U.S. patent application number 14/525201 was filed with the patent office on 2015-02-26 for compositions, devices and methods of use thereof for the treatment of cancers.
The applicant listed for this patent is INTARCIA THERAPEUTICS, INC.. Invention is credited to Karling Alice Leung.
Application Number | 20150057227 14/525201 |
Document ID | / |
Family ID | 46637352 |
Filed Date | 2015-02-26 |
United States Patent
Application |
20150057227 |
Kind Code |
A1 |
Leung; Karling Alice |
February 26, 2015 |
COMPOSITIONS, DEVICES AND METHODS OF USE THEREOF FOR THE TREATMENT
OF CANCERS
Abstract
The use of GLP-1 receptor agonists, such as glucagon-like
peptide-1 (GLP-1) or exenatide, for the treatment of cancer is
described. The GLP-1 receptor agonists are typically delivered
using an implanted osmotic delivery device that provides for
continuous delivery of the GLP-1 receptor agonist for at least one
month. Additional beneficial agents, such as anticancer agents, can
also be administered.
Inventors: |
Leung; Karling Alice;
(Oakland, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTARCIA THERAPEUTICS, INC. |
HAYWARD |
CA |
US |
|
|
Family ID: |
46637352 |
Appl. No.: |
14/525201 |
Filed: |
October 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13372326 |
Feb 13, 2012 |
|
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14525201 |
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61443628 |
Feb 16, 2011 |
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Current U.S.
Class: |
514/11.7 ;
604/500 |
Current CPC
Class: |
A61M 31/002 20130101;
A61K 38/26 20130101; A61K 45/06 20130101; A61P 35/00 20180101; A61P
3/10 20180101; A61M 37/00 20130101; C07K 14/605 20130101 |
Class at
Publication: |
514/11.7 ;
604/500 |
International
Class: |
A61K 38/26 20060101
A61K038/26; A61K 45/06 20060101 A61K045/06; A61M 31/00 20060101
A61M031/00; C07K 14/605 20060101 C07K014/605 |
Claims
1. A method of treating cancer in a subject in need of such
treatment, comprising administering a GLP-1 receptor agonist to the
subject.
2. The method of claim 1, wherein the GLP-1 receptor agonist is a
peptide, polypeptide or protein.
3. The method of claim 2, wherein the GLP-1 receptor agonist is a
glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, or an
analog of GLP-1.
4. The method of claim 3, wherein the GLP-1 receptor agonist is
GLP(7-36)amide comprising the sequence of SEQ ID NO:1.
5. The method of claim 3, wherein the GLP-1 receptor agonist is
selected from the group consisting of liraglutide, albiglutide,
semaglutide, and taspoglutide.
6. The method of claim 2, wherein the GLP-1 receptor agonist is
exenatide, a derivative of exenatide, or an analog of
exenatide.
7. The method of claim 6, wherein the GLP-1 receptor agonist is
synthetic exenatide peptide comprising the sequence of SEQ ID
NO:2.
8. The method of claim 6, wherein the GLP-1 receptor agonist is
lixisenatide.
9. The method of claim 1, wherein the GLP-1 receptor agonist is
provided in a suspension formulation comprising: (a) a particle
formulation comprising the GLP-1 receptor agonist; and (b) a
vehicle formulation, wherein the particle formulation is dispersed
in the vehicle.
10. The method of claim 9, wherein (a) the particle formulation
additionally comprises a disaccharide, methionine and a buffer and
(b) the vehicle formulation is a non-aqueous, single-phase
suspension vehicle comprising one or more pyrrolidone polymers and
one or more solvents selected from the group consisting of lauryl
lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof;
wherein the suspension vehicle exhibits viscous fluid
characteristics, and the particle formulation is dispersed in the
vehicle.
11. The method of claim 10, wherein the buffer is selected from the
group consisting of citrate, histidine, succinate, and mixtures
thereof.
12. The method of claim 10, wherein the disaccharide is selected
from the group consisting of lactose, sucrose, trehalose,
cellobiose, and mixtures thereof.
13. The method of claim 10, wherein the particle formulation is a
spray dried preparation of particles.
14. The method of claim 10, wherein the vehicle consists
essentially of polyvinylpyrrolidone and benzyl benzoate.
15. The method of claim 14, wherein the vehicle is about 50%
solvent and about 50% polymer.
16. The method of claim 10, wherein the suspension formulation has
an overall moisture content of less than or equal to about 10 wt
%.
17. The method of claim 9, wherein the CLP-1 receptor agonist is
delivered using an implantable osmotic delivery device.
18. The method of claim 1, wherein the GLP-1 receptor agonist is
provided in an injectable formulation.
19. The method of claim 1, wherein one or more beneficial agent in
addition to the GLP-1 receptor agonist is delivered to the subject,
and the beneficial agent is an anticancer agent, a chemotherapeutic
agent, or an antidiabetic agent.
20. The method of claim 19, wherein the additional beneficial agent
is delivered using an implantable osmotic delivery device.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
13/372,326, filed Feb. 13, 2012. U.S. Ser. No. 13/372,326 claims
the benefit of U.S. Provisional Application No. 61/443,628, filed
16 Feb. 2011. The contents of the aforementioned patent
applications are herein incorporated by reference in their
entireties.
TECHNICAL FIELD
[0002] The present invention relates to formulations and methods
for treating cancer. Aspects of the present invention provide
formulations of glucagon-like peptide-1 (GLP-1) receptor agonists
for use in mammals for the treatment of cancers.
INCORPORATION BY REFERENCE OF SEQUENCE LISTING
[0003] The contents of the text file named "ITCA-040C01US ST25",
which was created on Oct. 27, 2014 and is 1,236 bytes in size, are
hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0004] Glycolysis is the metabolic pathway that converts glucose
into pyruvate. The free energy released in this process is used to
form the high-energy compounds ATP and NADH. Increased aerobic
glycolysis is seen in a variety of cancer cells, a phenomenon known
as the Warburg theory. Under aerobic conditions, some tumor cells
produce as much as 60% of their ATP through glycolysis (Nakashima
et al., Cancer Res. (1984) 44:5702-5706) as opposed to normal cells
which normally generate ATP through mitochondrial oxidative
phosphorylation. In addition to increased aerobic glycolysis,
increased glycolysis is also seen in tumors that reach a size that
exceeds the capacity of blood supply due to hypoxia. For a review
of the Warburg theory and implications thereof, see, e.g., Chen et
al., J. Bioenerg. Biomenzbr. (2007) 39:267-274.
[0005] Glucagon-like peptide-1 (GLP-1) is an important hormone and
a fragment of the human proglucagon molecule. GLP-1 is rapidly
metabolized by a peptidase (dipeptidylpeptidase IV or DPP-IV). A
fragment of GLP-1, glucagon-like peptide-1 (7-36) amide (also known
as GLP-1 (7-36)amide, glucagon-like insulinotropic peptide, or
GLIP) is a gastrointestinal peptide that potentiates the release of
insulin in physiologic concentrations (Gutniak et al., N Engl J Med
(1992) 14:326(20):1316-22). Food intake, as well as stimulation of
the sympathetic nervous system, stimulates secretion of GLP-1 in
the small intestine of mammals. Further, GLP-1 stimulates the
production and secretion of insulin, the release of somatostatin,
glucose utilization by increasing insulin sensitivity, and, in
animal studies, also stimulates beta-cell function and
proliferation. GLP-1(7-36)amide and GLP-1(7-37) normalize fasting
hyperglycemia in type 2 diabetic patients (Nauck, M. A., et al.,
Diabet. Med. 15(11):937-45 (1998)).
[0006] Exendin-4, a GLP-1 receptor agonist, is a molecule purified
from Heloderma suspectuni venom (Eng, et al., Biol. Chem. (1992)
267:7402-7405) and shows structural relationship to the hormone
GLP-1(7-36)amide. Exendin-4 and truncated exendin-(9-39)amide
specifically interact with the GLP-1 receptor on insulinoma-derived
cells and on lung membranes (Goke et al., J Biol. Chem. (1993)
268:19650-19655). Exendin-4 has approximately 53% identity to human
GLP-1 (Pohl, et al., J. Biol. Chem. (1998) 273:9778-9784). Unlike
GLP-1, however, exendin-4 is resistant to degradation by DPP-IV. A
glycine substitution confers resistance to degradation by DPP-1V
(Young, et al., Diabetes (1999) 48(5):1026-1034).
[0007] The increased dependency of cancer cells on the glycolytic
pathway is an important metabolic difference between normal and
malignant cells. The present invention provides a unique solution
to disrupting cancer cell energy reliance on the glycolytic
pathway.
SUMMARY OF THE INVENTION
[0008] The present invention relates to compositions, devices and
methods for treating cancer. The invention utilizes GLP-1 receptor
agonists to restrict glucose as an energy source for cancer cells
and tumors. The GLP-1 receptor agonists can be used alone or in
combination with other beneficial agents, such as anticancer
agents, antidiabetic agents and the like, as well as in combination
with anticancer treatment modalities, such as radiation, surgery
and chemotherapeutic regimens.
[0009] Thus, in one aspect the invention relates to a method of
treating cancer in a subject in need of such treatment, comprising
administering a GLP-1 receptor agonist to said subject.
[0010] In certain aspects of the method, the GLP-1 receptor agonist
is a glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, or an
analog of GLP-1. In some embodiments, the GLP-1 receptor agonist is
GLP(7-36)amide comprising the sequence of SEQ ID NO:1.
[0011] In other aspects of the invention, the GLP-1 receptor
agonist is exenatide, a derivative of exenatide, or an analog of
exenatide, such as a synthetic exenatide peptide comprising the
sequence of SEQ ID NO:2.
[0012] In additional aspects of the invention, the GLP-1 receptor
agonist is selected from the group consisting of lixisenatide,
liraglutide (VICTOZA.TM.), albiglutide (SYNCRIA.TM.), semaglutide,
taspoglutide, BYETTA.TM., BYDUREON.TM. and LY2189265. In some
embodiments, formulations comprising the GLP-1 receptor agonist are
delivered by injection.
[0013] In further aspects, the GLP-1 receptor agonist is delivered
using an implanted drug delivery device, such as an osmotic
delivery device, that provides continuous delivery of a suspension
formulation of GLP-1 receptor agonist for a period of at least one
month.
[0014] In other aspects, the GLP-1 receptor agonist and/or other
beneficial agent is provided in a suspension formulation
comprising: (a) a particle formulation comprising said GLP-1
receptor agonist and/or beneficial agent; and (b) a vehicle
formulation, wherein the particle formulation is dispersed in the
vehicle.
[0015] In additional aspects, the suspension formulation may
further comprise a particle formulation comprising a GLP-1 receptor
agonist and/or beneficial agent and one or more stabilizers
selected from the group consisting of carbohydrates, antioxidants,
amino acids, buffers, and inorganic compounds. The suspension
formulation further comprises a non-aqueous, single-phase
suspension vehicle comprising one or more polymers and one or more
solvents. The suspension vehicle typically exhibits viscous fluid
characteristics and the particle formulation is dispersed in the
vehicle.
[0016] In another embodiment, the suspension formulation comprises
a particle formulation comprising a GLP-1 receptor agonist and/or a
beneficial agent, a disaccharide (e.g., sucrose), methionine, and a
buffer (e.g., citrate), and a non-aqueous, single-phase suspension
vehicle comprising one or more pyrrolidone polymer (e.g.,
polyvinylpyrollidone) and one or more solvent (e.g., lauryl
lactate, lauryl alcohol, benzyl benzoate, or mixtures thereof.
[0017] The particle formulations of the present invention may
further comprise a buffer, for example, selected from the group
consisting of citrate, histidine, succinate, and mixtures
thereof.
[0018] The particle formulations of the present invention may
further comprise an inorganic compound, for example, selected from
the group consisting of citrate, histidine, succinate, and mixtures
thereof. NaCl, Na.sub.2SO.sub.4, NaHCO.sub.3, KCl,
KH.sub.2PO.sub.4, CaCl.sub.2, and MgCl.sub.2.
[0019] The one or more stabilizers in the particle formulations may
comprise, for example, a carbohydrate selected from the group
consisting of lactose, sucrose, trehalose, mannitol, cellobiose,
and mixtures thereof.
[0020] The one or more stabilizers in the particle formulations may
comprise, for example, a antioxidant selected from the group
consisting of methionine, ascorbic acid, sodium thiosulfate,
ethylenediaminetetraacetic acid (EDTA), citric acid, cysteins,
thioglycerol, thioglycolic acid, thiosorbitol, butylated
hydroxanisol, butylated hydroxyltoluene, and propyl gallate, and
mixtures thereof.
[0021] The one or more stabilizers in the particle formulations may
comprise an amino acid.
[0022] In one embodiment, the solvent of the suspension vehicle of
the present invention is selected from the group consisting of
lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures
thereof. An example of a polymer that can be used to formulate the
suspension vehicle is a pyrrolidone (e.g., polyvinylpyrrolidone).
In a preferred embodiment, the polymer is a pyrrolidone and the
solvent is benzyl benzoate.
[0023] The suspension formulation typically has an overall moisture
content less than about 10 wt % and in a preferred embodiment less
than about 5 wt %.
[0024] In additional embodiments, a beneficial agent, such as an
anticancer agent, in addition to the GLP-1 receptor agonist is
delivered to said subject. In certain embodiments, the anticancer
agent is a chemotherapeutic agent and/or an anticancer antibody.
The additional beneficial agent can be delivered prior to,
subsequent to or concurrent with the GLP-1 receptor agonist. In
some embodiments, an implantable drug delivery device may be used
to deliver formulations comprising an anticancer agent. In one
embodiment, the device is an osmotic delivery device.
[0025] In some embodiments, implantable drug delivery devices
deliver a GLP-1 receptor agonist formulations and/or other
beneficial agent formulations at a substantially uniform rate for a
period of about one month to about a year. Such devices may, for
example, be implanted subcutaneously in convenient locations.
[0026] The present invention also includes methods of manufacturing
the suspension formulations, particle formulations, suspension
vehicles, and devices of the present invention as described
herein.
