U.S. patent application number 16/284995 was filed with the patent office on 2019-06-20 for intravascular delivery of nanoparticle compositions and uses thereof.
The applicant listed for this patent is Abraxis BioScience, LLC, Mercator MedSystems, Inc.. Invention is credited to Neil P. DESAI, Kirk SEWARD.
Application Number | 20190183789 16/284995 |
Document ID | / |
Family ID | 47072793 |
Filed Date | 2019-06-20 |
United States Patent
Application |
20190183789 |
Kind Code |
A1 |
SEWARD; Kirk ; et
al. |
June 20, 2019 |
INTRAVASCULAR DELIVERY OF NANOPARTICLE COMPOSITIONS AND USES
THEREOF
Abstract
The present invention provides methods of delivering a
composition comprising nanoparticles that comprise a macrolide and
an albumin by directly injecting the nanoparticle composition into
the blood vessel wall or the tissue surrounding the blood vessel
wall. The methods can be used for inhibiting negative remodeling or
vascular fibrosis in the blood vessel and are useful for treating
various diseases.
Inventors: |
SEWARD; Kirk; (San
Francisco, CA) ; DESAI; Neil P.; (Pacific Palisades,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Mercator MedSystems, Inc.
Abraxis BioScience, LLC |
San Leandro
Summit |
CA
NJ |
US
US |
|
|
Family ID: |
47072793 |
Appl. No.: |
16/284995 |
Filed: |
February 25, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15851478 |
Dec 21, 2017 |
10258565 |
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16284995 |
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14714131 |
May 15, 2015 |
9884013 |
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15851478 |
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14113568 |
Mar 7, 2014 |
9061014 |
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PCT/US2012/035626 |
Apr 27, 2012 |
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14714131 |
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61557851 |
Nov 9, 2011 |
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61518084 |
Apr 28, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/38 20130101;
A61M 25/0084 20130101; A61P 9/10 20180101; A61P 19/02 20180101;
A61K 9/0019 20130101; A61K 47/643 20170801; A61K 47/6921 20170801;
A61K 38/385 20130101; A61M 2025/0089 20130101; A61K 47/6931
20170801; A61M 25/104 20130101; A61P 9/14 20180101; A61P 9/06
20180101; A61P 9/00 20180101; A61K 31/436 20130101; A61P 9/04
20180101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/69 20060101 A61K047/69; A61K 47/64 20060101
A61K047/64; A61M 25/10 20060101 A61M025/10; A61K 38/38 20060101
A61K038/38; A61M 25/00 20060101 A61M025/00; A61K 31/436 20060101
A61K031/436 |
Claims
1. A method of inhibiting vascular fibrosis in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin.
2. The method of claim 1, wherein the vascular fibrosis is medial
vascular fibrosis or adventitial fibrosis.
3. The method of claim 1, wherein the blood vessel is an
artery.
4. The method of claim 3, wherein the artery is a coronary artery
or a peripheral artery.
5. The method of claim 3, wherein the artery is selected from the
group consisting of renal artery, cerebral artery, pulmonary
artery, and artery in the leg.
6. The method of claim 1, wherein the nanoparticle composition is
injected into the blood vessel wall.
7. The method of claim 1, wherein the nanoparticle composition is
injected into the tissue surrounding the blood vessel wall.
8. The method of claim 7, wherein the nanoparticle composition is
injected into the adventitial tissue of the blood vessel.
9. The method of claim 1, wherein the nanoparticle composition is
injected at a dose of about 0.001 mg to about 100 mg.
10. The method of claim 9, where the nanoparticle composition is
injected at a dose of about 0.05 mg to about 5 mg.
11. The method of claim 1, wherein the injection volume of the
nanoparticle composition is about 0.01 ml to about 50 ml.
12. The method of claim 11, wherein the injection volume of the
nanoparticle composition is about 0.5 ml to about 5 ml.
13. The method of claim 1, wherein the nanoparticle composition is
injected though a catheter with a needle.
14. The method of claim 1, wherein the nanoparticle composition is
injected distal or proximal to the disease site.
15. The method of claim 1, wherein the nanoparticle composition is
injected at least about 2 cm away from the disease site.
16. The method of claim 1, wherein the nanoparticle composition is
injected at or adjacent to the disease site.
17. The method of claim 1, wherein the individual has any one of:
angina, myocardial infarction, congestive heart failure, cardiac
arrhythmia, peripheral artery disease, claudication, or chronic
limb ischemia.
18. A method of promoting positive remodeling in a blood vessel in
an individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin.
19. A catheter with a needle, wherein the needle contains a
composition comprising nanoparticles comprising a macrolide and an
albumin, wherein the needle is deployable and can be advanced
intravascularly through a blood vessel wall.
Description
RELATED APPLICATIONS
[0001] This application claims priority benefit of U.S. Provisional
Application Ser. No. 61/518,084, filed Apr. 28, 2011 and U.S.
Provisional Application Ser. No. 61/557,851, filed Nov. 9, 2011,
the contents of each are hereby incorporated herein by reference in
their entirety.
TECHNICAL FIELD
[0002] The present invention relates to methods of delivering and
use of a composition comprising nanoparticles that comprise a
macrolide and an albumin by directly injecting the nanoparticle
composition into the blood vessel wall or the tissue surrounding
the blood vessel wall.
BACKGROUND
[0003] Coronary artery disease is one of the leading causes of
death throughout the world. While coronary artery bypass surgery is
an effective treatment for stenosed arteries resulting from
atherosclerosis and other causes, it is a highly invasive procedure
and requires substantial hospital and recovery time. Percutaneous
transluminal coronary angioplasty (PTCA), commonly referred to as
balloon angioplasty, is less invasive, less traumatic, and
significantly less expensive than bypass surgery. The effectiveness
of balloon angioplasty has improved significantly with the
introduction of stenting which involves the placement of a scaffold
structure within the artery which has been treated by balloon
angioplasty. The stent inhibits abrupt reclosure of the artery and
has some benefit in reducing subsequent restenosis resulting from
hyperplasia. Despite such improvement, patients who have undergone
angioplasty procedures with subsequent stenting still suffer from a
high incidence of restenosis resulting from hyperplasia. Implanting
of stents which have been coated with anti-proliferative drugs can
significantly reduce the occurrence of hyperplasia.
[0004] Albumin-based nanoparticle compositions have been developed
as a drug delivery system for delivering substantially water
insoluble drugs such as a taxanes. See, for example, U.S. Pat. Nos.
5,916,596; 6,506,405; 6,749,868, and 6,537,579, 7,820,788, and
7,923,536. It is generally believed that the albumin-based
nanoparticle, such as Abraxane.RTM., when introduced into the blood
stream, would dissolve into albumin-drug complexes. Such complexes
utilize the natural properties of the protein albumin to transport
and deliver substantially water insoluble drugs to the site of
disease, such as tumor sites. In addition, the albumin-based
nanoparticle technology offers the ability to improve a drug's
solubility by avoiding the need for toxic chemicals, such as
solvents, in the administration process, thus potentially improving
safety through the elimination of solvent-related side effects.
[0005] The disclosures of all publications, patents, patent
applications and published patent applications referred to herein
are hereby incorporated herein by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
[0006] The present application in some embodiment provides a method
of delivering a composition comprising nanoparticles comprising
albumin and a macrolide to a blood vessel, wherein the method
comprises injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin. In some embodiments, there is provided a method of
inhibiting negative remodeling in a blood vessel in an individual
in need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin. In some embodiments, there is provided a method of
inhibiting vascular fibrosis (such as medial fibrosis or adventitia
fibrosis) in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin. In some embodiments, there is provided a method of
reducing proliferation index in a blood vessel in an individual in
need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin. In some embodiments, there is provided a method of
promoting positive remodeling in a blood vessel in an individual in
need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin.
[0007] In some embodiments, the blood vessel is an artery, such as
a coronary artery or a peripheral artery. In some embodiments, the
artery is selected from the group consisting of renal artery,
cerebral artery, pulmonary artery, and artery in the leg. In some
embodiments, the blood vessel is a vein.
[0008] In some embodiments, the nanoparticle composition is
injected into the blood vessel wall. In some embodiments, the
nanoparticle composition is injected into the tissue surrounding
the blood vessel wall. In some embodiments, the nanoparticle
composition is injected into the adventitial tissue of the blood
vessel.
[0009] In some embodiments, the nanoparticle composition is
injected at a dose of about 0.001 mg to about 100 mg, including for
example about 0.05 mg to about 5 mg. In some embodiments, the
injection volume of the nanoparticle composition is about 0.01 ml
to about 50 ml, including for example, about 0.5 ml to about 5 ml.
In some embodiments, the nanoparticle composition is injected
though a catheter with a needle, such as a deployable needle. In
some embodiments, the nanoparticle composition is injected at least
once a year. In some embodiments, the nanoparticle composition is
injected only once.
[0010] In some embodiments, the nanoparticle composition is
injected distal to the disease site. In some embodiments, the
nanoparticle composition is injected proximal to the disease site.
In some embodiments, the nanoparticle composition is injected at or
adjacent to the disease site. In some embodiments, the nanoparticle
composition is injected remotely from the disease site. In some
embodiments, the nanoparticle composition is injected at least
about 2 cm (including for example at least any of 3, 4, 5, 6, 7, 8,
9, or 10 cm) away from the disease site.
[0011] In some embodiment according to any of the above
embodiments, the individual has any one of: angina, myocardial
infarction, congestive heart failure, cardiac arrhythmia,
peripheral artery disease, claudication, or chronic limb ischemia.
In some embodiments, the individual is a human. In some
embodiments, the method is carried out during vascular
interventional procedure, including but not limited to, angioplasty
(such as percutaneous translumenal coronary angioplasty), stenting,
or atherectomy. In some embodiments, the method is carried out
after a vascular interventional procedure, including but not
limited to, angioplasty, stenting, or atherectomy.
[0012] In some embodiments according to any of the above
embodiments, the macrolide is rapamycin or a derivative thereof. In
some embodiments, the macrolide is rapamycin. In some embodiments
according to any of the above embodiments, the nanoparticles in the
composition have an average diameter of no greater than about 200
nm, such as no greater than about 100 nm. In some embodiments, the
nanoparticles in the composition have an average diameter of no
less than about 70 nm. In some embodiments, the macrolide in the
nanoparticles is coated with albumin.
