U.S. patent application number 14/664172 was filed with the patent office on 2015-07-09 for coated devices and methods of making coated devices that reduce smooth muscle cell proliferation and platelet activity.
The applicant listed for this patent is THE BOARD OF SUPERVISORS OF LOUISIANA STATE UNIVERSITY AND AGRICULTURAL AND MECHANICAL COLLEGE, NANOCOPOEIA, INC.. Invention is credited to Tammy R. DUGAS, John Devlin FOLEY, Alok KHANDELWAL, James John KLEINEDLER.
Application Number | 20150190253 14/664172 |
Document ID | / |
Family ID | 40626137 |
Filed Date | 2015-07-09 |
United States Patent
Application |
20150190253 |
Kind Code |
A1 |
DUGAS; Tammy R. ; et
al. |
July 9, 2015 |
COATED DEVICES AND METHODS OF MAKING COATED DEVICES THAT REDUCE
SMOOTH MUSCLE CELL PROLIFERATION AND PLATELET ACTIVITY
Abstract
The present invention relates generally to the maintenance of
blow flood using drug eluting stents and/or other coated medical
devices to increased length of time of blood flow. Further, the
present invention relates to drug-releasing coated devices for
reducing smooth muscle cell proliferation and platelet activity to
further limit restenosis utilizing resveratrol and quercetin,
polyphenols that are linked to the cardioprotection of red wine
consumption. The present invention also provides products and
methods for treating or preventing atherosclerosis, stenosis,
restenosis, smooth muscle cell proliferation, platelet cell
activation and other clotting mechanisms, occlusive disease, or
other abnormal lumenal cellular proliferation condition in a
location within the body of a patient.
Inventors: |
DUGAS; Tammy R.; (Bossier
City, LA) ; KHANDELWAL; Alok; (Shreveport, LA)
; KLEINEDLER; James John; (Plymouth, MN) ; FOLEY;
John Devlin; (Lino Lakes, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE BOARD OF SUPERVISORS OF LOUISIANA STATE UNIVERSITY AND
AGRICULTURAL AND MECHANICAL COLLEGE
NANOCOPOEIA, INC. |
Batton Rouge
St. Paul |
LA
MO |
US
US |
|
|
Family ID: |
40626137 |
Appl. No.: |
14/664172 |
Filed: |
March 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12740890 |
Aug 25, 2010 |
8992471 |
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PCT/US08/82440 |
Nov 5, 2008 |
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14664172 |
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61001916 |
Nov 5, 2007 |
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61F 2/915 20130101;
A61F 2250/0067 20130101; A61L 2300/422 20130101; A61F 2002/91508
20130101; A61F 2/82 20130101; A61L 2300/416 20130101; A61L 31/10
20130101; A61P 9/00 20180101; A61F 2210/0076 20130101; A61L 31/16
20130101; A61L 31/146 20130101; A61L 2300/608 20130101; A61F
2002/91558 20130101 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1-68. (canceled)
69. A drug eluting intravascular stent comprising: (a) a generally
cylindrical stent body; (b) an adherent layer coating on the stent
comprising a composite of a first active agent selected from the
group consisting of resveratrol, pharmaceutically acceptable salts
thereof, and pharmaceutically acceptable derivatives thereof, and a
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts thereof, and
pharmaceutically acceptable derivatives thereof, wherein said first
and second active agent are dispersed within the polymer.
70. The stent according to claim 69, wherein the stent body has a
metal surface.
71. The stent according to claim 69, wherein the stent body is
micro- or nanoporous.
72. The stent according to claim 69, wherein the stent body has a
polymeric surface.
73. The stent of claim 69 wherein the composite includes a polymer
and the active ingredients are one of on a polymer layer and in the
polymer layer.
74. The stent according to claim 73, wherein the polymer is a
bioabsorbable polymer.
75. The stent according to claim 73, wherein the polymer is a
biostable polymer.