[0027] 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
[0028] FIGS. 1A and 1B present the sequences of two representative
GLP-1 receptor agonists: FIG. 1A, glucagon-like peptide 1
(7-36)amide (GLP-1(7-36)amide) (SEQ ID NO:1), and FIG. 1B,
synthetic exenatide peptide (SEQ ID NO:2).
[0029] FIG. 2 presents a partial cross-sectional view of one
embodiment of an osmotic delivery device useful in the practice of
the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0030] 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.
1.0.0 DEFINITIONS
[0031] 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 GLP-1 receptor agonist" includes
a combination of two or more such molecules, reference to "a
peptide" includes one or more peptides, mixtures of peptides, and
the like.
[0032] 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.
[0033] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0034] 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
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).
[0035] 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.
[0036] 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.
[0037] The term "GLP-1 receptor agonist" as used herein refers to
an agent capable of binding and activating the GLP-1 receptor. The
term includes GLP-1 hormones, as well as GLP-1 peptides, peptide
analogs thereof, or peptide derivatives thereof. Also encompassed
by the term GLP-1 receptor agonist are other molecules that are
capable of binding and activating the GLP-1 receptor, such as
without limitation, an exenatide peptide, a peptide analog thereof,
or a peptide derivative thereof. Specific examples of preferred
GLP-1 receptor agonists include exenatide having the amino acid
sequence of exendin-4, GLP-1(7-36)amide, lixisenatide, liraglutide
(VICTOZA.TM.), albiglutide (SYNCRIA.TM.), semaglutide,
taspoglutide, BYETTA.TM., BYDUREON.TM. and LY2189265. The term also
includes small molecules capable of binding and activating the
GLP-1 receptor. See, e.g., Sloop et al., Diabetes (2010)
59:3099-3107.
[0038] The term "anticancer agent" refers to any agent that
exhibits anti-tumor activity as defined below. Such agents include,
without limitation, chemotherapeutic agents (i.e., a chemical
compound or combination of compounds useful in the treatment of
cancer), anticancer antibodies, agents that disrupt nucleic acid
transcription and/or translation, such as antisense
oligonucleotides, small interfering RNA (siRNA), and the like.
[0039] By "anti-tumor activity" is intended a reduction in the rate
of cell proliferation, and hence a decline in growth rate of an
existing tumor or in a tumor that arises during therapy, and/or
destruction of existing neoplastic (tumor) cells or newly formed
neoplastic cells, and hence a stabilization or decrease in the
overall size of a tumor during therapy.
[0040] By "antidiabetic agent" is meant any agent that when
administered to a subject either directly or indirectly causes a
reduction in glucose levels. Such agents include, without
limitation, agents for treating types 1 and 2 diabetes, such as but
not limited to, GLP-1 receptor agonists; small molecules such as
metformin, tolbutamide, glibenclamide, glipizide, gliquidone,
glibornuride, tolazamide, sulfonylureas, meglitinides (e.g.,
repaglinide, and nateglinide); thiazolidinediones (TZDs), such as
pioglitazone; SGLT.sub.1 and SGLT.sub.2 inhibitors; alpha
glucosidase inhibitors; amylin (as well as synthetic analogs such
as pramlintide); dipeptidyl peptidase IV (DPP-1V) inhibitors (e.g.,
saxagliptin, sitagliptin, alogliptin and vildagliptin); long/short
acting insulins; glucagon receptor antagonists; GRP agonists (e.g.,
GRP-119 and GRP-40), and the like. Use of oral dipeptidyl
peptidase-IV (DPP-IV or DPP-4) inhibitors orally to prevent
cleavage of GLP-1 may be particularly useful when the formulation
comprises a GLP-1 that is cleavable by dipeptidyl peptidase-1V
(see, e.g., U.S. Pat. No. 7,205,409, incorporated herein by
reference in its entirety).
[0041] An "antibody" intends a molecule that binds to an epitope of
interest present in an antigen. The term "antibody" as used herein
includes antibodies obtained from both polyclonal and monoclonal
preparations, as well as, the following: hybrid (chimeric) antibody
molecules (see, for example, Winter et al., Nature (1991)
349:293-299; and U.S. Pat. No. 4,816,567); F(ab')2 and F(ab)
fragments; Fv molecules (non-covalent heterodimers, see, for
example, Inbar et al., Proc Natl Acad Sci USA (1972) 69:2659-2662;
and Ehrlich et al., Biochem (1980) 19:4091-4096); single-chain Fv
molecules (sFv) (see, for example, Huston et al., Proc Natl Acad
Sci USA (1988) 85:5879-5883); dimeric and trimeric antibody
fragment constructs; diabodies; avamers; aptamers; affitins;
affitins; anticalins; affibody molecules; designed ankyrin repeat
proteins; domain antibodies; minibodies (see, e.g., Pack et al.,
Biochem (1992) 31:1579-1584; Cumber et al., J Immunology (1992)
149B:120-126); humanized antibody molecules (see, for example,
Riechmann et al., Nature (1988) 332:323-327; Verhoeyan et al.,
Science (1988) 239:1534-1536; and U.K. Patent Publication No. GB
2,276,169, published 21 Sep. 1994); and, any functional fragments
obtained from such molecules, or fusions thereof, wherein such
fragments and fusions retain immunological binding properties of
the parent antibody molecule. Chimeric antibodies composed of human
and non-human amino acid sequences may be formed from monoclonal
antibody molecules to reduce their immunogenicity in humans (Winter
et al. (1991) Nature 349:293; Lobuglio et al. (1989) Proc. Nat.
Acad. Sci. USA 86:4220; Shaw et al. (1987) J Immunol. 138:4534; and
Brown et al. (1987) Cancer Res. 47:3577; Rieclunann et al. (1988)
Nature 332:323; Verhoeyen et al. (1988) Science 239:1534; and Jones
et al. (1986) Nature 321:522; EP Publication No. 519,596, published
23 Dec. 1992; and U.K. Patent Publication No. GB 2,276,169,
published 21 Sep. 1994).
[0042] As used herein, the term "monoclonal antibody" refers to an
antibody composition having a homogeneous antibody population. The
term is not limited regarding the species or source of the
antibody, nor is it intended to be limited by the manner in which
it is made. The term encompasses whole immunoglobulins as well as
fragments such as Fab, F(ab').sub.2, Fv, and other fragments, as
well as chimeric and humanized homogeneous antibody populations,
that exhibit immunological binding properties of the parent
monoclonal antibody molecule.
[0043] As used herein, the term "anti-cancer antibody" encompasses
antibodies that have been designed to target cancer cells,
particularly cell-surface antigens residing on cells of a
particular cancer of interest.
[0044] 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.
[0045] 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.
[0046] The phrase "single-phase" as used herein refers to a solid,
semisolid, or liquid homogeneous system that is physically and
chemically uniform throughout.
[0047] The term "dispersed" as used herein refers to dissolving,
dispersing, suspending, or otherwise distributing a compound, for
example, a peptide, in a suspension vehicle.
[0048] A "homogeneous suspension" typically refers to a particle
that is insoluble in a suspension vehicle and is distributed
uniformly in a suspension vehicle.
[0049] 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.
[0050] 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.
[0051] 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) [0052] where F/A=shear stress (force per
unit area). [0053] .mu.=a proportionality constant (viscosity), and
[0054] V/L=the velocity per layer thickness (shear rate).
[0055] 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 a viscometer,
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 particles suspended therein from
settling during storage and use in a method of delivery, for
example, in an implantable, drug delivery device.
[0056] 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 5 wt %, and more preferably less than about
4 wt %.
[0057] 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
macaque, chimpanzees and other apes and monkey 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. Thus, both adult and newborn individuals are
intended to be covered.
[0058] 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 GLP-1 receptor agonist, e.g., GLP-1
(7-36)amide, exenatide, and derivatives or analogs thereof. The
devices and methods of the present invention are well suited for
the delivery of polypeptides as well as small molecules and
combinations thereof.
[0059] The term "osmotic delivery device" as used herein typically
refers to a device used for delivery of one or more GLP-1 receptor
agonists, or other beneficial agents to a subject, wherein the
device comprises, for example, a reservoir (made, for example, from
a titanium alloy) having a lumen that contains, in one chamber, a
beneficial agent formulation (e.g., comprising one or more
beneficial agent) and, in another chamber, an osmotic agent
formulation. A piston assembly positioned in the lumen isolates the
beneficial agent formulation from the osmotic agent formulation. A
semi-permeable membrane (also termed a semi-permeable plug) is
positioned at a first distal end of the reservoir adjacent the
osmotic agent formulation. A diffusion moderator (which defines a
delivery orifice through which the beneficial agent formulation
exits the device) is positioned at a second distal end of the
reservoir adjacent the suspension formulation. The piston assembly
and the diffusion moderator define a chamber that contains the
beneficial agent formulation and the piston assembly and the
semipermeable membrane define a chamber that contains the osmotic
agent formulation. The terms "flow modulator," "diffusion
modulator," "flow moderator," and "diffusion moderator" are used
interchangeably herein. 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.TM.
delivery device.
2.0.0 GENERAL OVERVIEW OF THE INVENTION
[0060] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
types of drug delivery, particular types of drug delivery devices,
particular sources of peptides, 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.
[0061] In one aspect, the present invention relates to methods of
treating cancer in a subject in need of treatment, including, but
not limited to, treating hematological tumors and solid tumors. The
method comprises providing delivery of a GLP-1 receptor agonist
formulation to a subject in need thereof. In certain embodiments,
the GLP-1 receptor agonist formulation is delivered using an
osmotic delivery device at a substantially uniform rate. The length
of delivery of the formulation is determined based on the cancer
being treated. In some embodiments, for example, the administration
period is for at least about one month, at least about one month to
about one year, at least about three months to about one year, at
least about four months to about one year, at least about five
months to about one year, at least about six months to about one
year, at least about eight months to about one year, at least about
nine months to about one year, or at least about 10 months to about
one year. The period of administration can also exceed one year if
necessary, such as from one year to two years. The method may
further include subcutaneously inserting an osmotic delivery
device, loaded with the GLP-1 receptor agonist formulation, into
the subject.
[0062] In other embodiments of the invention, the GLP-1 receptor
agonist is delivered parenterally (including by subcutaneous,
intravenous, intramedullary, intraarticular, intramuscular, or
intraperitoneal injection) rectally, topically, transdermally,
intranasally, by inhalation, or orally (for example, in capsules,
suspensions, or tablets). Injectable formulations of GLP-1 agonists
are known and include, without limitation, lixisenatide,
liraglutide (VICTOZA.TM.), albiglutide (SYNCRIA.TM.), semaglutide,
taspoglutide, BYETTA.TM., BYDLIREON.TM. and LY2189265.
[0063] In one embodiment of the present invention the formulation
comprises a glucagon-like peptide-1 (GLP-1), a derivative of GLP-1,
or an analog of GLP-1.
[0064] In certain embodiments, the GLP-1 receptor agonist is
GLP-1(7-36)amide shown in FIG. 1A (SEQ ID NO:1).
[0065] In another embodiment of the present invention the
formulation comprises exenatide, a derivative of exenatide, or an
analog of exenatide. In certain embodiments, the exenatide is the
exenatide peptide shown in FIG. 1B (SEQ ID NO:2).
[0066] In certain embodiments, additional beneficial agents are
provided with the GLP-1 receptor agonist formulations, such as
anticancer agents, including without limitation, chemotherapeutic
agents, anticancer antibodies, antisense nucleotides, siRNA,
anticancer vaccines, and the like. Such additional beneficial
agents are described in detail below. Administration of these
agents is not limited to any particular delivery system and may
include, without limitation, delivery using osmotic delivery
devices as described herein if the agent is suitable for such
delivery, or may be parenteral (including subcutaneous,
intravenous, intramedullary, intraarticular, intramuscular, or
intraperitoneal injection), rectal, topical, transdermal,
intranasal, by inhalation, or oral (for example, in capsules,
suspensions, or tablets). Administration of the additional agents
to an individual may occur in a single dose or in repeat
administrations, and in any of a variety of physiologically
acceptable salt forms, and/or with an acceptable pharmaceutical
carrier and/or additive as part of a pharmaceutical composition.
Physiologically acceptable salt forms and standard pharmaceutical
formulation techniques and excipients are well known to persons
skilled in the art (see, e.g., Physicians' Desk Reference (PDR)
2009, 63th ed. (PDR.net), Medical Economics Company; and Remington:
The Science and Practice of Pharmacy, eds. Gennado et al., 21th ed,
Lippincott, Williams & Wilkins, 2005).
[0067] In certain embodiments, the GLP-1 receptor agonist and/or
suitable additional beneficial agents, if present, are provided in
a suspension formulation, comprising a particle formulation and a
suspension vehicle. The particle formulation includes, but is not
limited to, the GLP-1 receptor agonist or other agent of interest
and one or more stabilizers. The one or more stabilizers are
typically selected from the group consisting of carbohydrates,
antioxidants, amino acids, and buffers. The suspension vehicle is
typically a non-aqueous, single-phase suspension vehicle comprising
one or more polymers and one or more solvents. The suspension
vehicle exhibits viscous fluid characteristics. The particle
formulation is uniformly dispersed in the vehicle.
[0068] The particle formulation of the present invention typically
includes one or more of the following stabilizers: one or more
carbohydrates (e.g., a disaccharide, such as, lactose, sucrose,
trehalose, cellobiose, and mixtures thereof); one or more
antioxidants (e.g., methionine, ascorbic acid, sodium thiosulfate,
ethylenediaminetetraacetic acid (EDTA), citric acid, butylated
hydroxyltoluene, and mixtures thereof); and one or more buffers
(e.g., citrate, histidine, succinate, and mixtures thereof). In a
preferred embodiment, the particle formulation comprises a GLP-1
receptor agonist, sucrose, methionine, and citrate buffer. The
ratio of the GLP-1 receptor agonist to sucrose+methionine is
typically about 1/20, about 1/10, about 1/5, about 1/2, about 2/1,
about 5/1, about 10/1, or about 20/1, preferably between about 1/5
to 5/1, more preferably between about 1/3 to 3/1. The particle
formulation is preferably a particle formulation prepared by spray
drying and has a low moisture content, preferably less than or
equal to about 10 wt %, more preferably less or equal to about 5 wt
%. Alternatively, the particle formulation can be lyophilized.