[0013] Also provided are kits and devices for use in any of the
methods described herein. For example, in some embodiments, there
is provided a catheter with a needle (such as a deployable needle),
wherein the needle contains a composition comprising nanoparticles
comprising a macrolide and an albumin. In some embodiments, the
macrolide is rapamycin. In some embodiments, the nanoparticles
comprise a macrolide coated with albumin. In some embodiments, the
nanoparticles in the composition have an average diameter of no
greater than about 200 nm, such as no greater than about 100 nm. In
some embodiments, the nanoparticles in the composition have an
average diameter of no less than about 70 nm.
[0014] These and other aspects and advantages of the present
invention will become apparent from the subsequent detailed
description and the appended claims. It is to be understood that
one, some, or all of the properties of the various embodiments
described herein may be combined to form other embodiments of the
present invention.
BRIEF DESCRIPTION OF FIGURES
[0015] FIGS. 1A and 1B provide images of the micro-infusion
catheter utilized for periadventitial injection of Nab-rapamycin in
the femoral artery. FIG. 1A shows a deflated balloon which sheathes
the needle. FIG. 1B shows an inflated balloon with the needle
extruding outward.
[0016] FIGS. 2A and 2B provide two flow charts for the study design
involving periadventitial injection of Nab-rapamycin in a porcine
femoral artery balloon angioplasty injury model. FIG. 2A shows a
flow chart for pharmacokinetics studies. FIG. 2B shows a flow chart
for histopathology studies.
[0017] FIGS. 3A, 3B, 3C, 3D, 3E, and 3F show a representative
angiogram series for periadventitial injection of Nab-rapamycin in
the femoral artery.
[0018] FIGS. 4A, 4B, 4C, and 4D show reduction of luminal stenosis
after periadventitial delivery of Nab-rapamycin as measured by mean
lumen cross-sectional area (FIG. 4A), mean artery cross sectional
area (FIG. 4B), mean percent luminal stenosis (FIG. 4C), and
average medial fibrosis (FIG. 4D).
[0019] FIGS. 5A and 5B show the pharmacokinetics of Nab-rapamycin
after periadventitial delivery in femoral arteries as measured by
serum rapamycin concentration (FIG. 5A) and tissue rapamycin
concentration (FIG. 5B).
[0020] FIGS. 6A, 6B, 6C, and 6D show histopathology staining of
femoral arteries treated with vehicle (FIGS. 6C and 6D) or with
Nab-rapamycin (FIGS. 6A and 6B) by periadventitial delivery. FIGS.
6A and 6C show staining with H&E. FIGS. 6B and 6D show staining
with trichrome.
[0021] FIG. 7A shows the proliferative index after periadventitial
delivery of Nab-rapamycin or a control. FIG. 7B shows the
endothelialization after periadventitial delivery of Nab-rapamycin
or a control.
[0022] FIG. 8A shows the proliferative index after periadventitial
delivery of Nab-rapamycin at days 3, 8, and 28. FIG. 8B shows the
endothelialization after periadventitial delivery of Nab-rapamycin
at days 3, 8, and 28.
[0023] FIG. 9A shows adventitial leukocyte infiltration after
periadventitial delivery of Nab-rapamycin or a control at days 3,
8, and 28. FIG. 9B shows mean number of adventitial vessels after
periadventitial delivery of Nab-rapamycin or a control at day
28.
[0024] FIG. 10 shows re-endothelialization of target arteries after
periadventitial delivery of Nab-rapamycin or a control at days 3,
8, and 28.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present application provides methods of delivering a
composition comprising nanoparticles comprising a macrolide and an
albumin (the "nanoparticle composition") to a blood vessel, wherein
the method comprises injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin. Such method can be useful, for example, for inhibiting
negative remodeling in the blood vessel and/or inhibiting vascular
fibrosis in the blood vessel, and are thus useful for treating
various diseases associated with negative remodeling and/or
vascular fibrosis.
[0026] Using a porcine femoral artery balloon injury model, it was
shown that a nanoparticle composition comprising a macrolide and an
albumin, namely, Nanoparticle Albumin-Bound (Nab) Rapamycin
(Nab-Rapamycin), when injected into the periadventitial tissue of a
blood vessel, significantly decreased negative remodeling of the
balloon-injured blood vessel and medial fibrosis in the blood
vessel. Within one hour after the injection, the rapamycin level in
the perivascular tissue was about 1500 times higher than that in
the blood within an hour, and rapamycin was retained in the
perivascular tissue for at least 8 days. Periadventitial injection
of a nanoparticle composition therefore can be an effective method
for inhibiting negative remodeling, inhibiting vascular fibrosis,
as well as for treating various diseases associated with negative
remodeling and/or vascular fibrosis.
[0027] Thus, the present application in one aspect provides a
method of inhibiting negative remodeling or vascular fibrosis in
the blood vessel of an individual in need thereof, comprising
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide and an albumin.
[0028] In another aspect, there is provided a method of delivering
a composition comprising nanoparticles comprising a macrolide and
an albumin to a blood vessel, wherein the method comprises
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide and an albumin.
[0029] Further provided are kits and devices (such as a catheter
with a needle) that are useful for the methods described
herein.
Definitions
[0030] The term "individual" refers to a mammal and includes, but
is not limited to, human, bovine, horse, feline, canine, rodent, or
primate.
[0031] It is understood that aspect and embodiments of the
invention described herein include "consisting" and/or "consisting
essentially of" aspects and embodiments.
[0032] Reference to "about" a value or parameter herein includes
(and describes) variations that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X".
[0033] As used herein and in the appended claims, the singular
forms "a," "or," and "the" include plural referents unless the
context clearly dictates otherwise.
Methods of the Present Invention
[0034] The present application in some embodiments provides a
method of delivering a composition comprising nanoparticles
comprising albumin and a macrolide (such as rapamycin or a
derivative thereof, for example rapamycin) to a blood vessel,
wherein the method comprises injecting into the blood vessel wall
or tissue surrounding the blood vessel wall an effective amount of
a composition comprising nanoparticles comprising a macrolide and
an albumin. In some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin) to a blood vessel,
wherein the method comprises injecting into the blood vessel wall
or tissue surrounding the blood vessel wall an effective amount of
a composition comprising nanoparticles comprising a macrolide and
an albumin (such as human serum albumin), wherein the macrolide in
the nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of delivering a composition comprising
nanoparticles comprising albumin and a macrolide (such as
rapamycin) to a blood vessel, wherein the method comprises
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide and an albumin (such as human
serum albumin), wherein the average particle size of the
nanoparticles in the composition is no greater than about 200 nm
(such as less than about 200 nm, for example no greater than about
100 nm). In some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin) to a blood vessel,
wherein the method comprises injecting into the blood vessel wall
or tissue surrounding the blood vessel wall an effective amount of
a composition comprising nanoparticles comprising rapamycin and an
albumin (such as human serum albumin), wherein the rapamycin in the
nanoparticles is coated with the albumin, and wherein the average
particle size of the nanoparticles in the composition is no greater
than about 200 nm (such as less than about 200 nm for example no
greater than about 100 nm). In some embodiments, there is provided
a method of delivering Nab-rapamycin to a blood vessel, wherein the
method comprises injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to a disease site (or lesion site), such as
no more than about 2, 1, or 0.5 cm away from the disease site (or
lesion site). In some embodiments, the nanoparticle composition is
injected remotely from a disease site (such example at least about
any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cm away from the disease
site).
[0035] A typical blood vessel wall has an endothelium which is the
layer of the wall which is exposed to the blood vessel lumen.
Underlying the endothelium is the basement membrane which in turn
is surrounded by the intima. The intima, in turn, is surrounded by
the internal elastic lamina over which is located the media. In
turn, the media is covered by the external elastic lamina which
acts as the outer barrier separating the blood vessel wall from the
adventitial tissue, which surrounds the blood vessel wall. The
methods described herein include injection of the nanoparticle
composition into any one of these layers of the blood vessel wall.
In some embodiments, the nanoparticle composition is injected into
the endothelium. In some embodiments, the nanoparticle composition
is injected into the basement membrane. In some embodiments, the
nanoparticle composition is injected into the intima. In some
embodiments, the nanoparticle composition is injected into the
internal elastic lamina. In some embodiments, the nanoparticle is
injected into the media. In some embodiments, the nanoparticle is
injected into the external elastic lamina. In some embodiments, the
nanoparticle composition is injected into any one of the following
regions of a blood vessel: tunica intima (contains endothelium,
basement membrane, internal elastic lamina), tunica media (contains
smooth muscle cells), and tunica adventitia (contains external
elastic membrane, collagen fibres).
[0036] "Tissue surrounding the blood vessel wall," used herein
interchangeably with the terms "perivascular" or "periadventitial,"
refers to the region over the outer surface of the blood vessel
wall. This includes the adventitial tissue of the blood vessel, as
well as regions beyond the adventitial tissue. By controlling the
site of the injection of the nanoparticle compositions, the
nanoparticle composition can be injected to the specific desired
locations.
[0037] Methods and devices have been developed for the purpose of
injecting therapeutic agents into the blood vessel wall and tissues
surrounding the blood vessel wall. For example, catheters carrying
needles capable of delivering therapeutic and other agents deep
into the adventitial layer surrounding blood vessel lumens have
been described in U.S. Pat. No. 6,547,303, 6,860,867 and U.S.
Patent Application Publication Nos. 2007/0106257, 2010/0305546, and
2009/0142306, the content of each of these are specifically
incorporated herein by reference in their entirety. The methods of
the present invention in some embodiments use a catheter having a
needle for the injection of the nanoparticle composition. In some
embodiments, the needle is deployable. The catheter can be advanced
intravascularly to a target injection site (which may or may not be
a disease region) in a blood vessel. The needle in the catheter is
advanced through the blood vessel wall so that an aperture on the
needle is positioned in the desired region (for example the
perivascular region), and the nanoparticle compositions can be
injected through the aperture of the needled into the desired
region.