76. The stent according to claim 69, wherein a weight of the first
active agent and a weight of the second active agent are in a ratio
which is selected from the group consisting of about 1:1, about
1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4, about 4:1,
about 1:5, about 5:1, about 1:10, about 10:1, about 1:20, about
20:1, about 1:25, about 25:1, about 1:50, about 50:1, about 1:100,
about 100:1, about 1:200, about 200:1, about 1:250, about 250:1,
about 1:500, and about 500:1.
77. The stent according to claim 69, wherein a weight of the first
active agent and a weight of the second active agent are in a ratio
which is selected from the group consisting of about 1:5, about
1:2, and about 1:1.
78. The stent of claim 69 wherein the composite includes a polymer
selected from the group consisting of polystyrene-polyisobutylene
block copolymers, polyethylene terephthalate, poly(lactide),
poly(lactide-co-glycolide), poly(caprolactone),
poly(lactide-co-caprolactone),
poly(-hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly lactides and mixtures thereof.
79. The stent according to claim 73 wherein a first weight
comprises a combined weight of the first and second active agents;
a second weight comprises a weight of the polymer; and the first
weight and the second weight are in a ratio selected form the group
consisting of about 1:1, about 1:2, about 2:1, about 1:2.5, about
2.5:1, about 1:4, about 4:1, about 1:5, about 5:1, about 1:10,
about 10:1, about 1:20, about 20:1, about 1:25, about 25:1, about
1:50, about 50:1, about 1:100, about 100:1, about 1:200, about
200:1, about 1:250, about 250:1, about 1:500, and about 500:1.
80. The stent according to claim 69, wherein the composite includes
a plurality of layers.
81. The stent according to claim 73, wherein the composite includes
a plurality of layers and a ratio of pharmaceutically active agents
to polymer is varied in some of the layers.
82. The stent of claim 69 wherein at least one active agent is
selected from agents which treat or prevent atherosclerosis,
stenosis, restenosis, smooth muscle cell proliferation, platelet
cell activation and other clotting mechanisms, occlusive disease,
or other abnormal lumenal cellular proliferation condition within a
body of a patient.
83. The stent of claim 69, wherein the concentration of the first
active agent based on the surface area of the stent ranges from
about 1 to about 5 .mu.g/mm.sup.2, and the concentration of the
second active agent based on the surface area of the stent ranges
from about 1 to 5 .mu.g/mm.sup.2.
84. The stent of claim 69, wherein each of the active agents have
release profiles selected from the group consisting of the same
release profile and different release profiles.
85. The stent of claim 69, wherein the active agents have a release
profile which is selected from the group consisting of a rapid
release profile and a delayed release profile.
86. The stent of claim 69, wherein a rapid profile coating releases
at least one of the active agents substantially within one to a few
hours.
87. The stent of claim 69, wherein a delayed profile coating
releases at least one of the active agents over a period of at
least one month, at least two months, at least six months, or at
least one year.
88. The stent of claim 69, wherein the composite comprises a single
layer.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates generally to the maintenance
of blow flood using drug eluting stents and other medical devices
to increase length of time of blood flow. Further, the present
invention relates to drug-releasing stents and/or other coated
medical devices for reducing smooth muscle cell proliferation and
platelet activity to further limit restenosis utilizing resveratrol
and quercetin, polyphenols that are linked to the cardioprotection
of red wine consumption. The present invention also provides
products and methods for treating or preventing atherosclerosis,
stenosis, restenosis, smooth muscle cell proliferation, platelet
cell activation and other clotting mechanisms, occlusive disease,
or other abnormal lumenal cellular proliferation condition in a
location within the body of a patient.
DESCRIPTION OF RELATED ART
[0002] Atherosclerosis is a disease characterized by
cholesterol-laden plaque formation within the artery wall, leading
to vessel narrowing and blood flow reduction. Occlusion of certain
key arteries can precipitate a major cardiac event. In the United
States, the prevalence rate of atherosclerosis is predicted to be 1
in 58 or 1.70%
(www.wrongdiagnosis.com/a/atherosclerosis/prevalence.htm).