[0069] The suspension vehicle for use in the present formulations
comprises one or more solvents and one or more polymers. Preferably
the solvent is selected from the group consisting of lauryl
lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof.
More preferably the solvent is lauryl lactate or benzyl benzoate.
Preferably the polymer is a pyrrolidone polymer. In some
embodiments the polymer is polyvinylpyrrolidone (e.g.,
polyvinylpyrrolidone K-17, which typically has an approximate
average molecular weight range of 7,900-10,800). In one embodiment,
the solvent consists essentially of benzyl benzoate and
polyvinylpyrrolidone.
[0070] The suspension formulation typically has a low overall
moisture content, for example, less than or equal to about 10 wt %
and in a preferred embodiment less than or equal to about 5 wt
%.
[0071] 2.1.0 Compositions and Formulations
[0072] 2.1.1 GLP-1 Receptor Agonists
[0073] 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., they
are insulinotropic), which results in decreases in serum glucose
concentrations (see, e.g., Mojsov, S., Int. J. Peptide Protein
Research (1992) 40:333-343). The sequence of GLP-1(7-36)amide is
shown in FIG. 1A and SEQ ID NO:1.
[0074] 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, all of which are
incorporated herein by reference in their entireties), 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.TM. (liraglutide; U.S. Pat. Nos.
6,268,343, 6,458,924, 7,235,627, incorporated herein by reference
in their entireties). Once-daily injectable VICTOZA.TM.
(liraglutide) is commercially available in the United States,
Europe, and Japan. Other injectable GLP-1 peptides for use with the
present invention are described above and include, without
limitation taspoglutide, albiglutide (SYNCRIA.TM.), LY2189265 and
semaglutide. For ease of reference 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."
[0075] The molecule exenatide has the amino acid sequence of
exendin-4 (Kolterman O. G., et al., J. Clin. Endocrinol. Metab.
(2003) 88(7):3082-3089) 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.TM.. Another injectable exenatide
under development is BYDUREON.TM.. Exendin-3 and exendin-4 are
known in the art and were originally isolated from Heloderma spp.
(Eng, et al., J. Biol. Chem. (1990) 265:20259-62; Eng., et al., J.
Biol. Chem. (1992) 267:7402-05). 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, all of which are incorporated herein by
reference in their entireties). One example of an exenatide
derivative useful in the practice of the present invention is
lixisenatide (see, e.g., U.S. Pat. No. 6,528,486, incorporated
herein by reference in its entirety). 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."
[0076] 2.1.2 Suspension Formulations
[0077] In one aspect, the present invention utilizes particle
formulations of GLP-1 receptor agonists described above that can be
used to prepare suspension formulations. The GLP-1 receptor
agonists for use with the present invention shall not be limited by
method of synthesis or manufacture and shall include those obtained
from natural sources, or synthesized or manufactured by recombinant
(whether produced from cDNA or genomic DNA), synthetic, transgenic,
and gene-activated methods. In preferred embodiments of the present
invention, the GLP-1 receptor agonist is a GLP-1 peptide or an
exendin peptide (as described above), for example, GLP-1(7-36)amide
or exenatide, such as the exenatide peptide shown in FIG. 1B and
SEQ ID NO:2. The present invention also includes combinations of
two or more such agents, for example, GLP-1(7-36)amide and GIP.
[0078] Particle formulations are preferably chemically and
physically stable for at least one month, preferably at least three
months, more preferably at least six 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, particle formulations are preferably chemically and
physically stable for at least three months, preferably at least
six 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.
[0079] A 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 peptide particles are formed after about three months,
preferably after about six months, preferably after about 12 months
at delivery temperature and after about six months, after about 12
months, and preferably after about 24 months at storage
temperature.
[0080] A 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 peptide particles are formed after about three
months, preferably after about six months, at delivery temperature
and about 6 months, preferably about 12 months, at storage
temperature.
[0081] To preserve protein stability, a GLP-1 receptor agonist
solution is generally 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
peptide. 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. No mobility of molecules
correlates with no instability issues. Tg is also dependent on the
moisture level in the product formulation. Generally, the more
moisture, the lower the Tg of the composition.
[0082] 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, milling,
granulation, ultrasonic drop creation, crystallization,
precipitation, or other techniques available in the art for forming
particles from a mixture of components. The particles are
preferably substantially uniform in shape and size.
[0083] A typical spray dry process may include, for example,
loading a spray solution containing a peptide, for example,
GLP-1(7-36)amide or exenatide, and stabilizing excipients into a
sample chamber. The sample chamber is typically maintained at a
desired temperature, for example, refrigeration to room
temperature. Refrigeration generally promotes stability of the
protein. A solution, emulsion, or suspension is introduced to the
spray dryer where the fluid is atomized into droplets. Droplets can
be formed by use of a rotary atomizer, pressure nozzle, pneumatic
nozzle, or sonic nozzle. The mist of droplets is immediately
brought into contact with a drying gas in a drying chamber. The
drying gas removes solvent from the droplets and carries the
particles into a collection chamber. In spray drying, factors that
can affect yield include, but are not limited to, localized charges
on particles (which may promote adhesion of the particles to the
spray dryer) and aerodynamics of the particles (which may make it
difficult to collect the particles). In general, yield of the spray
dry process depends in part on the particle formulation.
[0084] In one embodiment, the particles are sized such that they
can be delivered via an implantable 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%, 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 device, wherein the
delivery orifice diameter of the implant is in a range of, for
example, about 0.1 to about 0.5 mm, particle sizes may be
preferably less than about 50 microns, more preferably less than
about 10 microns, more preferably in a range from about 3 to about
7 microns. In one embodiment, the orifice is about 0.25 mm (250
microns) and the particle size is approximately 3-5 microns.
[0085] In a preferred embodiment, when the particles are
incorporated in a suspension vehicle they do not settle in less
than about three months at delivery temperature. 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 an
embodiment of the particle formulation for use in an implantable
osmotic delivery device, wherein the delivery orifice diameter of
the implant is in a range of, for example, about 0.1 to about 0.5
mm, particle sizes may be preferably less than about 50 microns,
more preferably less than about 10 microns, more preferably in a
range from about 3 to about 7 microns.
[0086] In one embodiment, a particle formulation for use with the
present invention comprises one or more GLP-1 receptor agonists, as
described above and one or more stabilizers. The stabilizers may
be, for example, carbohydrate, antioxidant, amino acid, buffer, or
inorganic compound. The amounts of stabilizers in the particle
formulation can be determined experimentally based on the
activities of the stabilizers and buffers and the desired
characteristics of the formulation. Typically, the amount of
carbohydrate in the formulation is determined by aggregation
concerns. In general, the carbohydrate level should not be too high
so as to avoid promoting crystal growth in the presence of water
due to excess carbohydrate unbound to insulinotropic peptide.
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 components in the formulation is determined by
pre-processing concerns, stability concerns, and formability of
particles during spray drying. Buffer may be required to stabilize
the GLP-1 receptor agonist during processing, e.g., solution
preparation and spray drying, when all excipients are
solubilized.
[0087] 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 non-reducing sugars, such as sucrose,
trehalose, and raffinose.
[0088] 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.
[0089] 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.
[0090] 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. It is to be understood that buffers can be added to the
solution before formation of the particles, for example, by spray
drying. However, after the dry particle formation is prepared, the
buffer component no longer serves as a buffer in the dried
particles. For ease of reference herein, when referring to buffer
components, the term buffer is used.
[0091] Examples of inorganic compounds that may be included in the
particle formulation include, but are not limited to, NaCl,
Na.sub.2SO.sub.4, NaHCO.sub.3, KCl, KH.sub.2PO.sub.4, CaCl.sub.2,
and MgCl.sub.2.
[0092] In addition, the particle formulation may include other
excipients, such as but not limited to surfactants and salts.
Examples of surfactants include, but are not limited to,
Polysorbate 20, Polysorbate 80, PLURONIC.TM., F68, and sodium
docecyl sulfate (SDS). Examples of other excipients include, but
are not limited to, mannitol and glycine. Examples of salts
include, but are not limited to, sodium chloride, calcium chloride,
and magnesium chloride.
[0093] In one embodiment, the particle formulation comprises, for
example, exenatide peptide, sucrose (carbohydrate), methionine
(antioxidant), and sodium citrate/citric acid.
[0094] All components included in the particle formulation are
typically acceptable for pharmaceutical use in mammals, in
particular, in humans.
[0095] Particle size distribution of the dry particle powder can be
well controlled (0.1 micron -20 micron), for example, by using the
methods of spray drying or lyophilization to prepare the particle
formulations. The process parameters for formation of the dry
powder are optimal to produce particles with desired particle size
distribution, density, and surface area.
[0096] The selected excipients and stabilizers in the particle
formulation may provide, for example, the following functions:
density modification of the dry powder; preservation of the peptide
chemical stability; maintenance of the peptide's physical stability
(e.g., high glass transition temperature, and avoiding phase to
phase transition); producing homogenous dispersions in suspension;
and modification of hydrophobicity and/or hydrophilicity to
manipulate dry powder solubility in selected solvents.
[0097] See U.S. Patent Publication No. 2008/0260840, incorporated
herein by reference in its entirety, for detailed methods of
producing particle formulations.
[0098] In summary, GLP-1 receptor agonists can be formulated into
dried powders in solid state, which preserves maximum chemical and
biological stability of proteins or peptides. The particle
formulation offers long term storage stability at high temperature,
and therefore, allows delivery to a subject of stable and
biologically effective peptide for extended periods of time.
[0099] Although the particle formulations described above are with
reference to GLP-1 receptor agonists, such particle formulations
can also be formed with any other suitable agents, such as other
suitable beneficial polypeptides, including suitable anticancer
polypeptides, antibodies and the like, described in detail
below.
[0100] Suspension formulations for use with the present invention
can be produced using particle formulations as described above. See
U.S. Patent Publication No. 2008/0260840, incorporated herein by
reference in its entirety, for detailed methods of producing such
suspension formulations. In one aspect of the present invention,
the suspension formulation includes a suspension vehicle to provide
a stable environment in which the GLP-1 receptor agonist particle
formulation (or other suitable particle formulation) is dispersed.
The particle formulations are chemically and physically stable (as
described above) in the suspension vehicle. The suspension vehicle
typically comprises one or more polymers and one or more solvents
that form a solution of sufficient viscosity to uniformly suspend
the particles comprising the GLP-1 receptor agonist or other
suitable agent. In addition to the GLP-1 receptor agonist, the
suspension formulations can be used with any suitable agents, such
as other suitable beneficial polypeptides, including suitable
anticancer polypeptides, antibodies and the like, described in
detail below.
[0101] The viscosity of the suspension vehicle is typically
sufficient to prevent the particle formulation from settling during
storage and use in a method of delivery, for example, in an
implantable, drug 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. The disintegration of the suspension vehicle may occur
by one or more physical or chemical degradative processes, such as
by enzymatic action, oxidation, reduction, hydrolysis (e.g.,
proteolysis), displacement (e.g., ion exchange), or dissolution by
solubilization, emulsion or micelle formation. After the suspension
vehicle disintegrates, components of the suspension vehicle are
absorbed or otherwise dissipated by the body and surrounding tissue
of the patient.
[0102] The solvent in which the polymer is dissolved may affect
characteristics of the suspension formulation, such as the behavior
of the 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, 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.
[0103] 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%. However,
typically particles comprising the GLP-1 receptor agonists are
substantially insoluble in the solvent. 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 combinations
thereof.
[0104] Examples of polymers for formulation of the suspension
vehicles include, but are not limited to, a polyester (e.g.,
polylactic acid or polylacticpolyglycolic acid), pyrrolidone
polymer (e.g., polyvinylpyrrolidone (PVP) 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. In one embodiment, the polymer is PVP 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).
Polyvinylpyrrolidone can be characterized by its K-value (e.g.,
K-17), which is a viscosity index. 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.
[0105] Generally speaking, a suspension vehicle according to the
present invention may vary in composition based on the desired
performance characteristics. In one embodiment, the suspension
vehicle may comprise about 40% to about 80% (w/w) polymer(s) and
about 20% to about 60% (w/w) solvent(s). Preferred embodiments of a
suspension vehicle include vehicles formed of polymer(s) and
solvent(s) combined at the following ratios: about 25% solvent and
about 75% polymer; about 50% solvent and about 50% polymer; about
75% solvent and about 25% polymer.
[0106] 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 insulinotropic peptide at a desired rate. 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.
[0107] 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. The viscosity may be measured
at a selected temperature, for example, 33.degree. C., at a shear
rate of 10.sup.-4/sec, using a parallel plate rheometer. In some
embodiments, the viscosity of the suspension vehicle ranges from
approximately 5,000 poise to approximately 50,000 poise, such as
about 7,000 poise to about 40,000 poise, about 8,000 poise to about
20,000 poise, about 9,000 poise to about 25,000 poise, about 10,000
poise to about 20,000 poise, and the like. In preferred
embodiments, the viscosity range is between about 12,000 to about
18,000 poise at 33.degree. C.
[0108] 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.
[0109] 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,
incorporated herein by reference in its entirety).
[0110] The particle formulation, comprising a GLP-1 receptor
agonist, or other suitable agent, is added to the suspension
vehicle to form a suspension formulation. 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.
[0111] 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 %.
[0112] The suspension formulations of the present invention are
exemplified herein below with reference to exenatide and
GLP-1(7-36)amide as representative GLP-1 receptor agonists (see,
Example 3 and Example 4). These examples are not intended to be
limiting.
[0113] 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,
for example, dry powder 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.
3.0.0 DELIVERY OF SUSPENSION FORMULATIONS
[0114] The suspension formulations described herein may be used in
an implantable, drug delivery device to provide sustained delivery
of a compound over an extended period of time, such as over weeks,
months, or up to about one year. Such an implantable drug delivery
device is typically capable of delivering the compound at a desired
flow rate over a desired period of time. The suspension formulation
may be loaded into the implantable, drug delivery device by
conventional techniques.
[0115] The suspension formulation may be delivered, for example,
using an osmotically, mechanically, electromechanically, or
chemically driven drug delivery device. The active agent in the
suspension formulation is delivered at a flow rate that is
therapeutically effective to the subject in need of treatment.