[0038] For example, in some embodiments there is provided a method
of delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin or derivative thereof,
for example rapamycin) to a blood vessel, wherein the method
comprises injecting (for example via a catheter with a needle) into
the tissue surrounding the blood vessel wall an effective amount of
a composition comprising nanoparticles comprising a macrolide and
an albumin. In some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin) to a blood vessel,
wherein the method comprises injecting (for example via a catheter
with a needle) into the tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the macrolide in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin) to a blood vessel,
wherein the method comprises injecting (for example via a catheter
with a needle) into the tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the average particle size of the nanoparticles in
the composition is no greater than about 200 nm (such as less than
about 200 nm, for example no greater than about 100 nm). In some
embodiments, there is provided a method of delivering a composition
comprising nanoparticles comprising albumin and a macrolide (such
as rapamycin) to a blood vessel, wherein the method comprises
injecting (for example via a catheter with a needle) into the
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising rapamycin and an
albumin (such as human serum albumin), wherein the rapamycin in the
nanoparticles is coated with the albumin, and wherein the average
particle size of the nanoparticles in the composition is no greater
than about 200 nm (such as less than about 200 nm for example no
greater than about 100 nm). In some embodiments, there is provided
a method of delivering Nab-rapamycin to a blood vessel, wherein the
method comprises injecting (for example via a catheter with a
needle) into the tissue surrounding the blood vessel wall an
effective amount of Nab-rapamycin. In some embodiments, the
nanoparticle composition is injected at a disease site. In some
embodiments, the nanoparticle composition is injected distal to a
disease site (such example at least about any of 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 cm away from the disease site).
[0039] In some embodiments, the nanoparticle composition is
injected into the adventitial tissue of the blood vessel. The
adventitial tissue is the tissue surrounding the blood vessel, for
example the tissue beyond the external elastic lamina of an artery
or beyond the tunica media of a vein. The adventitia has a high
concentration of lipid. In some embodiments, the nanoparticle
composition is injected into the vasa vasorum region of the
adventitia. In some embodiments, the nanoparticle composition, upon
injection, can disperse through the adventitia circumferentially,
longitudinally, and/or transmurally from the injection site with
respect to the axis of the blood vessel from which the nanoparticle
composition is being injected (herein after referred to as
"volumetric distribution"). In some embodiments, the drug (in an
albumin-bound form or in nanoparticle form) distributes over a
distance of at least about 1 cm (for example at least about any of
2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, or more) longitudinally and/or
at least 1 cm (for example at least about any of 2 cm, 3 cm, 4 cm,
5 cm, 6 cm, 7 cm, or more) radially from the site of injection over
a time period no greater than 60 minutes. In some embodiments, a
concentration of a drug measured at all locations at least 2 cm
from the delivery site is at least 10% (such as at least about any
of 20%, 30%, 40%, or 50%) of the concentration at the delivery
site, for example after a period of 60 minutes. In some
embodiments, the drug (in an albumin-bound form or in nanoparticle
form) distributes transmurally throughout the endothelial and
intimal layers of the blood vessel, the media, and the muscular
layer. While periadventitial administration of pharmaceutical
agents has previously been reported to allow volumetric
distribution of a pharmaceutical agent, it was believed larger
substances are not efficiently distributed because volumetric
distribution was achieved by the lymphatic microcirculatory system
surrounding the blood vessel. The behavior of nanoparticle
compositions in the adventitial tissue was unknown. The present
invention thus differs from methods previously reported in these
aspects.
[0040] Thus, in some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as rapamycin) to a blood vessel,
wherein the method comprises injecting (for example via a catheter
with a needle) into the adventitial tissue of the blood vessel wall
an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin. In some embodiments, there
is provided a method of delivering a composition comprising
nanoparticles comprising albumin and a macrolide (such as
rapamycin) to a blood vessel, wherein the method comprises
injecting (for example via a catheter with a needle) into the
adventitial tissue of the blood vessel an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the macrolide in the
nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of delivering a composition comprising
nanoparticles comprising albumin and a macrolide (such as
rapamycin) to a blood vessel, wherein the method comprises
injecting (for example via a catheter with a needle) into the
adventitial tissue of the blood vessel an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of delivering a composition comprising nanoparticles
comprising albumin and a macrolide (such as rapamycin) to a blood
vessel, wherein the method comprises injecting (for example via a
catheter with a needle) into the adventitial tissue of the blood
vessel an effective amount of a composition comprising
nanoparticles comprising rapamycin and an albumin (such as human
serum albumin), wherein the rapamycin in the nanoparticles is
coated with the albumin, and wherein the average particle size of
the nanoparticles in the composition is no greater than about 200
nm (such as less than about 200 nm for example no greater than
about 100 nm). In some embodiments, there is provided a method of
delivering Nab-rapamycin to a blood vessel, wherein the method
comprises injecting (for example via a catheter with a needle) into
the adventitial tissue of the blood vessel wall an effective amount
of Nab-rapamycin. In some embodiments, the nanoparticle composition
is injected at or adjacent to a disease site (such as no more than
about 2, 1, or 0.5 cm away from the disease site). In some
embodiments, the nanoparticle composition is injected remotely from
a disease site (such example at least about any of 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 cm away from the disease site). In some
embodiments, the nanoparticle composition, upon injection, achieves
a volumetric distribution.
[0041] The blood vessel described in some embodiments is an artery,
such as a coronary artery or a peripheral artery. In some
embodiments, the artery is selected from the group consisting of
renal artery, cerebral artery, pulmonary artery, and artery in the
leg. In some embodiments, the blood vessel is an artery or vein
above the knee. In some embodiments, the blood vessel is an artery
or vein below the knee. In some embodiments, the blood vessel is a
femoral artery. In some embodiments, the blood vessel is a balloon
injured artery.
[0042] In some embodiments, the blood vessel is an artery selected
from any one of the following: abdominal aorta, anterior tibial
artery, arch of aorta, arcuate artery, axillary artery, brachial
artery, carotid artery, celiac artery, circumflex fibular artery,
common hepatic artery, common iliac artery, deep femoral artery,
deep palmar arterial arch, dorsal digital artery, dorsal metatarsal
artery, external carotid artery, external iliac artery, facial
artery, femoral artery, inferior mesenteric artery, internal iliac
artery, instestinal artery, lateral inferior genicular artery,
lateral superior genicular artery, palmar digital artery, peroneal
artery, popliteal artery, posterior tibial artery, profunda femoris
artery, pulmonary artery, radial artery, renal artery, splenic
artery, subclavian artery, superficial palmar arterial arch,
superior mesenteric artery, superior ulnar collateral artery, and
ulnar artery.
[0043] In some embodiments, the blood vessel is a vein. In some
embodiments, the blood vessel is a vein selected from any one of
the following: accessory cephalic vein, axillary vein, basilic
vein, brachial vein, cephalic vein, common iliac vein, dorsal
digital vein, dorsal metatarsal vein, external iliac vein, facial
vein, femoral vein, great saphenous vein, hepatic vein, inferior
mesenteric vein, inferior vena cava, intermediate antebrachial
vein, internal iliac vein, intestinal vein, jugular vein, lateral
circumflex femoral vein, left inferior pulmonary vein, left
superior pulmonary vein, palmar digital vein, portal vein,
posterior tibial vein, renal vein, retromanibular vein, saphenous
vein, small saphenous vein, splenic vein, subclavian vein, superior
mesenteric vein, and superior vena cava.
[0044] In some embodiments, the blood vessel is part of the
coronary vasculature (including the arterial and venous
vasculature), the cerebral vasculature, the hepatic vasculature,
the peripheral vasculature, and the vasculature of other organs and
tissue compartments.
[0045] In some embodiments, there is provided a method of
delivering a composition comprising nanoparticles comprising
albumin and a macrolide (such as a rapamycin or a derivative
thereof, for example rapamycin) to a blood vessel, wherein the
method comprises injecting (for example via a catheter with a
needle) periadventitially (i.e., injecting into the periadventitial
tissue) to a femoral artery an effective amount of a composition
comprising nanoparticles comprising a macrolide and an albumin. In
some embodiments, there is provided a method of delivering a
composition comprising nanoparticles comprising albumin and a
macrolide (such as a rapamycin or a derivative thereof, for example
rapamycin) to a blood vessel, wherein the method comprises
injecting (for example via a catheter with a needle)
periadventitially to a femoral artery an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the macrolide in the
nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of delivering a composition comprising
nanoparticles comprising albumin and a macrolide (such as a
rapamycin or a derivative thereof, for example rapamycin) to a
blood vessel, wherein the method comprises injecting (for example
via a catheter with a needle) periadventitially to a femoral artery
an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the average particle size of the nanoparticles in
the composition is no greater than about 200 nm (such as less than
about 200 nm, for example no greater than about 100 nm). In some
embodiments, there is provided a method of delivering a composition
comprising nanoparticles comprising albumin and a macrolide (such
as a rapamycin or a derivative thereof, for example rapamycin) to a
blood vessel, wherein the method comprises injecting (for example
via a catheter with a needle) periadventitially to a femoral artery
an effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin (such as human serum albumin),
wherein the rapamycin in the nanoparticles is coated with the
albumin, and wherein the average particle size of the nanoparticles
in the composition is no greater than about 200 nm (such as less
than about 200 nm for example no greater than about 100 nm). In
some embodiments, there is provided a method of delivering
Nab-rapamycin to a blood vessel, wherein the method comprises
injecting (for example via a catheter with a needle)
periadventitially to a femoral artery an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to a disease site (such as no more than
about 2, 1, or 0.5 cm away from the disease site). In some
embodiments, the nanoparticle composition is injected remotely from
a disease site (such example at least about any of 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 cm away from the disease site).
[0046] The delivery methods described herein are effective in
inhibiting one or more aspects of blood vessel abnormalities,
including for example, negative remodeling, vascular fibrosis,
restenosis, cell proliferation and migration of cells in the blood
vessel, and wound healing. In some embodiments, the method is
effective in promoting positive remodeling of the blood vessel.
[0047] The present application thus in some embodiments provides a
method of inhibiting negative remodeling in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising a macrolide (such as rapamycin) and an albumin. In some
embodiments, there is provided a method of inhibiting negative
remodeling in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the macrolide in the
nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of inhibiting negative remodeling in a
blood vessel in an individual in need thereof, comprising injecting
into the blood vessel wall or tissue surrounding the blood vessel
wall an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the average particle size of the nanoparticles in
the composition is no greater than about 200 nm (such as less than
about 200 nm, for example no greater than about 100 nm). In some
embodiments, there is provided a method of inhibiting negative
remodeling in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising rapamycin and an
albumin (such as human serum albumin), wherein the rapamycin in the
nanoparticles is coated with the albumin, and wherein the average
particle size of the nanoparticles in the composition is no greater
than about 200 nm (such as less than about 200 nm for example no
greater than about 100 nm). In some embodiments, there is provide a
method of inhibiting negative remodeling in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of Nab-rapamycin. In some embodiments, the
nanoparticle composition is injected at or adjacent to a site of
negative remodeling (such as no more than about 2, 1, or 0.5 cm
away from the site of negative remodeling). In some embodiments,
the nanoparticle composition is injected remotely from a site of
negative remodeling (such example at least about any of 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10 cm away from the site of negative remodeling).