Furthermore, atherosclerosis is the first-listed diagnosis for 35
of every 10,000 hospitalizations in the United States, or 0.35%
(www.cdc.gov/mmwr/preview/mmwrhtml/mm5626a5.htm). Over 70% of
patients with atherosclerosis receive some sort of treatment that
involves catheritization to correct the blockage. The first such
treatment using mechanical opening of the occluded areas relied
solely on balloon angioplasty. In this procedure, an inflatable
device is inserted through an artery to the blockage via a
catheter, at which point the balloon is inflated to create an
opening in the stenotic area. One approach to clearing an artery
that has been constricted or clogged due to stenosis is
percutaneous transluminal coronary angioplasty (PTCA) or balloon
coronary angioplasty. In this procedure, a balloon catheter is
inserted and expanded in the constricted portion of the vessel for
clearing the blockage. About one-third of patients who undergo PTCA
suffer from restenosis, the renarrowing of the widened segment,
within about six months of the procedure. Restenosed arteries may
have to undergo another angioplasty.
[0003] The limitation of balloon angioplasty is that it is often
only a short-term solution, as both the balloon inflation and
stretching of the vessel can denude the vessel wall of endothelium
and impart endothelial injury and dysfunction to the surrounding
areas. Platelets, lymphocytes and monocytes are then recruited to
the injured area. Release of basic fibroblast growth factor (bFGF)
and platelet derived growth factor (PDGF) from platelets and dying
vascular smooth muscle cells and endothelial cells promotes
vascular smooth muscle cells to migrate from the underlying medial
layer to the intima, where they begin proliferating. This vascular
smooth muscle cell (VSMC) proliferative response induces a
re-narrowing of the lumen (or "restenosis"), once again restricting
blood flow.
[0004] Balloon angioplasty has a restenosis rate of approximately
30% over 6 months and a high rate of coronary artery dissection
(www.ncbi.nlm.nih.gov/books/by.fcgi?highlight=balloon
%20angioplasty&rid=cardio.chapter.196#297). The high failure
rate of balloon angioplasty led to the use of bare metal stents to
improve blood flow. Bare metal stents have been used for the long
term maintenance of blow flood and prevention of restenosis. These
stents generally consist of expandable metal struts. They are
delivered in an unexpanded form to the affected area via a catheter
and inner balloon. Once at the site of injury, the balloon is
inflated such that the stent is locked in an expanded state. The
balloon is then deflated, and the catheter and balloon are removed
while the stent remains in place. Bare metal stents have a lowered
rate of restenosis in some cases, but failure has still varied
between 10%-40%
(www.clevelandclinic.org/heartcenter/pub/history/future/intervention.asp?-
firstCat=56&secondCat=57&thirdCat=481).
[0005] Stents are not 100% effective in preventing restenosis at
the implant site. Restenosis can occur over the length of the stent
and/or past the ends of the stent. Physicians have recently
employed new types of stents that are coated with a thin polymer
film loaded with a drug that inhibits smooth cell proliferation.
These drug-eluting stents (DES) were conceived as a way of further
limiting restenosis. In this technology, a coating of some chemical
compound is placed on the stent in such a manner that it is
released slowly over the course of several months.
[0006] The coating is applied to the stent prior to insertion into
the artery using methods well known in the art, such as a solvent
evaporation technique. The solvent evaporation technique entails
mixing the polymer and drug in a solvent. The solution comprising
polymer, drug, and solvent can then be applied to the surface of
the stent by either dipping or spraying. The stent is then
subjected to a drying process, during which the solvent is
evaporated, and the polymeric material, with the drug dispersed
therein, forms a thin film layer on the stent.
[0007] The release mechanism of the drug from the polymeric
materials depends on the nature of the polymeric material and the
drug to be incorporated. The drug diffuses through the polymer to
the polymer-fluid interface and then into the fluid. Release can
also occur through degradation of the polymeric material. The
degradation of the polymeric material can occur through a number of
mechanisms such as hydrolysis or enzymatic cleavage. The
degradation can occur via surface erosion or simultaneously
throughout the bulk of the polymer film. Degradation adds another
dimension to the timing and control drug release profiles in
addition to diffusion. In addition, polymer degradation insures
that large polymer chains that might elicit foreign body reactions
are not left behind.