[0116] The active agent, such as GLP-1(7-36)amide, exenatide, or
other suitable beneficial agent, may be delivered over a period
ranging from more than about one week to about one year or more,
preferably for about one month to about a year or more, more
preferably for about three months to about a year or more. The
implantable, drug delivery device may include a reservoir having at
least one orifice through which the agent is delivered. The
suspension formulation may be stored within the reservoir. In one
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.TM. 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, and 2008-0091176, all
of which are incorporated herein by reference in their
entireties).
[0117] The DUROS.TM. 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 water-permeable membrane and capped at the other
end by a diffusion moderator through which drug formulation 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.
[0118] The DUROS.TM. device releases a therapeutic agent at a
predetermined rate based on the principle of osmosis. Extracellular
fluid enters the DUROS.TM. 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, the reservoir of the
DUROS.TM. device is loaded with a suspension formulation
comprising, for example, GLP-1(7-36)amide or exenatide, wherein the
device is capable of delivering the suspension formulation to a
subject over an extended period of time (e.g., about one, about
two, about three, about six, or about 12 months) at a
predetermined, therapeutically effective delivery rate.
[0119] Other implantable, drug delivery devices may be used in the
practice of the present invention and may include regulator-type
implantable pumps that provide constant flow, adjustable flow, or
programmable flow of the compound, such as those available from
Codman & Shurtleff, Inc. (Raynham, Mass.), Medtronic, Inc.
(Minneapolis, Minn.), and Tricumed Medinzintechnik GmbH
(Germany).
[0120] Implantable devices, for example, the DUROS.TM. device,
provide the following advantages for administration of the
formulations of the present invention: true zero-order release of
the insulinotropic peptide pharmacokinetically; long-term release
period time (e.g., up to about 12 months); and reliable delivery
and dosing of the GLP-1 receptor agonist or other suitable
beneficial agent.
[0121] FIG. 2 depicts a representative osmotic delivery device
useful in the practice of the present invention. In FIG. 2, an
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, such as a GLP-1
receptor agonist (e.g., GLP-1 (7-36)amide or exenatide)
formulation, an anticancer agent, or the like and the chamber 20
contains an osmotic agent formulation. A semi-permeable membrane 18
is positioned at a 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 distal end
of the reservoir 12, adjacent the chamber 16 containing the
beneficial agent formulation. 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, incorporated herein by reference in its
entirety).
[0122] 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 beneficial
agent formulation is expelled 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.
[0123] 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. 2, it is shown to
have ridges that serve to frictionally engage the semi-permeable
membrane 18 with the interior surface of the reservoir 12.
[0124] The amount of beneficial agent employed in the delivery
device of the invention is that amount necessary to deliver a
therapeutically effective amount of the agent to achieve the
desired therapeutic result. In practice, this will vary depending
upon such variables, for example, as the particular agent, the site
of delivery, the severity of the condition, and the desired
therapeutic effect. 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.
[0125] Typically, the osmotic delivery device is implanted within
the subject, for example, subcutaneously. The device(s) can be
inserted in either or both arms (e.g., in the inside, outside, or
back of the upper arm) or into the abdomen. Preferred locations in
the abdomen are under the abdominal skin in the area extending
below the ribs and above the belt line. To provide a number of
locations for insertion of one or more osmotic delivery devices
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.
[0126] The suspension formulation may also be delivered from a drug
delivery device that is not implantable or implanted, for example,
an external pump such as a peristaltic pump used for subcutaneous
delivery in a hospital setting.
[0127] The suspension formulations of the present invention may
also be used in infusion pumps, for example, the ALZET.TM. osmotic
pumps which are miniature, infusion pumps for the continuous dosing
of laboratory animals (e.g., mice and rats).
[0128] The suspension formulations of the present invention may
also be used in the form of injections to provide highly
concentrated bolus doses of biologically active agents, such as the
GLP-1 receptor agonists, anti-cancer agents, etc.
4.0.0 ANTICANCER AGENTS
[0129] The GLP-1 receptor agonists, such as GLP-1(7-36)amide and
exenatide, can be delivered to a patient as a single modality
treatment or in combination with other beneficial agents, including
anticancer agents as described below, chemotherapeutic drugs,
anticancer antibodies, antisense molecules, siRNA, and the
like.
[0130] For example, one useful combination is with a tyrosine
kinase inhibitor, such as SUTENT.TM., NEXAVAR.TM., BIBF 1120,
ZD1839 (gefitinib), erlotinib, TYKERB.TM., and the like.
[0131] mTOR inhibitors, such as rapamycin (sirolimus), AZD8055,
NVP-BEZ235, deforolimus, everolimus, temsirolimus, GSK1059615,
WYE354, KU0063794, XL765 (all available from Selleck Chemicals)
will also find use in a combination treatment.
[0132] Other drugs for use in combination with the GLP-1 receptor
agonists (e.g., exenatide and GLP-1(7-36)amide), are those that
cause hypoxia in tumor tissues, such as metformin, and drugs that
inhibit the hypoxia inducible factor 1 such as CCAA/enhancer
binding protein a, PX-478, resveratrol, and the various small
molecule inhibitors described in Jones et al., Mol. Cancer. Ther.
(2006) 5:2193-2202.
[0133] Also useful are drugs that inhibit IGF-1, such as octreonide
acetate and tyrosine kinase inhibitors, that serve to block IGF-1
receptor signaling.
[0134] VEGF-inhibitors, such as anti-VEGF antibodies including
bevacizumab) (AVASTIN.TM., as well as prolactin, sunitinib and
sorafenib, may also be used in combination with the GLP-1 receptor
agonists.
[0135] Another useful combination therapy is the use of a sugar
analog, such as 2DG, subsequent to reducing glucose availability to
the cancer cells using GLP-1 receptor agonists, such as exenatide
and GLP-1(7-36)amide.
[0136] Cell cycle blockers will also find use herein, such as a
cyclin-dependent kinase (cdk)-inhibitor, e.g., olomoucin,
butyrolactone-I, n-butyrate, upregulators of cdk activity, e.g.,
flavopiridol, Chalcones (1,3-diphenylpropen-1-ones) and derivatives
thereof.
[0137] The histone deacetylase (HDAC) enzyme SIRT-1 and other
related sirtuin proteins, analogs and derivatives thereof will also
find use herein.
[0138] Also useful are peptides that induce cell apoptosis, such
TRAIL, antagonists or antibodies against integrin
.alpha..sub.v.beta..sub.3, anti-survivin antibodies and antagonists
of survivin, and numerous pro-apoptotic peptides, well known in the
art, such as described in Ellerby et al., Nat. Med. (1999)
5:1032-1038.
[0139] Examples of cytokines which can be administered in a
combination treatment include G-CSF, GM-CSF, M-CSF, IL-1.alpha.,
IL-1.beta., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12,
IL-18, IL-21, IL-23, IFN-.alpha., IFN-.beta., IFN-.gamma.,
IFN-.lamda., MIP-1.alpha., MIP-1.beta., TGF-.beta., TNF.alpha., and
TNF-.beta.
[0140] Examples of chemokines which can be administered include
BCA-1/BLC, BRAK, Chemokine CC-2, CTACK, CXCL-16, ELC, ENA, ENA-70,
ENA-74, ENA-78, Eotaxin, Exodus-2, Fractalkine, GCP-2, GRO, GRO
alpha (MGSA), GRO-beta, GRO-gamma, HCC-1, HCC-4, 1-309, IP-10,
1-TAC, LAG-1, LD78-beta, LEC/NCC-4, LL-37, Lymphotactin, MCP, MCAF
(MCP-1), MCP-2, MCP-3, MCP-4, MDC, MDC, MDC-2, MDC-4, MEC/CCL28,
MIG, MIP, MIP-1 alpha, MIP-1 beta, MIP-1 delta, MIP-3/MPIF-1, MIP-3
alpha, MIP-3 bet, MIP-4 (PARC), MIP-5, NAP-2, PARC PF-4, RANTES,
RANTES-2, SDF-1 alpha, SDF-1 beta, TARC, and TECK.
[0141] Examples of growth factors which can be delivered include
Human Amphiregulin, Human Angiogenesis Proteins, Human ACE, Human
Angiogenin, Human Angiopoietin, Human Angiostatin, Human
Endostatin, Human Betacellulin, Human BMP, Human BMP-13/CDMP-2,
Human BMP-14/CDMP-1, Human BMP-2, Human BMP-3, Human BMP-4, Human
BMP-5, Human BMP-6, Human BMP-7, Human BMP-8, Human BMP-9, Human
Colony Stimulating Factors, Human flt3-Ligand, Human G-CSF, Human
GM-CSF, Human M-CSF, Human Connective Tissue Growth Factor, Human
Cripto-1, Human Cryptic, Human ECGF, Human EGF, Human EG-VEGF,
Human Erythropoietin, Human Fetuin, Human FGF, Human FGF-1, Human
FGF-10, Human FGF-16, Human FGF-17, Human FGF-18, Human FGF-19,
Human FGF-2, Human FGF-20, Human FGF-3, Human FGF-4, Human FGF-5,
Human FGF-6, Human FGF-7/KGF, Human FGF-8, Human FGF-9, Human
FGF-acidic, Human FGF-basic, Human GDF-11, Human GDF-15, Human
Growth Hormone Releasing Factor, Human HB-EGF, Human Heregulin,
Human HGF, Human IGF, Human IGF-1, Human IGF-11, Human Inhibin,
Human KGF, Human LCGF, Human LIF, Human Miscellaneous Growth
Factors, Human MSP, Human Myostatin, Human Myostatin Propeptide,
Human Nerve Growth Factor, Human Oncostatin M, Human PD-ECGF, Human
PDGF, Human PDGF (AA Homodimer), Human PDGF (AB Heterodimer), Human
PDGF (BB Homodimer), Human PDGF (CC Homodimer), Human PLGF, Human
PLGF-1, Human PLGF-2, Human SCF, Human SMDF, Human Stem Cell Growth
Factor, Human SCGF-alpha, Human SCGF-beta, Human Thrombopoietin,
Human Transforming Growth Factor, Human TGF-alpha, and Human
TGF-beta.
[0142] In some embodiments, chemotherapeutic agents used in the
methods of the invention are selected from antimetabolites; enzyme
inhibitors including topoisomerase I and II inhibitors, tyrosine
and serine/threonine kinase inhibitors and COX2 inhibitors, tubulin
binders, proteasome inhibitors, anticancer alkylating agents
including bifunctional and monofunctional alkylating agents and
methylating agents, anticancer antibiotics, anticancer antibodies
and active fragments and fusions thereof and antibody-drug
conjugates, bisphosphonates, antiestrogens and antiandrogens,
anticancer cytokines, anticancer enzymes, immunomodulatory agents,
anticancer peptides, anticancer retinoids, anticancer steroids and
related agents, anticancer phototherapeutics, normal tissue
protectors and antihormonal agents including aromatase
inhibitors.
[0143] Antimetabolites may include folate analogs, which inhibit
dihydrofolate reductase resulting in DNA breaks by blocking purine
and thymidylate synthesis. Examples of folate analogs include
methotrexate (FOLEX.TM.), trimetrexate (NEUTREXIN.TM.) and
pemetrexed (ALIMTA.TM.). Other anitmetabolites are nucleoside
analogs that disrupt DNA or RNA synthesis, such as purine or
pyrimidine analogs. Examples of purine analogs include allopurinol
(ZYLOPRIM.TM.), mercaptopurine (PURINETHOL.TM.), fludarabine
(FLUDARA.TM.), thioguanine (6-TG), cladribine (LEUSTATIN.TM.,
2-CdA), and pentostatin (NIPENT.TM.). Examples of pyrimidine
analogs include capecitabine (XELODA.TM.), cytarabine
(CYTOSAR.TM.), liposomal cytarabine (DEPOCYT.TM.), floxuridine
(FUDR.TM.), fluororouracil (ADRUCIL.TM.), gemcitabine (GEMZAR.TM.),
and clofarabine (CLOLAR.TM.), decitabine (DACOGEN.TM.) and
azacitadine (VIDAZA.TM.).
[0144] Topoisomerase II inhibitors bind to topoisomerase II and
DNA, preventing the resealing of DNA strands during replication,
and leading to DNA strand breaks, such as epipodophyllotoxins.
Examples of epipodophyllotoxins include etoposide (VEPESID.TM.,
ETOPOPHOS.TM.) and teniposide (VUMON.TM., VM26.TM.). Alternatively,
topoisomerase II inhibitors, such as anthracycline antibiotics,
intercalate between DNA base pairs leading to free radicals and
also topoisomerase II inhibition. Examples of anthracyclines
include daunorubicin (DANOIJXOME.TM., CERUBIDINE.TM.), liposomal
daunorubicin (DAUNOXOME.TM.), doxorubicin (ADRIAMYCIN.TM.,
RUBEX.TM.), liposomal doxorubicin (DOXIL.TM.), epirubicin
(ELLENCE.TM.), valrubicin (VALSTAR.TM.), and idarubicin
(IDAMYCIN.TM.). Mitoxantrone (NOVANTRONE.TM.) also inhibits
topoisomerase II and is an anticancer therapeutic.
[0145] Topoisomerase I inhibitors bind to topoisomerase I and DNA,
preventing DNA strand breaks, such as, e.g., camptothecins,
including irinotecan (CAMPTOSAR.TM.) and topotecan
(HYCAMTIN.TM.).
[0146] Anticancer kinase inhibitors inhibit phosphorylation of a
protein or small molecule messenger in a an intracellular signaling
pathway in malignant cells or vascular or stromal cells, such as,
e.g., imatinib mseylate (GLEEVEC.TM.), gefitinib (IRESSA.TM.) or
erlotinib (TARCEVA.TM.), sorafenib (NEXAVAR.TM.), sunitinib
(SUTENT.TM.), nilotinib (TASIGN.TM.), everolimus (AFINITOR.TM.),
lapatinib (TYKERB.TM.), dasatinib (SPRYCEL.TM.), BRAF inhibitors
such as GSK218436 (GlaxoSmithKline, London UK) and vemurafenib
(Plexxikon Inc., CA) and MEK inhibitors.