In some embodiments, the injection is via a catheter with a
needle.
[0048] Negative remodeling includes the physiologic or pathologic
response of a blood vessel to a stimulus resulting in a reduction
of vessel diameter and lumen diameter. Such a stimulus could be
provided by, for example, a change in blood flow or an angioplasty
procedure. In some embodiments, the injection of the nanoparticle
composition leads to an increase of vessel diameter by about any of
10%, 20%, 30%, 40%, 60%, 70%, 80%, 95%, or more, compared to the
diameter of a vessel of without the injection. Negative remodeling
can be quantified, for example, angiographically as the percent
diameter stenosis at the lesion site (or disease site). Another
method of determining the degree of remodeling involves measuring
in-lesion external elastic lamina area using intravascular
ultrasound (IVUS). IVUS is a technique that can image the external
elastic lamina as well as the vascular lumen. In some embodiments,
the negative remodeling is associated with a vascular
interventional procedure, such as angioplasty, stenting, or
atherectomy. The nanoparticle composition can therefore be injected
during or after the vascular interventional procedure.
[0049] In some embodiments, there is provided a method of promoting
positive remodeling in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide (such
as rapamycin) and an albumin. In some embodiments, there is
provided a method of promoting positive remodeling in a blood
vessel in an individual in need thereof, comprising injecting into
the blood vessel wall or tissue surrounding the blood vessel wall
an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the macrolide in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
promoting positive remodeling in a blood vessel in an individual in
need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of promoting positive remodeling in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin (such as human serum albumin),
wherein the rapamycin in the nanoparticles is coated with the
albumin, and wherein the average particle size of the nanoparticles
in the composition is no greater than about 200 nm (such as less
than about 200 nm for example no greater than about 100 nm). In
some embodiments, there is provide a method of promoting positive
remodeling in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to a site of negative remodeling (such as
no more than about 2, 1, or 0.5 cm away from the site of negative
remodeling). In some embodiments, the nanoparticle composition is
injected remotely from a site of negative remodeling (such example
at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cm away from
the site of negative remodeling). In some embodiments, the
injection is via a catheter with a needle.
[0050] Positive remodeling used herein refers to an increase of
vessel diameter as compared to the diameter of a vessel without the
injection. In some embodiments, the injection of the nanoparticle
composition leads to an increase of vessel diameter by about any of
10%, 20%, 30%, 40%, 60%, 70%, 80%, 95%, or more, compared to the
diameter of a vessel of without the injection.
[0051] In some embodiments, there is provided a method of
inhibiting vascular fibrosis (such as medial vascular fibrosis) in
a blood vessel in an individual in need thereof, comprising
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide (such as rapamycin) and an
albumin. In some embodiments, there is provided a method of
inhibiting vascular fibrosis (such as medial vascular fibrosis) in
a blood vessel in an individual in need thereof, comprising
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide and an albumin (such as human
serum albumin), wherein the macrolide in the nanoparticles is
coated with the albumin. In some embodiments, there is provided a
method of inhibiting vascular fibrosis (such as medial vascular
fibrosis) in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of inhibiting vascular fibrosis (such as medial vascular
fibrosis) in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising rapamycin and an
albumin (such as human serum albumin), wherein the rapamycin in the
nanoparticles is coated with the albumin, and wherein the average
particle size of the nanoparticles in the composition is no greater
than about 200 nm (such as less than about 200 nm for example no
greater than about 100 nm). In some embodiments, there is provided
a method of inhibiting vascular fibrosis (such as medial vascular
fibrosis) in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to the site of vascular fibrosis (for
example no greater than about any of 2, 1, 0.5 cm away from the
site of vascular fibrosis). In some embodiments, the nanoparticle
composition is injected remotely from a site of vascular fibrosis
(such example at least about any of 2, 3, 4, 5, 6, 7, 8, 9, or 10
cm away from the site of vascular fibrosis). In some embodiments,
the injection is via a catheter with a needle.
[0052] Vascular fibrosis as used herein refers to the extensive
fibrous (connective) tissue formation in the blood vessel, and
includes, for example, medial fibrosis or adventitial fibrosis.
Vascular fibrosis is frequently associated with abundant deposition
of extracellular matrix and proliferation of myofibroblasts and
fibroblasts. The method described herein therefore in some
embodiments inhibits fibrous tissue formation in the blood vessel,
for example inhibits about any of 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, or 90% fibrous tissue formation compared to a vessel
without the injection. In some embodiments, the method inhibits
deposition of extracellular matrix in the blood vessel, for example
inhibits about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or
90% deposition of extracellular matrix compared to a vessel without
the injection. In some embodiments, the method inhibits
proliferation of myofibroblast in the blood vessel, for example
inhibits about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or
90% proliferation of myofibroblast compared to a vessel without the
injection. In some embodiments, the method inhibits proliferation
of fibroblast in the blood vessel, for example inhibits about any
of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% proliferation of
fibroblast compared to a vessel without the injection. In some
embodiments, the vascular fibrosis is associated with a vascular
interventional procedure, such as angioplasty, stenting, or
atherectomy. The nanoparticle composition can therefore be injected
during or after the vascular interventional procedure.
[0053] The method described herein therefore in some embodiments
inhibits luminal stenosis, for example inhibits about any of 10%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% luminal stenosis compared
to a vessel without the injection. In some embodiments, the luminal
stenosis is associated with a vascular interventional procedure,
such as angioplasty, stenting, or atherectomy. The nanoparticle
composition can therefore be injected during or after the vascular
interventional procedure.
[0054] In some embodiments, there is provided a method of treating
restenosis in a blood vessel in an individual in need thereof,
comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide (such
as rapamycin) and an albumin. In some embodiments, there is
provided a method of treating restenosis in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the macrolide in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
treating restenosis in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of treating restenosis in a blood vessel in an individual
in need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising rapamycin and an
albumin (such as human serum albumin), wherein the rapamycin in the
nanoparticles is coated with the albumin, and wherein the average
particle size of the nanoparticles in the composition is no greater
than about 200 nm (such as less than about 200 nm for example no
greater than about 100 nm). In some embodiments, there is provided
a method of treating restenosis in a blood vessel in an individual
in need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to a disease site (for example no more than
about 2, 1, or 0.5 cm away from the disease site). In some
embodiments, the nanoparticle composition is injected remotely from
a disease site (such example at least about any of 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 cm away from the disease site). In some
embodiments, the injection is via a catheter with a needle.
[0055] In some embodiments, there is provided a method of reducing
adventitial leukocytes in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide (such
as rapamycin) and an albumin. In some embodiments, there is
provided a method of reducing adventitial leukocytes in a blood
vessel in an individual in need thereof, comprising injecting into
the blood vessel wall or tissue surrounding the blood vessel wall
an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the macrolide in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
reducing adventitial leukocytes in a blood vessel in an individual
in need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of reducing adventitial leukocytes in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin (such as human serum albumin),
wherein the rapamycin in the nanoparticles is coated with the
albumin, and wherein the average particle size of the nanoparticles
in the composition is no greater than about 200 nm (such as less
than about 200 nm for example no greater than about 100 nm). In
some embodiments, there is provided a method of reducing
adventitial leukocytes in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected into the adventitial tissue.
[0056] In some embodiments, there is provided a method of reducing
adventitial vessels in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide (such
as rapamycin) and an albumin. In some embodiments, there is
provided a method of reducing adventitial vessels in a blood vessel
in an individual in need thereof, comprising injecting into the
blood vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the macrolide in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
reducing adventitial vessels in a blood vessel in an individual in
need thereof, comprising injecting into the blood vessel wall or
tissue surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the average particle
size of the nanoparticles in the composition is no greater than
about 200 nm (such as less than about 200 nm, for example no
greater than about 100 nm). In some embodiments, there is provided
a method of reducing adventitial vessels in a blood vessel in an
individual in need thereof, comprising injecting into the blood
vessel wall or tissue surrounding the blood vessel wall an
effective amount of a composition comprising nanoparticles
comprising rapamycin and an albumin (such as human serum albumin),
wherein the rapamycin in the nanoparticles is coated with the
albumin, and wherein the average particle size of the nanoparticles
in the composition is no greater than about 200 nm (such as less
than about 200 nm for example no greater than about 100 nm). In
some embodiments, there is provided a method of reducing
adventitial vessels in a blood vessel in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected into the adventitial tissue.
[0057] In some embodiments, the individual is human. In some
embodiments, the individual is at least about any of 35, 40, 45,
50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments,
the individual is of Asian ancestry. In some embodiments, the
individual is a male. In some embodiments, the individual is a
female. In some embodiments, the individual has a disease as
discussed below.
[0058] The methods described herein are useful for treating a
variety of diseases. These include, for example, angina, aortic
stenosis, arteriosclerosis obliterans, carotid artery stenosis,
cerebrovascular artery disease, cerebrovascular occlusive disease,
coronary artery disease, dilated cardiomyopathy, cardiomyopathy,
ischemic cardiomyopathy, intermittent claudication, peripheral
artery stenosis, renal artery disease, restenosis, small vessel
disease, stenosis, aortic stenosis, Aortic valve stenosis, hyaline
arteriolosclerosis, hyperplastic arteriosclerosis, mitrial
stenosis, pulmonary valve stenosis, tricuspid valve stenosis, deep
vein thrombosis, peripheral venous disease, and thrombophlebitis.
The methods described herein may encompass the treatment of any one
or more of these diseases.