[0008] An important consideration in using coated stents is the
release rate of the drug from the coating. It is desirable that an
effective therapeutic amount of the drug be released from the stent
for the longest period of time possible. Burst release, a high
release rate immediately following implantation, is undesirable and
a persistent problem. While typically not harmful to the patient, a
burst release "wastes" the limited supply of the drug by releasing
several times the effective amount required and shortens the
duration of the release period. Several techniques have been
developed in an attempt to reduce burst release. For example, U.S.
Pat. No. 6,258,121 to Yang et al. discloses a method of altering
the release rate by blending two polymers with differing release
rates and incorporating them into a single layer.
[0009] Though this generation of DES holds promise, the currently
approved drugs have unfavorable side effects such as the inhibition
the formation of a functional vascular endothelium. This can cause
potentially life threatening late terms events. Thus, there remains
a need for an improved system and method that increases blood flow
through stenotic areas and reduces restenosis without side effects
from the drugs coating the device. In view of the foregoing, the
development of a device having a coating of polymeric material with
improved biologically active agent or agents dispersed therein
would be a significant advance in the art. The current invention
treats and/or prevents atherosclerosis, stenosis, restenosis,
smooth muscle cell proliferation, platelet cell activation and
other clotting mechanisms, occlusive disease, or other abnormal
lumenal cellular proliferation condition in a location within the
body of a patient, and can be effective in delivering a wide range
of other therapeutic agents to the implant site over a relatively
extended period of time.
[0010] All references cited herein are incorporated herein by
reference in their entireties.
BRIEF SUMMARY OF THE INVENTION
[0011] The invention provides a drug eluting intravascular stent
comprising: (a) a generally cylindrical stent body; (b) an adherent
layer on the stent comprising a composite of polymer and a first
active agent selected from the group consisting of resveratrol,
pharmaceutically acceptable salts, and pharmaceutically acceptable
derivatives thereof, and an optional second active agent selected
from the group consisting of quercetin, pharmaceutically acceptable
salts, and pharmaceutically acceptable derivatives thereof,
dispersed within the polymer. The invention further provides a
stent wherein the stent body has a metal surface. The invention
further provides a stent wherein the stent body is micro- or
nanoporous. The invention further provides a stent wherein the
stent body has a polymeric surface. The invention further provides
a stent wherein the polymer is a bioabsorbable polymer. The
invention further provides a stent wherein the polymer is a
biostable polymer. The invention further provides a stent wherein
the first and second active agents are in a ratio which is selected
from the group consisting of about 1:1, about 1:2, about 2:1, about
1:2.5, about 2.5:1, about 1:4, about 4:1, about 1:5, about 5:1,
about 1:10, about 10:1, about 1:20, about 20:1, about 1:25, about
25:1, about 1:50, about 50:1, about 1:100, about 100:1, about
1:200, about 200:1, about 1:250, about 250:1, about 1:500, and
about 500:1 by weight percent. The invention further provides a
stent wherein the first and second active agents are in a ratio
which is selected from the group consisting of about 1:5, about
1:2, and about 1:1 by weight percent.