[0147] Tubulin binders include agents that bind to microtubules,
shift the microtubules toward polymerization, and are active in the
M phase, such as taxanes including docetaxel (TAXOTERE.TM.) and
paclitaxel (TAXOL.TM.) and epothilones including ixabepilone
(IXEMPRA.TM.) and eribulin mesylate. Other tubulin binders act by
inhibiting polymerization and mitotic spindle formation, and are
active in the S phase, such as, e.g., vinca alkaloids, including
vinblastine (VELBAN.TM.), vincristine (ONCOVIN.TM.), and
vinorelbine (NAVELBINE.TM.). Other tubulin binders include ILX-651
(TASIDOTIN.TM.) and estramustine (EMCYT.TM.), which inhibit
microtubule assembly and disassembly.
[0148] Proteasome inhibitors block the trypsin-like,
chymotrypsin-like and/or peptidylglutamyl peptide hydrolyzing-like
protease activities in nuclear and cytoplasmic proteasomes.
Examples of proteasome inhibitors include bortezomib
(VELCADE.TM.).
[0149] Anticancer alkylating agents are reactive molecules that
bind to DNA and interfere with DNA replication. These agents
include, but are not limited to, alkyl sulfonates such as busulfan
(MYLERAN.TM.), platinum analogs such as carboplatin
(PARAPLATIN.TM.), cisplatin (PLATINOL.TM.-AQ, and oxaliplatin
(ELOXATIN.TM.), nitrosoureas such as carmustine (BICNU.TM.),
lomustine (CCNU.TM., CEENU.TM.), and streptozocin (ZANOSAle),
nitrogen mustards including chlorambucil (LEUKERAN.TM.), uracil
mustard, cyclophosphamide (CYTOXAN.TM.), ifosfamide (IFEX.TM.),
meclorethamine (MUSTARGEN.TM.), and melphalan (ALKERAN.TM., L-PAM),
bendamustine (TREANDA.TM.), triazenes such as dacarbazine
(DTIC-DOME.TM.), procarbazine (MATULANE.TM.), temozolomide
(TEMODAR.TM.), ethylenimines including hexamethylamine
(HEXALEN.TM.), and thiotepa (THIOPLEX.TM.), hydroxyurea
(HYDREA.TM., arsenic trioxide (TRISENOX.TM.), mitomycin C
(MUTAMYCIN.TM., MITOZYTREX.TM.) and trabectedin (YONDELIS.TM.).
[0150] Anticancer antibiotics act by a variety of mechanisms
including inhibition of protein synthesis generation of oxygen free
radicals in the vicinity of DNA and other mechanisms. Examples of
anticancer antibiotics include actinomycin D (COSMEGEN.TM.),
bleomycin sulfate (BLENOXANE.TM.) and plicamycin
(MITHRACIN.TM.).
[0151] Anticancer antibodies bind to specific molecular targets on
cells or in the extracellular space. Anticancer antibodies act by
neutralizing the activity of the target, attracting immune cells to
the target cell or by being directly or indirectly cytotoxic toward
the target cell. Anticancer antibodies include, but are not limited
to, anti-CD52 antibodies such as alemtuzumab (CAMPATH.TM.);
anti-VEGF antibodies including bevacizumab (AVASTIN.TM.); anti-CD33
antibodies, including gemtuzumab ozogamicin (MYLOTARG.TM.);
anti-CD20 antibodies including ibritumomab (ZEVALINTm), rituximab
(RITUXAN.TM.), tositumomab (BEXXAR.TM.) and ofatumumab
(ARZERRA.TM.); anti-EGFR antibodies such as cetuximab (ERBITUX.TM.)
and panitumumab (VECTIBEX.TM.); anti-Her2 antibodies, including
trastuzumab (HERCEPTIN.TM.); anti-CTLA4 antibodies including
Ipilimumab (YERVOY.TM.); adnectins; and domain antibodies. Active
fragments and fusions of these antibodies will also find use
herein.
[0152] Anticancer cytokines include, but are not limited to,
aldesleukin (PROLEUKIN.TM.), denileukin diftitox (ONTAK.TM.),
GM-CSF (sargramostim, PROKINE.TM., LEUKINE.TM.), interferon alfa-2b
(INTRON.TM.-A), PEGinterferon alpha (PEGASYS.TM. or PEGINTRON.TM.)
and consensus interferon (INFERGEN.TM.).
[0153] Immunomodulatory agents are effective by increasing the
response of the immune system of the host to the malignancy.
Immunomodulatory agents include, but are not limited to, Bacillus
Calmette-Gurerin (BCG Vaccine), levamisole (ERGAMISOL.TM.),
thalidomide (THALIDOMID.TM.), sipuleucel-T (PROVENGE.TM.), and
lenalidomide (REVLIMID.TM.).
[0154] Anticancer retinoids include, but are not limited to,
aliretinoin (PANRETIN.TM.), bexarotene (TARGRETIN.TM.) and
tretinoin (VESANOID.TM., ATRA.TM.); other agents include octreotide
acetate (SANDOSTATIN.TM.).
[0155] Anticancer enzymes include asparaginase (ELSPAR.TM.),
pegademase (ADAGEN.TM.), and pegaspargase (ONCASPAR.TM.).
[0156] Anticancer steroids and related agents include dexamethasone
(DECADRON.TM.), predisone (DELTASONE.TM.), prednisolone
(DELTA-CORTEF.TM.) and mitotane (LYSODREN.TM.).
[0157] Normal tissue protectors include, but are not limited to,
amifostine (ETHYOL.TM.), darbepoetin alfa (ARANESP.TM.),
dexrazoxane (ZINECARD.TM.), epoetin alfa (EPOGEN.TM., PROCRIT.TM.),
filgrastim (NEUPOGEN.TM.), folinic acid (leucovorin), allopurinol
(ALOPRIM.TM.) mesna (MESNEX.TM.), oprelvekin (NEUMEGA.TM.),
pegfilgrastim (NEULASTA.TM.), GM-CSF (sargramostim, PROKINE.TM.,
LEUKINE.TM.), raloxifene (EVISTA.TM.) and eltrombopag
(PROMACTA.TM.).
[0158] Phototherapeutics are agents that sensitize cells so that
exposure to a specific frequency of laser light induces abundant
free radical formation and DNA alkylation. These agents include,
but are not limited to, porfimer sodium (PHOTOFRIN.TM.).
[0159] Antihormones include LHRH agonists, which compete with
gonadotropin by binding to the hypothalamus causing an initial
surge of LH and FSH followed by down regulation by negative
feedback, including goserelin (ZOLADEX.TM.), leuprolide (LUPRON.TM.
or ELIGARD.TM.), and triptorelin (TRELSTAR.TM.); and antiandrogens,
which competitively bind and inhibit the binding of androgens to
androgen receptors, such as hicalutamide (CASODEX.TM.), flutamide
(EULEXIN.TM.), nilutamide (NILANDRON.TM.), aminoglutethimide
(CYTADREN.TM.), and abarelix (PLENAXIS.TM.); and antiestrogens,
which competitively bind and inhibit the binding of estrogens to
estrogen receptors such as tamoxifen (NOLVADEX.TM.),
fluoxymesterone (HALOTESTIN.TM.) and megestrol (MEGACE.TM.),
bisphosphonates including pamidronate (AREDIA.TM.) and zoledronate
(ZOMETA.TM.), and aromatase inhibitors including anastrozole
(ARIMIDEX.TM.), exemestane (AROMASIN.TM.), fulvestrant
(FASLODEX.TM.), and letrozole (FEMARA.TM.), androgen biosynthesis
inhibitors such as abiraterone acetate (ZITIGA.TM.), androgen
signaling inhibitor such as MDV 3100.
[0160] ATP-competitive inhibitors of c-Met/HGF receptor and/or the
nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) include
crizotinib, CH5424802 (Chugai Pharmaceutical Co., Ltd., Japan), and
AP26113 (ARIAD Pharmaceuticals, Inc., MA).
[0161] Exemplary agents including beneficial agents and anticancer
agents that can be delivered with the GLP-1 receptor agonist
compositions described herein include those described above and/or
shown in Table 1.
TABLE-US-00001 TABLE 1 Antimetabolites Folate Anatagonists
Methotrexate (FOLEX .TM.) Trimetrexate (NEUTREXIN .TM.) Pemetrexed
(ALIMTA .TM.) Purine Analogs Allopurinol (ZYLOPRIM .TM.)
Mercaptopurine (PURINETHOL .TM.) Fludarabine (FLUDARA .TM.)
Thioguanine (6-TG) Cladribine (LEUSTATIN .TM.) Pentostatin (NIPENT
.TM.) Pyrimidine Analogs Capecitabine (XELODA .TM.) Cytarabine
(CYTOSAR .TM.) Liposomal cytarabine (DEPOCYT .TM.) Floxuridine
(FUDR .TM.) Fluorouracil (ADRUCIL .TM.) Gemcitabine (GEMZAR .TM.)
Clofarabine (CLOLAR .TM.) Decitabine (DACOGEN .TM.) Azacitadine
(VIDAZA .TM.) Enzyme Inhibitors COX-2 Inhibitors (CELEBREX .TM.)
Topoisomerase II Inhibitors Epipodophyllotoxins Etoposide (VEPESID
.TM., ETOPOPHOS .TM.) Teniposide (VUMON .TM., VM 26 .TM.)
Anthracyclines Daunorubicin (CERUBIDINE .TM.) Liposomal
Daunorubicin (DAUNOXOME .TM.) Doxorubicin (ADRIAMYCIN .TM., RUBEX
.TM.) Liposomal Doxorubicin (DOXIL .TM.) Epirubicin (ELLENCE .TM.)
Valrubicin (VALSTAR .TM.) Idarubicin (IDAMYCIN .TM.) Mitoxantrone
(NOVANTRONE .TM.) Topoisomerase I Inhibitors Camptothecins
Irinotecan (CAMPTOSAR .TM.) Topotecan (HYCAMTIN .TM.) Anticancer
Kinase Inhibitors Imatinib mesylate (GLEEVEC .TM.) Gefitinib
(IRESSA .TM.) Erlotinib (TARCEVA .TM.) Sorafenib (NEXAVAR .TM.)
Sunitinib (SUTENT .TM.) Nilotinib (TASIGNA .TM.) Everolimus
(AFINITOR .TM.) Lapatinib (TYKERB .TM.) Dasatinib (SPRYCEL .TM.)
Antitubulins Taxanes Docetaxel (TAXOTERE .TM.) Paclitaxel (TAXOL
.TM.) Ixabepilone (IXEMPRA .TM.) Cabazitaxel (JEVTANA .TM.) Vinca
Alkaloids Vinblastine (VELBAN .TM.) Vincristine (ONCOVIN .TM.)
Vinorelbine (NAVELBINE .TM.) Vinflunine (JAVLOR .TM.) ILX-651
(TASIDOTIN .TM.) Tasidotin-C-carboxylate Estramustine (EMCYT .TM.)
Anticancer Phototherapeutics Porfimer Sodium (PHOTOFRIN .TM.)
Anticancer Antibodies Anti-CD52 Antibodies Alemtuzumab (CAMPATH
.TM.) Anti-CD33 Antibodies Gemtuzumab ozogamicin (MYLOTARG .TM.)
Anti-CD20 Antibodies Ibritumomab (ZEVALIN .TM.) Rituximab (RITUXAN
.TM.) Tositumomab (BEXXAR .TM.) Ofatumumab (ARZERRA .TM.) Anti-Her2
Antibodies Trastuzumab (HERCEPTIN .TM.) Anti-VEGF Bevacizumab
(AVASTIN .TM.) Anti-EGFR Cetuximab (ERBITUX .TM.) Anticancer
Retinoids Alitretinoin (PANRETIN .TM.) Bexarotene (TARGRETIN .TM.)
Tretinoin (VESANOID .TM., ATRA .TM.) Octreotide acetate
(SANDOSTATIN .TM.) Normal Tissue Protectors Amifostine (ETHYOL
.TM.) Darbepoetin alfa (ARANESP .TM.) Dexrazoxane (ZINECARD .TM.)
Epoetin alfa (EPOGEN .TM., PROCRIT .TM.) Filgrastim (NEUPOGEN .TM.)
Folinic Acid (leucovorin) Allopurinol (ALOPRIM .TM.) Mesna (MESNEX
.TM.) Oprelvekin (rhIL-11) (NEUMEGA .TM.) Pegfilgrastim (NEULASTA
.TM.) GM-CSF (sargramostim, PROKINE .TM., LEUKINE .TM.) Eltrombopag
(PROMACTA .TM.) AMD3100 (plerixafor, MOZOBIL .TM.) Alkylating
Agents Alkyl Sulfonates Busulfan (MYLERAN .TM.) Platinum Analogs
Carboplatin (PARAPLATIN .TM.) Cisplatin (PLATINOL .TM.-AQ)
Oxaliplatin (ELOXATIN .TM.) Nitrosoureas Carmustine (BICNU .TM.)
Lomustine (CCNU .TM., CEENU .TM.) Streptozocin (ZANOSAR .TM.)
Nitrogen Mustards Chlorambucil (LEUKERAN .TM.) Uracil mustard
Cyclophosphamide (CYTOXAN .TM.) Ifosfamide (IFEX .TM.)
Meclorethamine (MUSTARGEN .TM.) Melphalan (ALKERAN .TM., L-PAM)
Bendamustine (TREANDA .TM.) Triazenes Dacarbazine (DTIC-DOME .TM.)
Procarbazine (MATULANE .TM.) Temozolomide (TEMODAR .TM.)
Ethylenimines Hexamethylamine (HEXALEN .TM., altretamine, HEXASTAT
.TM.) Thiotepa (THIOPLEX .TM., TESPA .TM.) Hydroxyurea (HYDREA
.TM.) Arsenic trioxide (TRISENOX .TM.) Mitomycin C (MUTAMYCIN .TM.)
Trabectedin (YONDELIS .TM.) Anticancer Antibiotics Actinomycin D
(dactinomycin, COSMEGEN .TM.) Bleomycin sulfate (BLENOXANE .TM.)