[0059] In some embodiments, the disease is selected from the group
consisting of angina, myocardial infarction, congestive heart
failure, cardiac arrhythmia, peripheral artery disease,
claudication, or chronic limb ischemia. Thus, for example, in some
embodiments, there is provided a method of treating angina (or
myocardial infarction, or congestive heart failure, or cardiac
arrhythmia, or peripheral artery disease, or claudication, or
chronic limb ischemia) in an individual in need thereof, comprising
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising a macrolide (such as rapamycin) and an
albumin. In some embodiments, there is provided a method of
treating angina (or myocardial infarction, or congestive heart
failure, or cardiac arrhythmia, or peripheral artery disease, or
claudication, or chronic limb ischemia) in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of a
composition comprising nanoparticles comprising a macrolide and an
albumin (such as human serum albumin), wherein the macrolide in the
nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of treating angina (or myocardial
infarction, or congestive heart failure, or cardiac arrhythmia, or
peripheral artery disease, or claudication, or chronic limb
ischemia) in an individual in need thereof, comprising injecting
into the blood vessel wall or tissue surrounding the blood vessel
wall an effective amount of a composition comprising nanoparticles
comprising a macrolide and an albumin (such as human serum
albumin), wherein the average particle size of the nanoparticles in
the composition is no greater than about 200 nm (such as less than
about 200 nm, for example no greater than about 100 nm). In some
embodiments, there is provided a method of treating angina (or
myocardial infarction, or congestive heart failure, or cardiac
arrhythmia, or peripheral artery disease, or claudication, or
chronic limb ischemia) in an individual in need thereof, comprising
injecting into the blood vessel wall or tissue surrounding the
blood vessel wall an effective amount of a composition comprising
nanoparticles comprising rapamycin and an albumin (such as human
serum albumin), wherein the rapamycin in the nanoparticles is
coated with the albumin, and wherein the average particle size of
the nanoparticles in the composition is no greater than about 200
nm (such as less than about 200 nm for example no greater than
about 100 nm). In some embodiments, there is provided a method of
treating angina (or myocardial infarction, or congestive heart
failure, or cardiac arrhythmia, or peripheral artery disease, or
claudication, or chronic limb ischemia) in an individual in need
thereof, comprising injecting into the blood vessel wall or tissue
surrounding the blood vessel wall an effective amount of
Nab-rapamycin. In some embodiments, the nanoparticle composition is
injected at or adjacent to a disease site (for example no more than
about 2, 1, or 0.5 cm away from the disease site). In some
embodiments, the nanoparticle composition is injected remotely from
a disease site (such example at least about any of 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10 cm away from the disease site). In some
embodiments, the injection is via a catheter with a needle. In some
embodiments, the nanoparticle composition is injected during or
after the vascular interventional procedure, such as angioplasty,
stenting, or atherectomy.
[0060] The methods described herein in some embodiments comprise
injecting the nanoparticle composition distal to the disease site.
In some embodiments, the nanoparticle composition is injected
proximal to the disease site. The delivery site may be located
within the same blood vessel as the disease treatment region at a
location which is longitudinally spaced-apart from the region, or
may be located in a different blood vessel. In some embodiments,
the nanoparticle composition is injected at or adjacent to the
disease site (for example no more than about any of 2, 1, or 0.5 cm
away (for example longitudinally away) from the disease site). In
some embodiments, the nanoparticle composition is injected remotely
from the disease site (for example about any of 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 cm away (for example longitudinally away) from the
disease site). In some embodiments, the disease treatment region
may have been previously stented where the delivery site is spaced
away from the stent, either longitudinally away from the stent in
the same coronary artery or remote from the stent in another
coronary artery or vein.
[0061] The methods described herein in some embodiments comprise
injecting the nanoparticle composition with a needle (such as a
deployable needle). The needle can be positioned such that the
nanoparticle composition is delivered to a desired site. The
methods in some embodiments thus comprise positioning a needle
through the wall of a blood vessel and delivering an effective
amount of the nanoparticle composition into the wall of the blood
vessel or the tissue surrounding the blood vessel wall. For
example, in some embodiments, the aperture of the needle lies
beyond the external elastic lamina of the blood vessel so that the
nanoparticle composition is delivered to the adventitial tissue
surrounding the blood vessel. In some embodiments, the aperture of
the needle is positioned at a distance that is no more than about
0.1 mm, about 0.2 mm, 0.5 mm, 0.8 mm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm,
6 cm, 7 cm, or 8 cm beyond the external elastic lamina of the blood
vessel.
[0062] In some embodiments, the aperture is positioned at a
distance from the inner wall of the blood vessel that is at least
about 10% (including for example at least about 20%, 30%, 40%, 60%,
70%, 80%, 90%) of the mean luminal diameter of the blood vessel at
the injection site. In some embodiments, the aperture is positioned
at a distance from the inner wall of the blood vessel that is about
10% to about 75% (including for example about 20% to about 60%,
about 30% to about 50%) of the mean luminal diameter of the blood
vessel at the injection site.
[0063] Confirmation of the position of the needle aperture can be
achieved in a variety of ways. For example, a bolus of contrast
agent or other visible media can be injected through the needle
after initial positioning of the needle is achieved. By observing
the distribution of the media, for example fluroscopically, the
position of the aperture can be assessed. In some embodiments,
various sensors can be attached or otherwise coupled to the needle,
usually near the delivery aperture, in order to detect the position
of the needle. Exemplary sensors include temperature sensors, pH
sensors, electrical impedance sensors, and the like. It is also
possible to measure the back pressure on an injected suspension in
order to determine the needle position. Injection into the blood
vessel wall will typically result in a greater back pressure than
injection into the adventitial space. It is also possible to
monitor the insertion force of the needle, e.g., by providing a
deflection gauge on a portion of the needle.
Dosing and Method of Administering the Nanoparticle
Compositions
[0064] The dose of the macrolide nanoparticle compositions injected
to an individual (such as a human) may vary with the type of blood
vessel for the injection, the purpose of the method, and the type
of disease being treated. In some embodiments, the amount of the
macrolide nanoparticle composition injected is sufficient to
inhibit negative remodeling by more than about any of 5%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%,
80%, 85%, or 90%. Inhibition of negative remodeling can be
assessed, for example, by measuring the vessel or luminal diameter
of the blood vessel. In some embodiments, the amount of the
macrolide nanoparticle composition injected is sufficient to
promote positive remodeling by more than about any of 5%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%,
80%, 85%, or 90%.
[0065] In some embodiments, the amount of the macrolide
nanoparticle composition injected is sufficient to inhibit vascular
fibrosis by more than about any of 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90%.
In some embodiments, the vascular fibrosis is medial fibrosis. In
some embodiments, the vascular fibrosis is adventitial fibrosis.
Inhibition of vascular fibrosis can be assessed, for example, by
evaluating the amount of extracellular matrix deposition and/or
proliferation of myofibroblasts and fibroblasts. In some
embodiments, the vascular fibrosis is evaluated by histopathology
analysis, for example by staining with H&E or trichrome.
[0066] In some embodiments, the amount of the macrolide
nanoparticle composition injected is sufficient to reduce
proliferation index by more than about any of 5%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%,
85%, or 90%. In some embodiments, the amount of the macrolide
nanoparticle composition injected is sufficient to reduce luminal
stenosis by more than about any of 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90%.
In some embodiments, the amount of the macrolide nanoparticle
composition injected is sufficient to reduce adventitial leukocytes
by more than about any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90%. In some
embodiments, the amount of the macrolide nanoparticle composition
injected is sufficient to reduce adventitial vessels by more than
about any of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90%.
[0067] In some embodiments, the amount of the macrolide (e.g.,
rapamycin) in the composition is below the level that induces a
toxicological effect (i.e., an effect above a clinically acceptable
level of toxicity) or is at a level where a potential side effect
can be controlled or tolerated when the composition is injected to
the individual.
[0068] In some embodiments, the amount of a macrolide (e.g.,
rapamycin or derivative thereof, for example rapamycin) per
injection is within any one of the following ranges: about 0.001 to
about 100 mg, including for example about 0.001 to about 0.005 mg,
about 0.005 to about 0.025 mg, about 0.025 to about 0.1 mg, about
0.1 to about 0.5 mg, about 0.5 to about 1mg, about 1 to about 2 mg,
about 2 to about 3 mg, about 3 to about 4 mg, about 4 to about 5
mg, about 5 to about 6 mg, about 6 to about 7 mg, about 7 to about
8 mg, about 8 to about 9 mg, about 9 to about 10 mg, about 10 to
about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg,
about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about
75 mg, or about 50 to about 100 mg. In some embodiments, the amount
of a macrolide (e.g., rapamycin) per injection is in the range of
about 0.001 to about 100 mg, such as about 0.005 to about 80 mg,
about 0.05 to about 50 mg, about 0.1 to about 10 mg, about 0.1 to
about 5 mg, about 0.5 to about 5 mg, about 0.05 to about 5 mg, or
about 0.5 to about 2 mg.
[0069] In some embodiments, the concentration of the macrolide
(e.g., rapamycin) in the nanoparticle composition is dilute (about
0.1 mg/ml) or concentrated (about 100 mg/ml), including for example
any of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml,
about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4
to about 6 mg/ml, or about 5 mg/ml. In some embodiments, the
concentration of the macrolide (e.g., rapamycin) is at least about
any of 0.5 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml,
5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20
mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, or 50 mg/ml. In some
embodiments, the concentration of the macrolide (e.g., rapamycin)
is no more than about any of 100 mg/ml, 90 mg/ml, 80 mg/ml, 70
mg/ml, 60 mg/ml, 50 mg/ml, 40 mg/ml, 30 mg/ml, 20 mg/ml, 10 mg/ml,
or 5 mg/ml.
[0070] The volume of the nanoparticle composition per injection may
vary with the type of blood vessel for the injection, the purpose
of the method, and the type of disease being treated. In some
embodiments, the volume per injection is about 0.01 to about 50 ml,
including for example about 0.01 to about 0.05 ml, about 0.05 to
about 0.1 ml, about 0.1 to about 0.5 ml, about 0.5 to about 1 ml,
about 1 to about 2 ml, about 2 to about 3 ml, about 3 to about 5
ml, about 5 to about 10 ml, about 10 to about 20 ml, about 20 to
about 30 ml, about 30 to about 40 ml, about 40 to about 50 ml. In
some embodiments, the volume per injection is about 0.05 to about 2
ml, about 0.1 to 1 ml, about 0.25 to about 0.5 ml, or about 0.5 to
about 1 ml, or about 1 to about 5 ml.
[0071] Exemplary dosing frequencies for the administration of the
nanoparticle compositions include, but are not limited to, about
once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some
embodiments, the intervals between each administration are more
than about any of 1 month, 2 months, 3 months, 4 months, 5 months,
6 months, 8 months, or 12 months. In some embodiments, the
administration is administered every 3, 6, 9, 12, 15, 18, 21, or 24
months. In some embodiments, the administration is administered at
most every 3, 6, 9, 12, 15, 18, 21, or 24 months. In some
embodiments, the administration is administered at least every 3,
6, 9, 12, 15, 18, 21, or 24 months. In some embodiments, the
nanoparticle composition is injected only once.