[0012] The invention provides a drug eluting intravascular stent
comprising: (a) a generally cylindrical stent body; (b) an adherent
layer on the stent comprising a composite of polymer and at least
one active agent dispersed within the polymer, wherein the at least
one active agent is selected from the group consisting of
resveratrol, pharmaceutically acceptable salts of resveratrol,
pharmaceutically acceptable derivatives of resveratrol, quercetin,
pharmaceutically acceptable salts of quercetin, pharmaceutically
acceptable derivatives of quercetin, combinations thereof, and
mixtures thereof. The invention further provides a stent wherein
the coating is a polymer selected from the group consisting of
polystyrene-polyisobutylene block copolymers, polyethylene
terephthalate, poly(lactide), poly(lactide-co-glycolide),
poly(caprolactone), poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof. The invention further
provides a stent wherein the first and second active agents and
polymer are in a ratio selected from the group consisting of about
1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4,
about 4:1, about 1:5, about 5:1, about 1:10, about 10:1, about
1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,
about 1:100, about 100:1, about 1:200, about 200:1, about 1:250,
about 250:1, about 1:500, and about 500:1 by weight percent. The
invention further provides a stent wherein the composite includes a
plurality of layers. The invention further provides a stent wherein
the ratio of pharmaceutically active agents to polymer is varied in
some of the layers. The invention further provides a stent wherein
the biologically active agent is selected from agents which treat
or prevent atherosclerosis, stenosis, restenosis, smooth muscle
cell proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition within a body of a patient. The invention
further provides a stent wherein the concentration of the first
active agent based on the surface area of the stent ranges from
about 1 to about 5 .mu.g/mm.sup.2, and the concentration of the
optional second active agent based on the surface area of the stent
ranges from about 1 to about 5 .mu.g/mm.sup.2. The invention
further provides a stent, wherein each of the active agents may
have different release profiles. The invention further provides a
stent wherein the release profile of the active agents may be
selected between rapid and delayed. The invention further provides
a stent wherein a rapid profile coating releases an active agent
substantially within one to a few hours. The invention further
provides a stent wherein a delayed profile coating releases an
active agent and/or agents over a period of at least one month, at
least two months, at least six months, or at least one year.
[0013] The invention provides the use of a drug eluting
intravascular stent comprising: (a) a generally cylindrical stent
body; and (b) an adherent layer on the stent comprising a composite
of polymer and a first active agent selected from the group
consisting of resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer in the
manufacture of a medicament for the treatment or prevention of
atherosclerosis, stenosis, restenosis, smooth muscle cell
proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition in a location within the body of a
patient.
[0014] The invention further provides a drug eluting intravascular
stent comprising: (a) a generally cylindrical stent body; and (b)
an adherent layer on the stent comprising a composite of polymer
and a first active agent selected from the group consisting of
resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer for
use in the treatment or prevention of atherosclerosis, stenosis,
restenosis, smooth muscle cell proliferation, platelet cell
activation and other clotting mechanisms, occlusive disease, or
other abnormal lumenal cellular proliferation condition in a
location within the body of a patient.
[0015] The invention provides a method for treating or preventing
atherosclerosis, stenosis, restenosis, smooth muscle cell
proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition in a location within the body of a patient,
comprising: implanting a drug eluting intravascular stent
comprising: (a) a generally cylindrical stent body; and (b) an
adherent layer on the stent comprising a composite of polymer and a
first active agent selected from the group consisting of
resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer;
further wherein the pharmaceutically active agent is locally
delivered at the location in a manner that is adapted to
substantially treat or prevent the atherosclerosis, stenosis,
restenosis, smooth muscle cell proliferation, platelet cell
activation and other clotting mechanisms, occlusive disease, or
other abnormal lumenal cellular proliferation condition in the
patient. The invention further provides a method wherein the
polymer is selected from polystyrene-polyisobutylene block
copolymers, polyethylene terephthalate, poly(lactide),
poly(lactide-co-glycolide), poly(caprolactone),
poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof. The invention further
provides a method wherein the ratio of first to second active
agents is in a range selected from the group consisting of about
1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1, about 1:4,
about 4:1, about 1:5, about 5:1, about 1:10, about 10:1, about
1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,
about 1:100, about 100:1, about 1:200, about 200:1, about 1:250,
about 250:1, about 1:500, and about 500:1 by weight percent. The
invention further provides a method wherein, wherein the ratio of
first to second active agents is in the range selected from the
group consisting of about 1:5, about 1:2, and about 1:1 resveratrol
to quercetin by weight percent. The invention further provides a
method wherein, wherein the ratio of the first and second active
agents to polymer is in a range selected from the group consisting
of about 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1, about
1:4, about 4:1, about 1:5, about 5:1, about 1:10, about 10:1, about
1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,
about 1:100, about 100:1, about 1:200, about 200:1, about 1:250,
about 250:1, about 1:500, and about 500:1 by weight percent. The
invention further provides a method wherein the composite includes
a plurality of layers. The invention further provides a method
wherein the ratio of pharmaceutically active substances to polymer
is varied in some of the layers. The invention further provides a
method wherein each of the active agents may have different release
profiles. The invention further provides a method wherein the
release profile of the active agents may be selected between rapid
and delayed. The invention further provides a method wherein a
rapid profile coating releases an active agent substantially within
one to a few hours. The invention further provides a method wherein
a delayed profile coating releases an active agent and/or agents
over a period of at least one month, at least two months, at least
six months, or at least one year.