Plicamycin (MITHRACIN .TM.) Proteasome Inhibitors Bortezomib
(VELCADE .TM.) Anticancer Anti-hormones LHRH Agonists Histrelin
(VANTAS .TM.) Goserelin (ZOLADEX .TM.) Leuprolide (LUPRON .TM.,
ELIGARD .TM.) Triptorelin (TRELSTAR .TM.) Anti-Androgens
Bicalutamide (CASODEX .TM.) Flutamide (EULEXIN .TM.) Nilutamide
(NILANDRON .TM.) Aminoglutethimide (CYTADREN .TM.) Abarelix
(PLENAXIS .TM.) Anti-Estrogens and Aromatase Inhibitors Tamoxifen
(NOLVADEX .TM.) Raloxifene (EVISTA .TM.) Anastrozole (ARIMIDEX
.TM.) Exemestane (AROMASIN .TM.) Fulvestrant (FASLODEX .TM.)
Letrozole (FEMARA .TM.) Fluoxymesterone (HALOTESTIN .TM.) Megestrol
acetate (MEGACE .TM.) Bisphosphonates Pamidronate (AREDIA .TM.)
Zoledronate (ZOMETA .TM.) Ibandronate (BONIVA .TM.) Anticancer
Enzymes Asparaginase (ELSPAR .TM.) Pegademase (ADAGEN .TM.)
Pegaspargase (ONCASPAR .TM.) Anticancer Cytokines Aldesleukin
(rhIL-2) (PROLEUKIN .TM.) Denileukin Diftitox (ONTAK .TM.)
Interferon alfa-2b (INTRON .TM. A) Peginterferon alfa-2a (PEGASYS
.TM.)
[0162] Treatment will depend on the cancer in question. Tests can
be performed prior to treatment to specifically tailor a treatment
for a patient. Such tests may include genetic or protein marker
testing of tumor markers to determine susceptibility or resistance
to a particular drug or class of drugs. For example, recently a
mutation in von Hippel-Landau (VHL) gene have been found to be
associated with a more favorable drug response for drugs such as
SUTENT.TM., NEXAVAR.TM., and AVASTIN.TM.. Other genetic and protein
tests can be performed to link a treatment to an appropriate
patient population.
[0163] The agents described above can be provided in formulations
obtained from the manufacturer. Such formulations typically include
the active components mixed with a pharmaceutically acceptable
vehicle or excipient. The vehicle may contain minor amounts of
auxiliary substances such as wetting or emulsifying agents. The
formulations may also include ancillary substances, such as
pharmacological agents, cytokines, or other biological response
modifiers.
[0164] In other embodiments of the invention, the pharmaceutical
composition comprising the agent is a sustained-release
formulation, and/or a formulation that is administered using a
sustained-release device. Such devices are well known in the art,
and include, for example, transdermal patches, and miniature
implantable pumps (such as described herein) that can provide for
drug delivery over time in a continuous, steady-state fashion at a
variety of doses to achieve a sustained-release effect with either
a non-sustained-release or a sustained release pharmaceutical
composition. For example, polypeptide agents and antibodies
described herein are suitable agents for delivery using an osmotic
delivery device such as the DUROS.TM. implantable device described
above. In this embodiment, two or more such implantable delivery
devices can be used, one including the GLP-1 receptor agonist and
one or more including one or more additional beneficial agents,
such as anticancer polypeptide formulations, antibodies, and the
like. See, e.g., U.S. Patent Publication 2009/0202608, incorporated
herein by reference in its entirety, for a description of the use
of two or more implantable delivery devices.
[0165] The additional beneficial agents may also be formulated as
particle and suspension formulations as described herein, if
appropriate. Such particle and suspension formulations are useful
with polypeptide agents and antibodies and can be delivered using
implantable devices as described above. In addition to the
suspension formulations, comprising a suspension vehicle and
particle formulation, described above, some polypeptide agents
(e.g., leuprolide acetate) can be directly dissolved or dispersed
in a vehicle for delivery from implantable devices. For example,
some polypeptides (e.g., leuprolide acetate) can be dissolved in
non-aqueous polar aprotic solvents (e.g., dimethylsulfoxide) to
provide peptide formulations (see, e.g., U.S. Pat. Nos. 5,932,547;
6,235,712; 5,981,489, incorporated herein by reference in their
entireties). The use of one such formulation in an implantable
osmotic delivery device is described below in Example 5. Other
examples of peptide formulations include, but are not limited to,
non-aqueous protic peptide formulations (see, e.g., U.S. Pat. No.
6,066,619, incorporated herein by reference in its entirety) and
aqueous formulations of peptides (see, e.g., U.S. Pat. No.
6,068,850, incorporated herein by reference in its entirety).
[0166] Other suitable routes of administration for the beneficial
agents include parenteral administration, such as subcutaneous
(s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravenous
(i.v.), or infusion, oral (p.o.) and pulmonary, nasal, topical,
transdermal, and suppositories. Where the composition is
administered via pulmonary delivery, the therapeutically effective
dose is adjusted such that the soluble level of the agent in the
bloodstream, is equivalent to that obtained with a therapeutically
effective dose that is administered parenterally, for example s.c.,
i.p., i.m., or i.v. In some embodiments of the invention, the
pharmaceutical composition comprising the beneficial agent is
administered by i.m. or s.c. injection, particularly by i.m. or
s.c. injection locally to the region where the GLP-1 receptor
agonist is administered.
[0167] One or more therapeutically effective dose of the additional
beneficial agent, such as an anticancer agent will be administered.
By "therapeutically effective dose or amount" of each of these
agents is intended an amount that when administered in combination
with the other agents, brings about a positive therapeutic response
with respect to treatment of an individual with cancer. Of
particular interest is an amount of these agents that provides an
anti-tumor effect, as defined herein. In certain embodiments,
multiple therapeutically effective doses of the additional
beneficial agent will be provided.
[0168] The additional beneficial agents can be administered prior
to, concurrent with, or subsequent to administration of the GLP-1
receptor agonist. For example, initial treatment with a
chemotherapeutic agent can be performed, followed by implantation
of a delivery device including the GLP-1 receptor agonist
formulation or vice versa. Moreover, the additional beneficial
agent may be administered over the time that the GLP-1 receptor
agonist formulation is also being delivered. By "concurrent
therapy" is intended administration to a subject such that the
therapeutic effect of the combination of the substances is caused
in the subject undergoing therapy.
5.0.0 USES
[0169] The GLP-1 receptor agonists, e.g., exenatide and
GLP-1(7-36)amide, optionally in combination with other beneficial
agents, can be used to treat various cancers. In particular, as
explained above, cancer cells are known to exhibit increased
glycolysis as compared to normal cells. An advantage of the present
invention is that inhibiting glucose availability to cancer cells
by using a GLP-1 receptor agonist, such as exenatide and
GLP-1(7-36)amide, effectively reduces the amount of energy
metabolites such as ATP and NADH produced, thereby starving the
cancer cell of energy.
[0170] Any number of cancers can benefit from the delivery of GLP-1
receptor agonists. For example, tumors or cancers such as
hemangiomas, neufibromatosis, breast, colorectal, lung, brain and
CNS, renal, gynecological (e.g., ovarian, fallopian, cervical,
peritoneal), hematological (lymphoma, multiple myeloma, leukemia),
neuroendocrine, mesothelioma, melanoma, prostate, esophagus, liver,
gastric, rectal, carcinoid tumors; head and neck, squamous cell
carcinoma, sarcomas, pancreas, colon, thymoma, thyroid, small
intestine, bladder, testicular, bile duct, gall bladder, kidney,
gastrointestinal stromal tumors, endometrial cancers and
choriocarcinoma. A list of cancers that may benefit from delivery
of the GLP-1 receptor agonists is shown in Table 2.
TABLE-US-00002 TABLE 2 Acute Lymphoblastic Leukemia, Adult Acute
Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Adult
Acute Myeloid Leukemia, Childhood Adrenocortical Carcinoma
Adrenocortical Carcinoma, Childhood AIDS-Related Cancers
AIDS-Related Lymphoma Anal Cancer Appendix Cancer Atypical
Teratoid/Rhabdoid Tumor, Childhood, Central Nervous System Basal
Cell Carcinoma, see Skin Cancer (Non-melanoma) Bladder Cancer
Bladder Cancer, Childhood Bone Cancer, Osteosarcoma and Malignant
Fibrous Histiocytoma Brain Stem Glioma, Childhood Brain Tumor,
Adult Brain Tumor, Brain Stem Glioma, Childhood Brain Tumor,
Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Childhood
Brain Tumor, Central Nervous System Embryonal Tumors, Childhood
Brain Tumor, Cerebellar Astrocytoma, Childhood Brain Tumor,
Cerebral Astrocytoma/Malignant Glioma, Childhood Brain Tumor,
Craniopharyngioma, Childhood Brain Tumor, Ependymoblastoma,
Childhood Brain Tumor, Ependymoma, Childhood Brain Tumor,
Medulloblastoma, Childhood Brain Tumor, Medulloepithelioma,
Childhood Brain Tumor, Pineal Parenchymal Tumors of Intermediate
Differentiation, Childhood Brain Tumor, Supratentorial Primitive
Neuroectodermal Tumors and Pineoblastoma, Childhood Brain Tumor,
Visual Pathway and Hypothalamic Glioma, Childhood Brain and Spinal
Cord Tumors, Childhood (Other) Breast Cancer Breast Cancer and
Pregnancy Breast Cancer, Childhood Breast Cancer Male Bronchial
Tumors, Childhood Burkitt Lymphoma Carcinoid Tumor, Childhood
Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary
Central Nervous System Embryonal Tumors, Childhood Central Nervous
System Lymphoma, Primary Cerebral Astrocytoma/Malignant Glioma,
Childhood Cervical Cancer Cervical Cancer, Childhood Childhood
Cancers Chordoma, Childhood Chronic Lymphocytic Leukemia Chronic
Myelogenous Leukemia Chronic Myeloproliferative Disorders Colon
Cancer Colorectal Cancer, Childhood Cutaneous T-Cell Lymphoma, see
Mycosis Fungoides and Sezary Syndrome Ependymoma, Childhood
Esophageal Cancer Esophageal Cancer, Childhood Ewing Family of
Tumors Extracranial Germ Cell Tumor, Childhood Extragonadal Germ
Cell Tumor Extrahepatic Bile Duct Cancer Eye Cancer, Intraocular
Melanoma Eye Cancer, Retinoblastoma Gallbladder Cancer
Gastrointestinal Carcinoid Tumor Gastrointestinal Stromal Tumor
(GIST) Gastrointestinal Stromal Cell Tumor, Childhood Germ Cell
Tumor, Extracranial, Childhood Germ Cell Tumor, Extragonadal Germ
Cell Tumor, Ovarian Gestational Trophoblastic Tumor Glioma, Adult
Glioma, Childhood, Brain Stem Glioma, Childhood Cerebral
Astrocytoma Hairy Cell Leukemia Head and Neck Cancer Hepatocellular
(Liver) Cancer, Adult, (Primary) Hepatocellular (Liver) Cancer,
Childhood, (Primary) Histiocytosis, Langerhans Cell Hodgkin
Lymphoma, Adult Hodgkin Lymphoma, Childhood Hypopharyngeal Cancer
Hypothalamic and Visual Pathway Glioma, Childhood Islet Cell Tumors
(Endocrine Pancreas) Kaposi Sarcoma Kidney (Renal Cell) Cancer
Kidney Cancer, Childhood Laryngeal Cancer Laryngeal Cancer,
Childhood Lip and Oral Cavity Cancer Liver Cancer, Adult, (Primary)
Liver Cancer, Childhood, (Primary) Malignant Fibrous Histiocytoma
of Bone and Osteosarcoma Mesothelioma, Adult, Malignant
Mesothelioma, Childhood Metastatic Squamous Neck Cancer with Occult
Primary Mouth Cancer Multiple Endocrine Neoplasia Syndrome,
Childhood Multiple Myeloma/Plasma Cell Neoplasm Mycosis Fungoides
Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative
Diseases Nasal Cavity and Paranasal Sinus Cancer Nasopharyngeal
Cancer Nasopharyngeal Cancer, Childhood Neuroblastoma Non-Hodgkin
Lymphoma, Adult Non-Hodgkin Lymphoma, Childhood Non-Small Cell Lung
Cancer Oral Cancer, Childhood Oral Cavity Cancer, Lip tongue and
mouth Oropharyngeal Cancer Ovarian Cancer, Childhood Ovarian
Epithelial Cancer Ovarian Germ Cell Tumor Ovarian Low Malignant
Potential Tumor Pancreatic Cancer Pancreatic Cancer, Childhood
Pancreatic Cancer, Islet Cell Tumors Papillomatosis, Childhood
Parathyroid Cancer Penile Cancer Pharyngeal Cancer Pheochromocytoma
Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors,
Childhood Pituitary Tumor Pleuropulmonary Blastoma Prostate Cancer
Rectal Cancer Respiratory Tract Carcinoma Involving the NUT Gene on
Chromosome 15 Rhabdomyosarcoma, Childhood Salivary Gland Cancer
Salivary Gland Cancer, Childhood Sarcoma, Ewing Family of Tumors
Sezary Syndrome Skin Cancer (Non-melanoma) Skin Cancer, Childhood
Skin Cancer (Melanoma) Skin Carcinoma, Merkel Cell Small Cell Lung
Cancer Small Intestine Cancer Soft Tissue Sarcoma, Adult Soft
Tissue Sarcoma, Childhood Squamous Neck Cancer with Occult Primary,
Metastatic Stomach (Gastric) Cancer Stomach (Gastric) Cancer,
Childhood Testicular Cancer Throat Cancer Thymoma and Thymic
Carcinoma Thymoma and Thymic Carcinoma, Childhood Thyroid Cancer
Thyroid Cancer, Childhood Transitional Cell Cancer of the Renal
Pelvis and Ureter Trophoblastic Tumor, Gestational Unusual Cancers
of Childhood Ureter and Renal Pelvis, Transitional Cell Cancer
Urethral Cancer Uterine Cancer, Endometrial Uterine Sarcoma Vaginal
Cancer Vaginal Cancer, Childhood Vulvar Cancer Waldenstrom
Macroglobulinemia Wilms Tumor
[0171] In some embodiments, the GLP-1 receptor agonists, are used
in the treatment of hematological tumors and/or solid tumors. In a
preferred embodiment, the GLP-1 receptor agonists, for example,
exenatide and GLP-1(7-36)amide, are used in the treatment of solid
tumors.