[0072] The nanoparticle composition can be injected during a
vascular interventional procedure. In some embodiments, the
nanoparticle composition is injected once during the vascular
interventional procedure. In some embodiments, the nanoparticle
composition is injected after a vascular interventional procedure.
Exemplary vascular interventional procedures include, but are not
limited to, angioplasty, stenting, and atherectomy.
Nanoparticle Compositions
[0073] The nanoparticle compositions described herein comprise
nanoparticles comprising (in various embodiments consisting
essentially of or consisting of) a macrolide (such as rapamycin)
and an albumin (such as human serum albumin). Nanoparticles of
poorly water soluble drugs (such as macrolide) have been disclosed
in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868,
6,537,579, 7,820,788, and also in U.S. Pat. Pub. Nos. 2006/0263434,
and 2007/0082838; PCT Patent Application WO08/137148, each of which
is incorporated by reference in their entirety.
[0074] In some embodiments, the composition comprises nanoparticles
with an average or mean diameter of no greater than about 1000
nanometers (nm), such as no greater than about any of 900, 800,
700, 600, 500, 400, 300, 200, and 100 nm. In some embodiments, the
average or mean diameters of the nanoparticles is no greater than
about 200 nm. In some embodiments, the average or mean diameters of
the nanoparticles is no greater than about 150 nm. In some
embodiments, the average or mean diameters of the nanoparticles is
no greater than about 100 nm. In some embodiments, the average or
mean diameter of the nanoparticles is about 20 to about 400 nm. In
some embodiments, the average or mean diameter of the nanoparticles
is about 40 to about 200 nm. In some embodiments, the average or
mean diameter of the nanoparticles is about 50 to about 100 nm. In
some embodiments, the nanoparticles are no less than about 50 nm.
In some embodiments, the nanoparticles are sterile-filterable.
[0075] In some embodiments, the nanoparticles in the composition
described herein have an average diameter of no greater than about
200 nm, including for example no greater than about any one of 190,
180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm.
In some embodiments, at least about 50% (for example at least about
any one of 60%, 70%, 80%, 90%, 95%, or 99%) of the nanoparticles in
the composition have a diameter of no greater than about 200 nm,
including for example no greater than about any one of 190, 180,
170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm.
[0076] In some embodiments, the nanoparticles in the composition
described herein have an average diameter of no less than about 50
nm, including for example no less than about any one of 50, 60, 70,
80, 90, or 100 nm. In some embodiments, at least about 50% (for
example at least about any one of 60%, 70%, 80%, 90%, 95%, or 99%)
of the nanoparticles in the composition have a diameter of no less
than about 50 nm, including for example no less than about any one
of 50, 60, 70, 80, 90, or 100 nm.
[0077] In some embodiments, at least about 50% (for example at
least any one of 60%, 70%, 80%, 90%, 95%, or 99%) of the
nanoparticles in the composition fall within the range of about 20
to about 400 nm, including for example about 20 to about 200 nm,
about 40 to about 200 nm, about 30 to about 180 nm, and any one of
about 40 to about 150, about 50 to about 120, and about 60 to about
100 nm.
[0078] In some embodiments, the albumin has sulfhydral groups that
can form disulfide bonds. In some embodiments, at least about 5%
(including for example at least about any one of 10%, 15%, 20%,
25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) of the albumin in the
nanoparticle portion of the composition are crosslinked (for
example crosslinked through one or more disulfide bonds).
[0079] In some embodiments, the nanoparticles comprise the
macrolide (such as rapamycin) coated with an albumin (e.g., human
serum albumin). In some embodiments, the composition comprises a
macrolide in both nanoparticle and non-nanoparticle forms (e.g., in
the form of rapamycin solutions or in the form of soluble
albumin/nanoparticle complexes), wherein at least about any one of
50%, 60%, 70%, 80%, 90%, 95%, or 99% of the macrolide in the
composition are in nanoparticle form. In some embodiments, the
macrolide in the nanoparticles constitutes more than about any one
of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticles by
weight. In some embodiments, the nanoparticles have a non-polymeric
matrix. In some embodiments, the nanoparticles comprise a core of a
macrolide that is substantially free of polymeric materials (such
as polymeric matrix).
[0080] In some embodiments, the composition comprises albumin in
both nanoparticle and non-nanoparticle portions of the composition,
wherein at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, or
99% of the albumin in the composition are in non-nanoparticle
portion of the composition.
[0081] In some embodiments, the weight ratio of albumin (such as
human serum albumin) and a macrolide in the nanoparticle
composition is about 18:1 or less, such as about 15:1 or less, for
example about 10:1 or less. In some embodiments, the weight ratio
of albumin (such as human serum albumin) and macrolide in the
composition falls within the range of any one of about 1:1 to about
18:1, about 2:1 to about 15:1, about 3:1 to about 13:1, about 4:1
to about 12:1, about 5:1 to about 10:1. In some embodiments, the
weight ratio of albumin and macrolide in the nanoparticle portion
of the composition is about any one of 1:2, 1:3, 1:4, 1:5, 1:10,
1:15, or less. In some embodiments, the weight ratio of the albumin
(such as human serum albumin) and the macrolide in the composition
is any one of the following: about 1:1 to about 18:1, about 1:1 to
about 15:1, about 1:1 to about 12:1, about 1:1 to about 10:1, about
1:1 to about 9:1, about 1:1 to about 8:1, about 1:1 to about 7:1,
about 1:1 to about 6:1, about 1:1 to about 5:1, about 1:1 to about
4:1, about 1:1 to about 3:1, about 1:1 to about 2:1, or about
1:1.
[0082] In some embodiments, the nanoparticle composition comprises
one or more of the above characteristics.
[0083] The nanoparticles described herein may be present in a dry
formulation (such as lyophilized composition) or suspended in a
biocompatible medium. Suitable biocompatible media include, but are
not limited to, water, buffered aqueous media, saline, buffered
saline, optionally buffered solutions of amino acids, optionally
buffered solutions of proteins, optionally buffered solutions of
sugars, optionally buffered solutions of vitamins, optionally
buffered solutions of synthetic polymers, lipid-containing
emulsions, and the like.
[0084] In some embodiments, the pharmaceutically acceptable carrier
comprises human serum albumin. Human serum albumin (HSA) is a
highly soluble globular protein of M.sub.r 65K and consists of 585
amino acids. HSA is the most abundant protein in the plasma and
accounts for 70-80% of the colloid osmotic pressure of human
plasma. The amino acid sequence of HSA contains a total of 17
disulphide bridges, one free thiol (Cys 34), and a single
tryptophan (Trp 214). Intravenous use of HSA solution has been
indicated for the prevention and treatment of hypovolumic shock
(see, e.g., Tullis, JAMA, 237, 355-360, 460-463, (1977)) and Houser
et al., Surgery, Gynecology and Obstetrics, 150, 811-816 (1980))
and in conjunction with exchange transfusion in the treatment of
neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in
Thrombosis and Hemostasis, 6, 85-120, (1980)). Other albumins are
contemplated, such as bovine serum albumin. Use of such non-human
albumins could be appropriate, for example, in the context of use
of these compositions in non-human mammals, such as the veterinary
(including domestic pets and agricultural context).
[0085] Human serum albumin (HSA) has multiple hydrophobic binding
sites (a total of eight for fatty acids, an endogenous ligand of
HSA) and binds a diverse set of macrolides, especially neutral and
negatively charged hydrophobic compounds (Goodman et al., The
Pharmacological Basis of Therapeutics, 9.sup.th ed, McGraw-Hill New
York (1996)). Two high affinity binding sites have been proposed in
subdomains IIA and IIIA of HSA, which are highly elongated
hydrophobic pockets with charged lysine and arginine residues near
the surface which function as attachment points for polar ligand
features (see, e.g., Fehske et al., Biochem. Pharmcol., 30, 687-92
(198a), Vorum, Dan. Med. Bull., 46, 379-99 (1999), Kragh-Hansen,
Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., Nat. Struct.
Biol., 5, 827-35 (1998), Sugio et al., Protein. Eng., 12, 439-46
(1999), He et al., Nature, 358, 209-15 (199b), and Carter et al.,
Adv. Protein. Chem., 45, 153-203 (1994)). Rapamycin and propofol
have been shown to bind HSA (see, e.g., Paal et al.,Eur. J.
Biochem., 268(7), 2187-91 (200a), Purcell et al., Biochim. Biophys.
Acta, 1478(a), 61-8 (2000), Altmayer et al., Arzneimittelforschung,
45, 1053-6 (1995), and Garrido et al., Rev. Esp. Anestestiol.
Reanim., 41, 308-12 (1994)). In addition, docetaxel has been shown
to bind to human plasma proteins (see, e.g., Urien et al., Invest.
New Drugs, 14(b), 147-51 (1996)).
[0086] The albumin (such as human serum albumin) in the composition
generally serves as a carrier for the macrolide, i.e., the albumin
in the composition makes the macrolide more readily suspendable in
an aqueous medium or helps maintain the suspension as compared to
compositions not comprising an albumin. This can avoid the use of
toxic solvents (or surfactants) for solubilizing the macrolide, and
thereby can reduce one or more side effects of administration of
the macrolide into an individual (such as a human). Thus, in some
embodiments, the composition described herein is substantially free
(such as free) of surfactants, such as Cremophor (including
Cremophor EL.RTM. (BASF)). In some embodiments, the nanoparticle
composition is substantially free (such as free) of surfactants. A
composition is "substantially free of Cremophor" or "substantially
free of surfactant" if the amount of Cremophor or surfactant in the
composition is not sufficient to cause one or more side effect(s)
in an individual when the nanoparticle composition is injected to
the individual. In some embodiments, the nanoparticle composition
contains less than about any one of 20%, 15%, 10%, 7.5%, 5%, 2.5%,
or 1% organic solvent or surfactant.
[0087] The amount of albumin in the composition described herein
will vary depending on other components in the composition. In some
embodiments, the composition comprises an albumin in an amount that
is sufficient to stabilize the macrolide in an aqueous suspension,
for example, in the form of a stable colloidal suspension (such as
a stable suspension of nanoparticles). In some embodiments, the
albumin is in an amount that reduces the sedimentation rate of the
macrolide in an aqueous medium. For particle-containing
compositions, the amount of the albumin also depends on the size
and density of nanoparticles of the macrolide.
[0088] A macrolide is "stabilized" in an aqueous suspension if it
remains suspended in an aqueous medium (such as without visible
precipitation or sedimentation) for an extended period of time,
such as for at least about any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The
suspension is generally, but not necessarily, suitable for
administration to an individual (such as human). Stability of the
suspension is generally (but not necessarily) evaluated at a
storage temperature (such as room temperature (such as
20-25.degree. C.) or refrigerated conditions (such as 4.degree.