[0016] The invention provides an implantable medical device,
comprising: an expandable balloon catheter having an outer surface;
and an adherent layer on the balloon catheter comprising a
composite of polymer and a first active agent selected from the
group consisting of resveratrol, pharmaceutically acceptable salts,
and pharmaceutically acceptable derivatives thereof, and an
optional second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer. The
invention further provides an implantable medical device wherein
the polymer is biodegradable. The invention further provides an
implantable medical device wherein the polymer is a bioabsorbable
polymer. The invention further provides an implantable medical
device wherein the polymer is selected from the group consisting of
polystyrene-polyisobutylene block copolymers, polyethylene
terephthalate, poly(lactide), poly(lactide-co-glycolide),
poly(caprolactone), poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof. The invention further
provides an implantable medical device wherein the concentration of
the first active agent based on the surface area of the balloon
catheter ranges from about 1 to about 5 m/mm.sup.2, and the
concentration of the optional second active agent based on the
surface area of the balloon ranges from about 1 to about 5
.mu.g/mm.sup.2. The invention further provides an implantable
medical device wherein the ratio which is in the range selected
from the group consisting of about 1:5, about 1:2, and about 1:1
resveratrol to quercetin by weight percent. The invention further
provides an implantable medical device wherein the first and second
active agents are in a ratio which is selected from the group
consisting of about 1:1, about 1:2, about 2:1, about 1:2.5, about
2.5:1, about 1:4, about 4:1, about 1:5, about 5:1, about 1:10,
about 10:1, about 1:20, about 20:1, about 1:25, about 25:1, about
1:50, about 50:1, about 1:100, about 100:1, about 1:200, about
200:1, about 1:250, about 250:1, about 1:500, and about 500:1 by
weight percent. The invention further provides an implantable
medical device wherein the ratio of the first and second active
agents to polymer is in a range selected from the group consisting
of about 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1, about
1:4, about 4:1, about 1:5, about 5:1, about 1:10, about 10:1, about
1:20, about 20:1, about 1:25, about 25:1, about 1:50, about 50:1,
about 1:100, about 100:1, about 1:200, about 200:1, about 1:250,
about 250:1, about 1:500, and about 500:1 by weight percent. The
invention further provides an implantable medical device wherein
the composite includes a plurality of layers. The invention further
provides an implantable medical device wherein the ratio of
pharmaceutically active substance to polymer is varied in some of
the layers. The invention further provides an implantable medical
device wherein each of the active agents may have different release
profiles. The invention further provides an implantable medical
device wherein the release profile of the active agents may be
selected between rapid and delayed. The invention further provides
an implantable medical device wherein a rapid profile coating
releases an active agent substantially within one to a few hours.
The invention further provides an implantable medical device
wherein a delayed profile coating releases an active agent and/or
agents over a period of at least one month, at least two months, at
least six months, or at least one year.
[0017] The invention provides the use of a catheter having an
expandable balloon catheter coated with a selected polymer and a
first active agent selected from the group consisting of
resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer in the
manufacture of a medicament for the treatment or prevention
atherosclerosis, stenosis, restenosis, smooth muscle cell
proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition in a location within the body of a
patient.