[0172] The GLP-1 receptor agonists are delivered in order to
provide a positive therapeutic response. By "positive therapeutic
response" it is intended the individual undergoing the combination
treatment of a GLP-1 receptor agonist, such as exenatide and
GLP-1(7-36)amide, and an additional beneficial agent exhibits an
improvement in one or more symptoms of the cancer for which the
individual is undergoing therapy. Therefore, for example, a
positive therapeutic response refers to one or more of the
following improvements in the disease: (1) reduction in tumor size;
(2) reduction in the number of cancer cells; (3) inhibition (i.e.,
slowing to some extent, preferably halting) of tumor growth; (4)
inhibition (i.e., slowing to some extent, preferably halting) of
cancer cell infiltration into peripheral organs; (5) inhibition
(i.e., slowing to some extent, preferably halting) of tumor
metastasis; and (6) some extent of relief from one or more symptoms
associated with the cancer. Such therapeutic responses may be
further characterized as to degree of improvement. Thus, for
example, an improvement may be characterized as a complete
response. By "complete response" is documentation of the
disappearance of all symptoms and signs of all measurable or
evaluable disease confirmed by physical examination, laboratory,
nuclear and radiographic studies (i.e., CT (computer tomography)
and/or MRI (magnetic resonance imaging)), and other non-invasive
procedures repeated for all initial abnormalities or sites positive
at the time of entry into the study. Alternatively, an improvement
in the disease may be categorized as stabilization of the disease
or may be a partial response. By "partial response" is intended a
reduction of greater than 50% in the sum of the products of the
perpendicular diameters of one or more measurable lesions when
compared with pretreatment measurements (for patients with
evaluable response only, partial response does not apply).
[0173] In one embodiment, the GLP-1 receptor agonist is delivered
in a suspension formulation, administered using an osmotic delivery
device as described above. Examples of target rates of delivery for
suspension formulations of the present invention, comprising GLP-1
receptor agonists, include, but are not limited to: suspension
formulations comprising particle formulations comprising GLP-1
(e.g., GLP-1(7-36)amide), between about 20 .mu.g/day and about 900
.mu.g/day, preferably between about 100 .mu.g/day and about 600
.mu.g/day, for example, at about 480 .mu.g/day; and suspension
formulations comprising particle formulations comprising exenatide,
between about 5 .mu.g/day and about 320 .mu.g/day, preferably
between about 5 .mu.g/day and about 160 .mu.g/day, for example, at
about 10 .mu.g/day to about 20 .mu.g/day, such as 10, 20, 40, 60,
80, 100, 120 .mu.g/day, or any integers between the above ranges.
An exit sheer rate of the suspension formulation from the osmotic
delivery device is determined such that the target daily target
delivery rate of the GLP-1 receptor agonist is reasonably achieved
by substantially continuous, uniform delivery of the suspension
formulation from the osmotic delivery device. Examples of exit
sheer rates include, but are not limited to, about 1 to about
1.times.10.sup.4 reciprocal second, preferably about
4.times.10.sup.-2 to about 6.times.10.sup.4 reciprocal second, more
preferably 5.times.10.sup.-3 to 1.times.10.sup.-3 reciprocal
second.
[0174] As explained above, a subject being treated with the GLP-1
receptor agonist formulations of the present invention may also
benefit from co-treatment with other beneficial agents, including
anticancer agents described above, as well as antidiabetic
agents.
[0175] Additional beneficial agents that can be delivered include,
but are not limited to, pharmacologically beneficial peptides
proteins, polypeptides, genes, gene products, other gene therapy
agents, or other small molecules. The additional beneficial agents
are useful for the treatment of a variety of conditions including
but not limited to hemophilia and other blood disorders, growth
disorders, diabetes, leukemia and lymphoma, hepatitis, renal
failure, bacterial infection, viral infection (e.g., infection by
HIV, HCV, etc.), hereditary diseases such as cerbrosidase
deficiency and adenosine deaminase deficiency, hypertension, septic
shock, autoimmune diseases (e.g., Graves disease, systemic lupus
erythematosus and rheumatoid arthritis), shock and wasting
disorders, cystic fibrosis, lactose intolerance, Crohn's disease,
inflammatory bowel disease, Alzheimer's disease, metabolic
disorders (such as obesity), and cancers.
[0176] The polypeptides may include but are not limited to the
following: glucagon-like peptide 2 (GLP-2), cholecystokinin (CCK),
CCK octapeptide, 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/agonists such as
leuprolide, nafarelin and goserelin, LHRH antagonists; growth
hormone releasing factor; calcitonin; colchicine; gonadotropins
such as chorionic gonadotropin; antiandrogens such as flutamide,
nilutamide and cytoprerone; aromatase inhibitors such as
exemastane, letrozole and anastrazole; selective estrogen receptor
modulators such as raloxifene, lasoxifene; 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; leptin;
adiponectin; amylin, amylin analogs (e.g., pramlintide acetate);
pancreozymin; enkephalin; glucagon; endocrine agents secreted
internally and distributed by way of the bloodstream;
carbohydrases, nucleases, lipase, proteases, amylase, or the
like.
[0177] Further beneficial agents that may be delivered include but
are not limited to the following: alpha antitrypsin; factor VII;
factor IX, thrombin and other coagulation factors; insulin; 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, thrombopoietin,
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 and other members of the interleukin
family (e.g., IL-1, 6, 12, 15, 17, 18, 32); 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.
[0178] Further, the beneficial agents that may be administered
include, but are not limited to, organic compounds including those
compounds that transport across a vessel. Examples of beneficial
agents that may be used in the practice of the present invention
include, but are not limited to, the following: 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;
tricyclic antidepressants; 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, acetaminophen; local anesthetics
such as procaine, lidocaine, naepaine, piperocaine, tetracaine,
dibucane; antispasmodics and antiulcer 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, bacitracin, chlorotetracycline, levofloxacin,
erythromycin; anti-fungals such as Amphotericin B; anti-malarials
such as 4-aminoquinolines, 8-aminoquinolines and pyrimethamine;
hormonal agents such as prednisolone, cortisone, cortisol and
triamcinolone, androgenic steroids (for example,
methyltestosterone, fluoxmesterone), estrogenic steroids (for
example, 17-beta-estradiol and ethinyl 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; anti-neoplastic agents such as mechloroethamine, uracil
mustard, 5-fluorouracil, 6-thioguanine, procarbazine, paclitaxel,
docetaxel, carboplatin, gemcitabine, oxaliplatin, fludarabine,
ara-C, camptothecin, bortezomib, methrotrexate, capecitabine,
doxorubicin, vincristine, cyclophosphamide, etoposide; VEGF/EGF
inhibitors (for example, small molecules and antibodies); VEGF/EGF
receptor inhibitors; hypoglycemic drugs such as insulin related
compounds (for example, isophane insulin suspension, protamine zinc
insulin suspension, globin zinc insulin, extended insulin zinc
suspension) 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 inhibitors specifically targeting
viral surface proteins or viral receptors (for example, gp-41
inhibitor (T-20), CCR-5 inhibitor, enfuvirtide (FUZEON.TM.));
anti-nausea (such as scopolamine, dimenhydrinate, granisetron,
dolasetron, palonesetron, metaclopramide, ondansetron);
iodoxuridine, hydrocortisone, eserine, phospholine, iodide, as well
as other beneficial agents.
[0179] 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 beneficial agents disclosed herein may
be formulated singly or in combination (e.g., mixtures).
[0180] Peptide YY (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)), stimulate net absorption (MacFayden, R.
J., et al., Neuropeptides 7(3):219-27 (1986)), and two major in
vivo variants (PYY and PYY.sub.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 analogs and derivatives thereof,
including PYY.sub.3-36, are known in the art (e.g., U.S. Pat. Nos.
5,574,010 and 5,552,520). For ease of reference herein, the family
of PYY polypeptides, PYY derivatives, variants and analogs are
referred to collectively as PYY.
[0181] GIP is an insulinotropic peptide hormone (Efendic, S., Horm
Metab Res. (2004) 36:742-746) 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 stimulates
insulin secretion from pancreatic beta cells in the presence of
glucose (Tseng et al., PATAS (1993) 90:1992-1996). GIP circulates
as a biologically active 42-amino acid peptide. GIP is also known
as glucose-dependent insulinotropic protein. The sequence of GIP,
as well as peptide analogs and peptide derivatives thereof, are
known in the art (see, e.g., Meier J. J., Diabetes Metab Res Rev.
(2005) 21(2):91-117; Efendic S., Horm Metab Res. (2004)
36(11-12):742-746). For ease of reference herein, the family of GIP
polypeptides, GIP derivatives, variants and analogs are referred to
collectively as GIP.
[0182] 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
analogs and derivatives thereof, are known in the art (e.g., U.S.
Patent Publication Nos. 2005-0070469 and 2006-0094652). For ease of
reference herein, the family of oxyntomodulin polypeptides,
oxyntomodulin derivatives, variants and analogs are referred to
collectively as oxyntomodulin.
[0183] Amylin, as well as analogs and derivatives thereof: are
known in the art (e.g., U.S. Pat. Nos. 5,686,411, 5,814,600,
5,998,367, 6,114,304, 6,410,511, 6,608,029, and 6,610,824). For
ease of reference herein, the family of amylin polypeptides, amylin
derivatives, variants and analogs are referred to collectively as
amylin.
[0184] The cDNA sequence encoding the human leptin protein hormone
is known (e.g., Masuzaki, H., et al. (Diabetes 44: 855-858, 1995)).
Leptin, as well as analogs and derivatives thereof, are known in
the art (e.g., U.S. Pat. Nos. 5,521,283, 5,525,705, 5,532,336,
5,552,522, 5,552,523, 5,552,524, 5,554,727, 5,559,208, 5,563,243,
5,563,244, 5,563,245, 5,567,678, 5,567,803, 5,569,743, 5,569,744,
5,574,133, 5,580,954, 5,594,101, 5,594,104, 5,605,886, 5,691,309,
and 5,719,266; P.C.T. International Patent Publication Nos.
WO96/22308, WO96/31526, WO96/34885, 97/46585, WO97/16550, and WO
97/20933; European Patent Publication No. EP 0 741 187). For ease
of reference herein, the family of leptin polypeptides, leptin
derivatives, variants and analogs are referred to collectively as
leptin.
[0185] Further, oligonucleotides (e.g., RNA, DNA, alternative
backbones) may be used as beneficial agents in the practice of the
present invention. In one embodiment therapeutic RNA molecules may
include, but are not limited to, small nuclear RNAs (snRNAs), and
small interfering RNA strands (siRNA) for use in RNA interference
(RNAi) inhibition of gene expression. RNAi inhibition typically
occurs at the stage of translation or by hindering the
transcription of specific genes. RNAi targets include, but are not
limited to, RNA from viruses and genes with roles in regulating
development and genome maintenance.
[0186] The beneficial agents 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. The formulation used can have been in various art
known forms such as solution, dispersion, paste, cream, particle,
granule, tablet, emulsions, suspensions, powders and the like. In
addition to the one or more beneficial agents, the beneficial agent
formulation may optionally include pharmaceutically acceptable
carriers and/or additional ingredients such as antioxidants,
stabilizing agents, buffers, and permeation enhancers.
[0187] The amount of beneficial agent used is that amount necessary
to deliver a therapeutically effective amount of the agent to
achieve the desired therapeutic result. In practice, this will vary
depending upon such variables, for example, as the particular
agent, the site of delivery, 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.
[0188] The additional beneficial agent can be delivered using any
of the various delivery techniques outlined above, including
without limitation parenterally (including by subcutaneous,
intravenous, intramedullary, intraarticular, intramuscular, or
intraperitoneal injection) rectally, topically, transdermally,
intranasally, by inhalation, or orally (for example, in capsules,
suspensions, or tablets). In certain embodiments, the agent is in a
sustained-release formulation, or administered using a
sustained-release device. Such devices are well known in the art,
and include, for example, transdermal patches, and miniature
implantable pumps (such as the DUROS.TM. delivery device described
herein) that can provide for drug delivery over time in a
continuous, steady-state fashion at a variety of doses to achieve a
sustained-release effect with a non-sustained-release
pharmaceutical composition. If an osmotic delivery device is used,
the volume of a beneficial agent chamber comprising the beneficial
agent formulation is between about 50 .mu.l to about 1000 .mu.l,
more preferably between about 100 .mu.l and about 500 .mu.l, more
preferably between about 150 .mu.l and about 200 .mu.l. Moreover,
two or more such devices can be used, one including the GLP-1
receptor agonist and one or more including one or more additional
beneficial agents, such as an antidiabetic compound. See, e.g.,
U.S. Patent Publication 2009/0202608, incorporated herein by
reference in its entirety, for a description of the use of two or
more implantable delivery devices.
[0189] An example of a cancer treatment using delivery of an
anticancer agent from a first osmotic delivery device and delivery
of a GLP-1 receptor agonist from a second osmotic delivery device
is presented below in Example 5. In the example, the cancer is
prostate cancer, the anticancer agent is leuprolide acetate and the
GLP-1 receptor agonist is exenatide.
[0190] Other objects may be apparent to one of ordinary skill upon
reviewing the following specification and claims.
6.0.0 EXPERIMENTAL
[0191] 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 make and use the devices, methods, and
formulae of the present invention, and are not intended to limit
the scope of what the inventor regards as the invention. Efforts
have been made to ensure accuracy with respect to numbers used
(e.g., amounts, temperature, etc.) but some experimental errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and
pressure is at or near atmospheric.
[0192] The compositions produced according to the present invention
meet the specifications for content and purity required of
pharmaceutical products.
Example 1
Exenatide Particle Formulations
[0193] This example describes making exenatide particle
formulations.
[0194] A. Formulation 1
[0195] Exenatide (0.25 g) was dissolved in 50 mM sodium citrate
buffer at pH 6.04. The solution was dialyzed with a formulation
solution containing sodium citrate buffer, sucrose, and methionine.