C.)). For example, a suspension is stable at a storage temperature
if it exhibits no flocculation or particle agglomeration visible to
the naked eye or when viewed under the optical microscope at 1000
times, at about fifteen minutes after preparation of the
suspension. Stability can also be evaluated under accelerated
testing conditions, such as at a temperature that is higher than
about 40.degree. C.
[0089] In some embodiments, the albumin is present in an amount
that is sufficient to stabilize the macrolide in an aqueous
suspension at a certain concentration. For example, the
concentration of the macrolide in the composition is about 0.1 to
about 100 mg/ml, including for example any of about 0.1 to about 50
mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml,
about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5
mg /ml. In some embodiments, the concentration of the macrolide is
at least about any of 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4
mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15
mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, and 50 mg/ml. In
some embodiments, the albumin is present in an amount that avoids
use of surfactants (such as Cremophor), so that the composition is
free or substantially free of surfactant (such as Cremophor).
[0090] In some embodiments, the composition, in liquid form,
comprises from about 0.1% to about 50% (w/v) (e.g. about 0.5%
(w/v), about 5% (w/v), about 10% (w/v), about 15% (w/v), about 20%
(w/v), about 30% (w/v), about 40% (w/v), or about 50% (w/v)) of
albumin. In some embodiments, the composition, in liquid form,
comprises about 0.5% to about 5% (w/v) of albumin.
[0091] In some embodiments, the weight ratio of albumin, e.g.,
albumin, to the macrolide in the nanoparticle composition is such
that a sufficient amount of macrolide binds to, or is transported
by, the cell. While the weight ratio of albumin to macrolide will
have to be optimized for different albumin and macrolide
combinations, generally the weight ratio of albumin, e.g., albumin,
to macrolide (w/w) is about 0.01:1 to about 100:1, about 0.02:1 to
about 50:1, about 0.05:1 to about 20:1, about 0.1:1 to about 20:1,
about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to
about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or
about 9:1. In some embodiments, the albumin to macrolide weight
ratio is about any of 18:1 or less, 15:1 or less, 14:1 or less,
13:1 or less, 12:1 or less, 11:1 or less, 10:1 or less, 9:1 or
less, 8:1 or less, 7:1 or less, 6:1 or less, 5:1 or less, 4:1 or
less, and 3:1 or less. In some embodiments, the weight ratio of the
albumin (such as human serum albumin) to the macrolide in the
composition is any one of the following: about 1:1 to about 18:1,
about 1:1 to about 15:1, about 1:1 to about 12:1, about 1:1 to
about 10:1, about 1:1 to about 9:1, about 1:1 to about 8:1, about
1:1 to about 7:1, about 1:1 to about 6:1, about 1:1 to about 5:1,
about 1:1 to about 4:1, about 1:1 to about 3:1, about 1:1 to about
2:1, or about 1:1.
[0092] In some embodiments, the albumin allows the composition to
be injected to an individual (such as human) without significant
side effects. In some embodiments, the albumin (such as human serum
albumin) is in an amount that is effective to reduce one or more
side effects of administration of the macrolide to a human. The
term "reducing one or more side effects of administration of the
macrolide" refers to reduction, alleviation, elimination, or
avoidance of one or more undesirable effects caused by the
macrolide, as well as side effects caused by delivery vehicles
(such as solvents that render the macrolides suitable for
injection) used to deliver the macrolide. Such side effects
include, for example, myelosuppression, neurotoxicity,
hypersensitivity, inflammation, venous irritation, phlebitis, pain,
skin irritation, peripheral neuropathy, neutropenic fever,
anaphylactic reaction, venous thrombosis, extravasation, and
combinations thereof. These side effects, however, are merely
exemplary and other side effects, or combination of side effects,
associated with macrolides can be reduced.
[0093] In some embodiments, the nanoparticle composition comprises
Nab-rapamycin (Celgene Corp.). In some embodiments, the
nanoparticle composition is Nab-rapamycin. Nab-rapamycin is a
formulation of rapamycin stabilized by human albumin USP, which can
be dispersed in directly injectable physiological solution. When
dispersed in a suitable aqueous medium such as 0.9% sodium chloride
injection or 5% dextrose injection, Nab-rapamycin forms a stable
colloidal suspension of rapamycin. The mean particle size of the
nanoparticles in the colloidal suspension is about 90 nanometers.
Since HSA is freely soluble in water, Nab-rapamycin can be
reconstituted in a wide range of concentrations ranging from dilute
(0.1 mg/ml rapamycin) to concentrated (20 mg/ml rapamycin),
including for example about 2 mg/ml to about 8 mg/ml, or about 5
mg/ml.
[0094] Methods of making nanoparticle compositions are known in the
art. For example, nanoparticles containing macrolides (such as
rapamycin) and albumin (such as human serum albumin) can be
prepared under conditions of high shear forces (e.g., sonication,
high pressure homogenization, or the like). These methods are
disclosed in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405;
6,749,868, 6,537,579 and 7,820,788 and also in U.S. Pat. Pub. Nos.
2007/0082838, 2006/0263434 and PCT Application WO08/137148.
[0095] Briefly, the macrolide (such as rapamycin) is dissolved in
an organic solvent, and the solution can be added to an albumin
solution. The mixture is subjected to high pressure homogenization.
The organic solvent can then be removed by evaporation. The
dispersion obtained can be further lyophilized. Suitable organic
solvent include, for example, ketones, esters, ethers, chlorinated
solvents, and other solvents known in the art. For example, the
organic solvent can be methylene chloride or chloroform/ethanol
(for example with a ratio of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3,
1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1).
Other Components in the Nanoparticle Compositions
[0096] The nanoparticles described herein can be present in a
composition that include other agents, excipients, or stabilizers.
For example, to increase stability by increasing the negative zeta
potential of nanoparticles, one or more of negatively charged
components may be added. Such negatively charged components
include, but are not limited to bile salts of bile acids consisting
of glycocholic acid, cholic acid, chenodeoxycholic acid,
taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic
acid, litocholic acid, ursodeoxycholic acid, dehydrocholic acid and
others; phospholipids including lecithin (egg yolk) based
phospholipids which include the following phosphatidylcholines:
palmitoyloleoylphosphatidylcholine,
palmitoyllinoleoylphosphatidylcholine ,
stearoyllinoleoylphosphatidylcholine
stearoyloleoylphosphatidylcholine,
stearoylarachidoylphosphatidylcholine, and
dipalmitoylphosphatidylcholine. Other phospholipids including
L-.alpha.-dimyri stoylphosphatidylcholine (DMPC),
dioleoylphosphatidylcholine (DOPC), di stearyolphosphatidylcholine
(DSPC), hydrogenated soy phosphatidylcholine (HSPC), and other
related compounds. Negatively charged surfactants or emulsifiers
are also suitable as additives, e.g., sodium cholesteryl sulfate
and the like.
[0097] In some embodiments, the composition is suitable for
administration to a human. In some embodiments, the composition is
suitable for administration to a mammal such as, in the veterinary
context, domestic pets and agricultural animals. There are a wide
variety of suitable formulations of the nanoparticle composition
(see, e.g., U.S. Pat. Nos. 5,916,596, 6,096,331, and 7,820,788).
The following formulations and methods are merely exemplary and are
in no way limiting. Formulations suitable for oral administration
can consist of (a) liquid solutions, such as an effective amount of
the compound dissolved in diluents, such as water, saline, or
orange juice, (b) capsules, sachets or tablets, each containing a
predetermined amount of the active ingredient, as solids or
granules, (c) suspensions in an appropriate liquid, and (d)
suitable emulsions. Tablet forms can include one or more of
lactose, mannitol, corn starch, potato starch, microcrystalline
cellulose, acacia, gelatin, colloidal silicon dioxide,
croscarmellose sodium, talc, magnesium stearate, stearic acid, and
other excipients, colorants, diluents, buffering agents, moistening
agents, preservatives, flavoring agents, and pharmacologically
compatible excipients. Lozenge forms can comprise the active
ingredient in a flavor, usually sucrose and acacia or tragacanth,
as well as pastilles comprising the active ingredient in an inert
base, such as gelatin and glycerin, or sucrose and acacia,
emulsions, gels, and the like containing, in addition to the active
ingredient, such excipients as are known in the art.
[0098] Examples of suitable carriers, excipients, and diluents
include, but are not limited to, lactose, dextrose, sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose, water, saline solution,
syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc,
magnesium stearate, and mineral oil. The formulations can
additionally include lubricating agents, wetting agents,
emulsifying and suspending agents, preserving agents, sweetening
agents or flavoring agents.
[0099] Formulations suitable for parenteral administration such as
injection include aqueous and non-aqueous, isotonic sterile
injection solutions, which can contain anti-oxidants, buffers,
bacteriostats, and solutes that render the formulation compatible
with the blood of the intended recipient, and aqueous and
non-aqueous sterile suspensions that can include suspending agents,
solubilizers, thickening agents, stabilizers, and preservatives.
The formulations can be presented in unit-dose or multi-dose sealed
containers, such as ampules and vials, and can be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid excipient, for example, water, for injections,
immediately prior to use. Extemporaneous injection solutions and
suspensions can be prepared from sterile powders, granules, and
tablets of the kind previously described. Injectable formulations
are preferred.
[0100] In some embodiments, the composition is formulated to have a
pH range of about 4.5 to about 9.0, including for example pH ranges
of any of about 5.0 to about 8.0, about 6.5 to about 7.5, and about
6.5 to about 7.0. In some embodiments, the pH of the composition is
formulated to no less than about 6, including for example no less
than about any of 6.5, 7, or 8 (such as about 8). The composition
can also be made to be isotonic with blood by the addition of a
suitable tonicity modifier, such as glycerol.
Kits and Devices
[0101] The invention also provides kits and devices for use in any
of the methods described herein.