[0018] The invention provides a catheter having an expandable
balloon catheter coated with a selected polymer and a first active
agent selected from the group consisting of resveratrol,
pharmaceutically acceptable salts, and pharmaceutically acceptable
derivatives thereof, and an optional second active agent selected
from the group consisting of quercetin, pharmaceutically acceptable
salts, and pharmaceutically acceptable derivatives thereof,
dispersed within the polymer for use in treatment or prevention
atherosclerosis, stenosis, restenosis, smooth muscle cell
proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition in a location within the body of a
patient.
[0019] The invention provides a method of for treating or
preventing atherosclerosis, stenosis, restenosis, smooth muscle
cell proliferation, platelet cell activation and other clotting
mechanisms, occlusive disease, or other abnormal lumenal cellular
proliferation condition in a location within the body of a patient
in a luminal passage in a subject comprising: selecting a catheter
having an expandable balloon catheter; coating the balloon catheter
with a selected polymer and a first active agent selected from the
group consisting of resveratrol, pharmaceutically acceptable salts,
and pharmaceutically acceptable derivatives thereof, and an
optional second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer;
routing the catheter through a predetermined length of the luminal
passage; and expanding the balloon at one or more selected
positions along the predetermined length. The invention further
provides a method wherein the polymer is selected from the group
consisting of polystyrene-polyisobutylene block copolymers,
polyethylene terephthalate, poly(lactide),
poly(lactide-co-glycolide), poly(caprolactone),
poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof. The invention further
provides a method wherein the concentration of the first active
agent based on the surface area of the balloon catheter ranges from
about 1 to about 5 .mu.g/mm.sup.2, and the concentration of the
optional second active agent based on the surface area of the
balloon ranges from about 1 to about 5 .mu.g/mm.sup.2. The
invention further provides a method wherein the ratio of first and
second active agents is in a range selected from the group
consisting of about 1:1, about 1:2, about 2:1, about 1:2.5, about
2.5:1, about 1:4, about 4:1, about 1:5, about 5:1, about 1:10,
about 10:1, about 1:20, about 20:1, about 1:25, about 25:1, about
1:50, about 50:1, about 1:100, about 100:1, about 1:200, about
200:1, about 1:250, about 250:1, about 1:500, and about 500:1 by
weight percent. The invention further provides a method wherein the
ratio of the first and second active agents to polymer is in a
range of about 1:1, about 1:2, about 2:1, about 1:2.5, about 2.5:1,
about 1:4, about 4:1, about 1:5, about 5:1, about 1:10, about 10:1,
about 1:20, about 20:1, about 1:25, about 25:1, about 1:50, about
50:1, about 1:100, about 100:1, about 1:200, about 200:1, about
1:250, about 250:1, about 1:500, and about 500:1 by weight percent.
The invention further provides a method wherein the ratio first and
second active agents is in the range selected from the group
consisting of about 1:5, about 1:2, and about 1:1 resveratrol to
quercetin by weight percent. The invention further provides a
method wherein the composite includes a plurality of layers. The
invention further provides a method wherein the ratio of
pharmaceutically active substances to polymer is varied in some of
the layers. The invention further provides a method wherein each of
the active agents may have different release profiles. The
invention further provides a method wherein the release profile of
the active agents may be selected between rapid and delayed. The
invention further provides a method wherein a rapid profile coating
releases an active agent substantially within one to a few hours.
The invention further provides a method wherein a delayed profile
coating releases an active agent and/or agents over a period of at
least one month, at least two months, at least six months, or at
least one year.