The formulated solution was then spray dried using Buchi 290 with
0.7 mm nozzle, outlet temperature of 75.degree. C., atomization
pressure of 100 Psi, solid content of 2%, and flow rate of 2.8
mL/min. The dry powder contained 21.5% of exenatide with 4.7%
residual moisture and 0.228 g/ml density.
[0196] B. Formulations 2 and 3
[0197] Two additional formulations of exenatide were prepared
essentially by the method just described. Following here in Table 3
is a summary of the weight percentages (wt %) of the components of
the Formulations 1, 2 and 3.
TABLE-US-00003 TABLE 3 Particle Particle Particle Formulation 1
Formulation 2 Formulation 3 Component (wt %) (wt %) (wt %)
Exenatide 21.5 11.2 50.0 Sodium Citrate* 63.6 74.7 28.4 Citric
Acid* 7.1 9.1 3.6 Sucrose 3.9 2.5 9.0 Methionine 3.9 2.5 9.0
*Sodium Citrate/Citric Acid formed the citrate buffer in the
pre-spray drying process for preparation of this particle
formulation.
Example 2
GLP-1 (7-36)Amide Dry Powder
[0198] This example describes making a GLP-1(7-36)amide particle
formulation. GLP-1(7-36)amide (1.5 g) was dissolved in 5 mM sodium
citrate buffer at pH 4. The solution was dialyzed with a
formulation solution containing sodium citrate buffer and
methionine. The formulated solution was then spray dried using
Buchi 290 with 0.7 mm nozzle, outlet temperature of 70.degree. C.,
atomization pressure of 100 Psi, solid content of 1.5%, and flow
rate of 5 mL/min. The dry powder contained 90% of
GLP-1(7-36)amide.
Example 3
Exenatide Suspension Formulation
[0199] This example describes making suspension formulations
comprising a suspension vehicle and an exenatide particle
formulation.
[0200] A. Suspension Formulation of 20 Wt % Exenatide Particles
[0201] An exenatide particle formulation was generated by
spray-drying, and contained 20 wt % exenatide, 32 wt % sucrose, 16
wt % methionine and 32 wt % citrate buffer.
[0202] A suspension vehicle was formed by dissolving the polymer
polyvinylpyrrolidone in the solvent benzyl benzoate at
approximately a 50/50 ratio by weight. The vehicle viscosity was
approximately 12,000 to 18,000 poise when measured at 33.degree. C.
Particles containing the peptide exenatide were dispersed
throughout the vehicle at a concentration of 10% particles by
weight.
[0203] B. Suspension Formulations of Particle Formulations 1, 2,
and 3
[0204] A suspension vehicle was formed by dissolving the polymer
polyvinylpyrrolidone K-17 (typically having an approximate average
molecular weight range of 7,900-10,800) in the solvent benzyl
benzoate heated to approximately 65.degree. C. under a dry
atmosphere and reduced pressure at approximately a 50/50 ratio by
weight. The vehicle viscosity was approximately 12,000 to 18,000
poise when measured at 33.degree. C. Particle formulations 1-3,
described in Example 1, were dispersed throughout the vehicle at
the concentrations (by weight percent) shown in Table 4.
TABLE-US-00004 TABLE 4 Suspension Suspension Suspension Formulation
1 Formulation 2 Formulation 3 Component (wt %) (wt %) (wt %)
Particle Formulation 1 21.4 -- -- Particle Formulation 2 -- 11.73
-- Particle Formulation 3 -- -- 10.05 Polyvinylpyrrolidone 39.30
44.13 44.98 Benzyl Benzoate 39.30 44.13 44.98
Example 4
GLP-1(7-36)Amide Formulation
[0205] This example describes making a suspension formulation
comprising a suspension vehicle and an GLP-1(7-36)amide particle
formulation. A GLP-1(7-36)amide particle formulation was generated
by spray-drying, and contained 90 wt % GLP-1, 5 wt % methionine and
5 wt % citrate buffer.
[0206] A suspension vehicle containing the polymer
polyvinylpyrrolidone was dissolved in the solvent benzyl benzoate
at approximately a 50/50 ratio by weight. The vehicle viscosity was
approximately 12,000 to 18,000 poise when measured at 33.degree. C.
Particles containing the peptide GLP-1(7-36)amide were dispersed
throughout the vehicle at a concentration of 33% particles by
weight.
Example 5
Co-Treatment of Prostate Cancer Using Leuprolide Acetate and
Exenatide
[0207] Leuprolide acetate, an LHRH agonist, acts as a potent
inhibitor of gonadotropin secretion when given continuously and in
therapeutic doses. Animal and human studies indicate that following
an initial stimulation, chronic administration of leuprolide
acetate results in suppression of testicular steroidogenesis. This
effect is reversible upon discontinuation of drug therapy.
Administration of leuprolide acetate has resulted in inhibition of
the growth of certain hormone-dependent tumors (prostatic tumors in
Noble and Dunning male rats and DMBA-induced mammary tumors in
female rats) as well as atrophy of the reproductive organs. In
humans, administration of leuprolide acetate results in an initial
increase in circulating levels of luteinizing hormone (LH) and
follicle stimulating hormone (FSH), leading to a transient increase
in levels of the gonadal steroids (testosterone and
dihydrotestosterone in males). However, continuous administration
of leuprolide acetate results in decreased level of LH and FSH. In
males, testosterone is reduced to castrate levels. These decreases
occur within two to six weeks after initiation of treatment, and
castrate levels of testosterone in prostatic cancer patients have
been demonstrated for multiyear periods. Leuprolide acetate is not
active when given orally.
[0208] An implantable device containing leuprolide acetate for the
treatment of prostate cancer is assembled as described in U.S. Pat.
No. 5,728,396, incorporated herein by reference in its entirety.
The device includes the following components:
[0209] Reservoir (Titanium, Ti6A 14V alloy) (4 mm outside diameter,
3 mm inside diameter)
[0210] Piston (C-Flex.TM.)
[0211] Lubricant (silicone medical fluid) Compressed osmotic engine
(76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone,
0.5% Mg Stearate, 1.6% water) PEG 400 (8 mg added to osmotic engine
to fill air spaces) Membrane plug (polyurethane polymer, injection
molded to desired shape) Back diffusion Regulating Outlet
(polyethylene) Drug formulation (1) 0.150 g of 60% water and 40%
leuprolide acetate; or (2) leuprolide acetate dissolved in DMSO to
a measured content of 65 mg leuprolide.
[0212] To assemble the device, the piston and inner diameter of the
reservoir are lightly lubricated. The piston is inserted about 0.5
cm into the reservoir at the membrane end. PEG 400 is added into
the reservoir. Two osmotic engine tablets (40 mg each) are then
inserted into the reservoir from the membrane end. After insertion,
the osmotic engine is flush with the end of the reservoir. The
membrane plug is inserted by lining up the plug with the reservoir
and pushing gently until the retaining features of the plug are
fully engaged in the reservoir. Formulation is loaded into a
syringe which is then used to fill the reservoir from the outlet
end by injecting formulation into the open tube until the
formulation is about 3 mm from the end. The filled reservoir is
centrifuged (outlet end "up") to remove any air bubbles that have
been trapped in the formulation during filling. The outlet is
screwed into the open end of the reservoir until completely
engaged. As the outlet is screwed in, excess formulation exits out
of the orifice ensuring a uniform fill.
[0213] These devices deliver about 0.35 .mu.L/day leuprolide
formulation containing on average 150 .mu.g leuprolide in the
amount delivered per day. They provide delivery of leuprolide at
this rate for at least one year. The devices can achieve
approximately 70% steady-state delivery by day 14.
[0214] Exenatide suspension formulations are produced as described
in Example 1 and loaded into an implantable delivery device as
above. Two implantable devices, one including an exenatide
formulation and one including a leuprolide formulation are
implanted under local anesthetic and by means of an incision in a
patient suffering from advanced prostatic cancer. Implantation can
be accomplished using, for example, an implanter device. See e.g.,
U.S. Pat. No. 6,190,350, incorporated herein by reference in its
entirety. After an appropriate period of time, the implantable
delivery devices are removed under local anesthetic. New devices
may be inserted at that time.
7.0.0 FURTHER EXEMPLARY EMBODIMENTS OF THE PRESENT INVENTION
[0215] Embodiments of the present invention include, but are not
limited to, the following:
[0216] 1. A method of treating cancer in a subject in need of such
treatment, comprising: administering a GLP-1 receptor agonist to
said subject.
[0217] 2. The method of embodiment 1, wherein the GLP-1 receptor
agonist is a small molecule.
[0218] 3. The method of embodiment 1, wherein the GLP-1 receptor
agonist is a peptide, polypeptide or protein.
[0219] 4. The method of embodiment 3, wherein the GLP-1 receptor
agonist is a glucagon-like peptide-1 (GLP-1), a derivative of
GLP-1, or an analog of GLP-1.
[0220] 5. The method of embodiment 4, wherein the GLP-1 receptor
agonist is GLP(7-36)amide comprising the sequence of SEQ ID
NO:1.
[0221] 6. The method of embodiment 3, wherein the GLP-1 receptor
agonist is exenatide, a derivative of exenatide, or an analog of
exenatide.
[0222] 7. The method of embodiment 6, wherein the GLP-1 receptor
agonist is synthetic exenatide peptide comprising the sequence of
SEQ ID NO:2.
[0223] 8. The method of embodiment 4, wherein the GLP-1 receptor
agonist is selected from the group consisting of liraglutide,
albiglutide, semaglutide and taspoglutide.
[0224] 9. The method of embodiment 6, wherein the GLP-1 receptor
agonist is lixisenatide.
[0225] 10. The method of any one of embodiments 1-9, wherein the
GLP-1 receptor agonist is provided in a suspension formulation
comprising: (a) a particle formulation comprising said GLP-1
receptor agonist; and (b) a vehicle formulation, wherein the
particle formulation is dispersed in the vehicle.
[0226] 11. The method of embodiment 10, wherein (a) the particle
formulation additionally comprises a disaccharide, methionine and a
buffer and (b) the vehicle formulation is a non-aqueous,
single-phase suspension vehicle comprising one or more pyrrolidone
polymers and one or more solvents selected from the group
consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and
mixtures thereof; wherein the suspension vehicle exhibits viscous
fluid characteristics, and the particle formulation is dispersed in
the vehicle.
[0227] 12. The method of embodiment 11, wherein the buffer is
selected from the group consisting of citrate, histidine,
succinate, and mixtures thereof.
[0228] 13. The method of embodiment 12, wherein the buffer is
citrate.
[0229] 14. The method of embodiment 11, wherein the disaccharide is
selected from the group consisting of lactose, sucrose, trehalose,
cellobiose, and mixtures thereof.
[0230] 15. The method of embodiment 11, wherein the particle
formulation is a spray dried preparation of particles.
[0231] 16. The method of embodiment 11, wherein the solvent is
selected from the group consisting of lauryl lactate, benzyl
benzoate, and mixtures thereof.
[0232] 17. The method of embodiment 16, wherein the solvent
consists essentially of benzyl benzoate.
[0233] 18. The method of embodiment 11, wherein the pyrrolidone
polymer consists essentially of polyvinylpyrrolidone.
[0234] 19. The method of embodiment 11, wherein the vehicle
consists essentially of a pyrrolidone polymer and benzyl
benzoate.
[0235] 20. The method of embodiment 19, wherein the vehicle is
about 50% solvent and about 50% polymer.
[0236] 21. The method of embodiment 11, wherein the suspension
formulation has an overall moisture content of less than or equal
to about 10 wt %.
[0237] 22. The method of any one of embodiments 1-21, wherein the
GLP-1 receptor agonist is delivered using an implantable osmotic
delivery device.
[0238] 23. The method of embodiment 22, wherein the osmotic
delivery device provides continuous delivery of the GLP-1 receptor
agonist for a period of at least one month.
[0239] 24. The method of any one of embodiments 1-9, wherein the
GLP-1 receptor agonist is provided in an injectable
formulation.
[0240] 25. The method of any one of embodiments 1-24, wherein a
beneficial agent in addition to the GLP-1 receptor agonist is
delivered to said subject.
[0241] 26. The method of embodiment 25, wherein the additional
beneficial agent is an anticancer agent.
[0242] 27. The method of embodiment 26, wherein the anticancer
agent is a chemotherapeutic agent.
[0243] 28. The method of embodiment 26, wherein the anticancer
agent is an anticancer antibody.
[0244] 29. The method of any one of embodiments 25-28, wherein the
additional beneficial agent is an antidiabetic agent.
[0245] 30. The method of any one of embodiments 25-29, wherein the
additional beneficial agent is delivered using an implantable
osmotic delivery device.
[0246] 31. The method of embodiment 30, wherein the osmotic
delivery device provides continuous delivery of the GLP-1 receptor
agonist for a period of at least one month.
[0247] 32. The method of either one of embodiments 30 or 31,
wherein the additional beneficial agent is a luteinizing
hormone-releasing hormone (LHRH) agonist.
[0248] 33. The method of any one of embodiments 25-29, wherein the
additional beneficial agent is provided in an injectable
formulation.
[0249] 34. The method of any one of embodiments 25-29, wherein the
additional beneficial agent is provided in an oral formulation.
[0250] 35. The method of embodiment 25, wherein the additional
beneficial agent is GIP.
[0251] 36. The method of any one of embodiments 25-35, wherein the
additional beneficial agent is delivered prior to the GLP-1
receptor agonist.
[0252] 37. The method of any one of embodiments 25-35, wherein the
additional beneficial agent is delivered subsequent to the GLP-1
receptor agonist.
[0253] 38. The method of any one of embodiments 25-35, wherein the
additional beneficial agent is delivered concurrent with the GLP-1
receptor agonist.
[0254] 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.
Sequence CWU 1
1
2130PRTHomo sapiens 1His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser
Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp
Leu Val Lys Gly Arg 20 25 30 239PRTArtificial SequenceSynthetic
Polypeptide sequence, exenatide, having the exendin-4 polypeptide
sequence from Heloderma suspectum 2His Gly Glu Gly Thr Phe Thr Ser
Asp Leu Ser Lys Gln Met Glu Glu 1 5 10 15 Glu Ala Val Arg Leu Phe
Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30 Ser Gly Ala Pro
Pro Pro Ser 35
* * * * *