[0102] For example, in some embodiments, there is provided a
catheter with a needle (such as a deployable needle), wherein the
needle contains a composition comprising nanoparticle comprising a
macrolide (such as rapamycin) and an albumin. In some embodiments,
there is provided a catheter with a needle (such as a deployable
needle), wherein the needle contains a composition comprising
nanoparticle comprising a macrolide (such as rapamycin) coated with
an albumin. In some embodiments, there is provided a catheter with
a needle (such as a deployable needle), wherein the needle contains
a composition comprising nanoparticle comprising a macrolide (such
as rapamycin) and an albumin, wherein the average particle size of
the nanoparticles in the composition is no greater than about 200
nm (such as less than about 200 nm, for example no greater than
about 100 nm). In some embodiments, there is provided a catheter
with a needle (such as a deployable needle), wherein the needle
contains a composition comprising nanoparticle comprising a
macrolide (such as rapamycin) coated with an albumin, wherein the
average particle size of the nanoparticles in the composition is no
greater than about 200 nm (such as less than about 200 nm, for
example no greater than about 100 nm). In some embodiments, there
is provided a catheter with a needle (such as a deployable needle),
wherein the needle contains Nab-rapamycin. In some embodiments, the
needle is sheathed in a balloon. In some embodiments the diameter
of the needle is about 0.1 to about 3 mm, including for example
about 0.2 to about 2 mm, about 0.5 to about 1 mm, about 0.6 to
about 0.9 mm, or about 0.9 mm. The length of the needle is
typically between about 20 and 3000 microns, including for example
between about 20-50, about 50-100, about 100-200, about 200-300,
about 300-400, about 400-500, about 500-600, about 600-700, about
700-800, about 800-900, about 1-2, and about 2-3 microns. In some
embodiments, the catheter contains more than 1 (such as 2, 3, 4, 5,
6, 7, or more) needles.
[0103] Also provided are kits comprising one or more containers
comprising macrolide-containing nanoparticle compositions (or unit
dosage forms and/or articles of manufacture) and in some
embodiments, further comprise instructions for use in accordance
with any of the methods described herein. In some embodiments, the
kit comprises a catheter having a needle which can be advanced from
a blood vessel lumen through a wall of the blood vessel (for
example to position an aperture of the needle beyond an external
elastic lamina of the wall), and a nanoparticle composition
comprising a macrolide and albumin, wherein the nanoparticle
composition is injectable through the needle. In some embodiments,
the kit further comprises a syringe. In some embodiments, the
syringe is filled up with an effective amount of the nanoparticle
composition.
[0104] The kit may further comprise a description of selection of
individual suitable for treatment. Instructions supplied in the
kits of the invention are typically written instructions on a label
or package insert (e.g., a paper sheet included in the kit), but
machine-readable instructions (e.g., instructions carried on a
magnetic or optical storage disk) are also acceptable.
[0105] The kits of the invention are in suitable packaging.
Suitable packaging include, but is not limited to, vials, bottles,
jars, flexible packaging (e.g., seled Mylar or plastic bags), and
the like. Kits may optionally provide additional components such as
buffers and interpretative information. The present application
thus also provides articles of manufacture, which include vials
(such as sealed vials), bottles, jars, flexible packaging, and the
like.
[0106] The instructions relating to the use of the nanoparticle
compositions generally include information as to dosage, dosing
schedule, and specific instructions on delivering the nanoparticle
composition. The containers may be unit doses, bulk packages (e.g.,
multi-dose packages) or sub-unit doses. Kits may also include
multiple unit doses of the macrolide and pharmaceutical
compositions and instructions for use and packaged in quantities
sufficient for storage and use in pharmacies, for example, hospital
pharmacies and compounding pharmacies.
[0107] Those skilled in the art will recognize that several
embodiments are possible within the scope and spirit of this
invention. The invention will now be described in greater detail by
reference to the following non-limiting examples. The following
examples further illustrate the invention but, of course, should
not be construed as in any way limiting its scope.
EXAMPLES
Example 1. Method for Periadventitial Injection with Micro-Infusion
Catheter
[0108] This example demonstrates the injection of Nab-rapamycin
into the periadventitial tissue. Nab-rapamycin (Celgene
Corporation) was reconstituted in saline to 5 mg/ml prior to the
injection.
[0109] To inject Nab-rapamycin into the periadventitial tissue, the
Bullfrog.RTM. Micro-Infusion Catheter (Mercator Medsystems, San
Leandro Calif.) was introduced into the artery while deflated and
with the 0.9 mm needle sheathed within a balloon (FIG. 1A). When
the balloon was inflated, the needle extruded outward,
perpendicular to the axis of the catheter while a backinballoon
provided an opposing force to slide the needle into the artery wall
(FIG. 1B). Nab-rapamycin was then delivered into the
periadventitial tissue through the needle.
Example 2. Periadventitial Delivery of Nab-Rapamycin in a Porcine
Femoral Artery Balloon Injury Model
[0110] This experiment was conducted to determine whether
periadventitial delivery of Nab-rapamycin can decrease luminal
stenosis in a porcine femoral artery balloon angioplasty injury
model.
[0111] Sixteen juvenile male Yorkshire cross pigs (average weight
34.9.+-.2.3 kg) were used in 2 study arms (FIGS. 2A and 2B). After
induction of general anesthesia, percutaneous access was obtained
via the carotid artery. Animals were given intravenous heparin
(5000 units). All pigs were maintained on aspirin 81 mg daily after
the procedure. Femoral arteries were flushed with 1 liter lactated
Ringer's solution after sacrifice. Arteries were then harvested
(pharmacokinetics arm) or subsequently perfusion fixed at 120 mmHg
for 10 minutes with 10% buffered formalin before harvest
(histopathology arm).
[0112] Nab-rapamycin was injected by periadventitial injection. An
initial diagnostic angiogram showed the target femoral artery
diameter was 4 mm (FIG. 3A). The micro-infusion catheter was
positioned in the mid-femoral artery and the balloon was inflated
(FIG. 3B). A periadventitial injection of Nab-rapamycin solution
with 20% iodinated contrast (IsoVue 370) showed circumferential
coverage of the vessel (FIGS. 3C-3E). Completion angiogram revealed
a patent femoral artery (FIG. 3F). There was 100% procedural
success with 32 injection sites. Average injection time was 90
seconds (1 ml/min). There were no dissections, early or late
thromboses, hemorrhages or arteriovenous fistulas.
[0113] Histomorphometry results after periadventitial injection of
Nab-rapamycin in the femoral artery were analyzed. Femoral arteries
treated with periadventitial Nab-rapamycin had significantly larger
lumen cross-sectional areas p=0.01 (ANOVA) (FIG. 4A), as well as
significantly larger total vessel cross-sectional areas (FIG. 4B),
p=0.005 (ANOVA) at 28 days after treatment. There was a trend
toward decreasing percent luminal stenosis with Nab-rapamycin
treatment at 28 days. Femoral arteries treated with periadventitial
Nab-rapamycin (500 .quadrature.g) had a 42% reduction in luminal
stenosis at 28 days (19.5+3% vs 11.4+0.8%, p=0.0t-test) (FIG. 4C).
The average medial fibrosis score at 28 days was significantly less
in the Nab-rapamycin treated arteries compared to control arteries
treated with vehicle alone (FIG. 4D), p<0.0001 (ANOVA).
[0114] Pharmacokinetic results after periadventitial injection of
Nab-rapamycin in the femoral artery were analyzed. Blood (serum)
rapamycin levels rose in the first hour after a single
periadventitial injection of Nab-rapamycin at 500 .mu.g, but fell
by 1 day and were not detectable by 28 days (FIG. 5A). In the
femoral artery and surrounding perivascular tissue, the rapamycin
concentration was over 1500-times the serum concentration at 1
hour. Rapamycin persisted over 8 days and was not detectable by 28
days (FIG. 5B).
[0115] Histopathology results after periadventitial injection of
Nab-rapamycin in the femoral artery were analyzed. FIGS. 6A-6D show
representative sections of femoral arteries 28 days after treatment
with vehicle (FIGS. 6A and 6B) or Nab-rapamycin 500 .mu.g (FIGS. 6C
and 6D). Nab-rapamycin treatment was associated with significantly
reduced medial fibrosis with similar degrees of internal elastic
lamina injury (inset, 100.times.). Vessels were stained with
H&E (FIGS. 6A and 6C) and trichrome (FIGS. 6B and 6D) and
imaged at 25.times..
[0116] Further histomorphometry analyses showed that Nab-rapamycin
treatment was associated with significantly reduced proliferation
index (FIG. 7A). On the other hand, there was no difference in
endothelialization at 28 days in control and Nab-rapamycin treated
femoral arteries (FIG. 7B).
[0117] Further pharmacokinetics analyses showed that the
proliferation index fell significantly between 3 and 28 days in
balloon-injured arteries treated with 500 .mu.g Nab-rapamycin,
p=0.004 (ANOVA) (FIG. 8A). Re-endotheolialization occurred by 8
days (FIG. 8B).
[0118] Additionally, at 3 days, there were significantly fewer
adventitial leukocytes in arteries treated with periadventitial
Nab-rapamycin (FIG. 9A). By 28 days, Nab-rapamycin treated arteries
had significantly fewer adventitial vessels (FIG. 9B).
[0119] The results reported herein demonstrate that periadventitial
delivery of Nab-rapamycin is associated with a transient increase
and rapid fall in serum rapamycin levels. At 1 hour after
treatment, rapamycin levels in the perivascular tissue were over
1500 times those in the blood and rapamycin was retained in the
perivascular tissue for at least 8 days (FIG. 5B). Balloon injured
femoral arteries treated with Nab-rapamycin were significantly
larger than vehicle treated arteries, suggesting less negative
remodeling. Furthermore, periadventitial delivery of Nab-rapamycin
leads to significant decrease in medial fibrosis.
[0120] Nab-rapamycin treated arteries demonstrated significantly
less early (3 day) adventitial leukocyte infiltration. The Ki-67
proliferation index of Nab-rapamycin treated arteries was
significantly lower at 28 days (FIG. 8A).
[0121] There was no difference in endothelialization at 28 days in
control and Nab-rapamycin treated femoral arteries, and
re-endothelialization to balloon-injured Nab-rapamycin treated
vessels appeared to occur in the first week and appeared to
complete by 8 days (FIG. 10). Nab-rapamycin treatment leads to a
significantly lower proliferation and significantly lower medial
fibrosis scores, suggesting a mechanism by which rapamycin may
affect remodeling in balloon-injured femoral arteries.
[0122] A decrease in early adventitial leukocyte infiltration and
subsequent reduction in medial fibrosis and Ki-67 proliferation
index at 28 days suggests a mechanism by which periadventitial
Nab-rapamycin may have an effect.
[0123] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is apparent to those skilled in the art that
certain minor changes and modifications will be practiced.
Therefore, the description and examples should not be construed as
limiting the scope of the invention.
* * * * *