art, various
modification and variations of the above embodiments can be made
without departing from the spirit and scope of this invention. Such
modifications and variations are within the scope of this
invention.
* * * * *