[0020] The invention provides a method of electrospraying
nanoparticles on to a surface of an implantable medical device
selected from the group consisting of a catheter having an
expandable balloon and an intravascular stent, the method
comprising: providing a combination in solvent of a polymer and a
first active agent selected from the group consisting of
resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof, dispersed within the polymer
combination in solvent to an inner capillary of a coaxial capillary
spray nozzle; providing a solvent to an outer capillary of the
coaxial capillary spray nozzle; providing a difference in
electrical potential between an exit tip of a coaxial capillary
spray nozzle and the surface to cause electrospray from the nozzles
such that nanoparticles are formed and adhered to the surface to
provide a desired drug release profile. The invention further
provides a method wherein the polymer is selected from the group
consisting of polystyrene-polyisobutylene block copolymers,
polyethylene terephthalate, poly(lactide),
poly(lactide-co-glycolide), poly(caprolactone),
poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof.
[0021] The invention further provides a method wherein each of the
two active agents may have different release profiles. The
invention further provides a method wherein the release profile of
the active agent may be selected between rapid and delayed. The
invention further provides a method wherein a rapid profile coating
releases an active agent substantially within one to a few hours.
The invention further provides a method wherein a delayed profile
coating releases an active agent and/or agents over a period of at
least one month, at least two months, at least six months, or at
least one year.
[0022] invention provides a method of coating an implantable
medical device selected from the group consisting of a catheter
having an expandable balloon and an intravascular stent, the method
comprising: providing a coating solution comprising a polymer and a
first active agent selected from the group consisting of
resveratrol, pharmaceutically acceptable salts, and
pharmaceutically acceptable derivatives thereof, and an optional
second active agent selected from the group consisting of
quercetin, pharmaceutically acceptable salts, and pharmaceutically
acceptable derivatives thereof; providing an implantable medical
device; submerging the entire implantable medical device, or an
entire section of the implantable medical device, in the coating
solution; withdrawing the implantable medical device from the
coating solution; and drying the implantable medical device. The
invention further provides a method wherein the polymer is selected
from the group consisting of polystyrene-polyisobutylene block
copolymers, polyethylene terephthalate, poly(lactide),
poly(lactide-co-glycolide), poly(caprolactone),
poly(lactide-co-caprolactone),
poly-(hydroxybutyrate/hydroxyvalerate) copolymer,
poly(vinylpyrrolidone), polytetrafluoroethylene,
poly(2-hydroxyethylmethacrylate), poly(n-butyl methacrylate),
poly(ethylene-co-vinyl acetate), poly(vinylidene
fluoride-co-hexafluoropropene), poly(etherurethane urea),
silicones, acrylics, epoxides, polyesters, polyurethanes,
desaminotyrosine polyarylate, Parylenes [polyxylylenes],
polyphosphazene polymers, fluoropolymers, polyamides, isoolefin
homopolymers and copolymers, vinyl homopolymers and copolymers,
acrylate homopolymers and copolymers, methacrylate homopolymers and
copolymers, polyethers, polyesters, polycarbonates and copolymers,
polyethylene oxides, poly(ethylene glycol) and derivatives,
carbo-films, self-assembling polymer films and liposomes
cellulosics, chondroitin-sulfate, gelatin, amino acid-based
polymers, fibrin, chitin, extracellular matrix proteins,
heparinized coatings, phospholipid liposomes and self-assembled
arrays, poly-lactides and mixtures thereof. The invention further
provides a method wherein each of the active agents may have
different release profiles. The invention further provides a method
wherein the release profile of the active agents may be selected
between rapid and delayed. The invention further provides a method
wherein a rapid profile coating releases an active agent
substantially within one to a few hours. The invention further
provides a method wherein a delayed profile coating releases an
active agent and/or agents over a period of at least one month, at
least two months, at least six months, or at least one year.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
[0023] FIG. 1 is a diagram of a stent design according to an
embodiment of the present invention.
[0024] FIG. 2 is a bar chart showing the effects of resveratrol on
proliferation of rat aortic vascular smooth muscle cells according
to the present invention.
[0025] FIG. 3 is a bar chart showing the effect of resveratrol on
NF.kappa.B activation in vascular smooth muscle cells
[0026] FIG. 4 is a set of three digital photographs showing carotid
arteries from wildtype controls, wildtype mice subjected to
endothelial denudation, and wildtype mice administered resveratrol
for 4 weeks and subjected to endothelial denudation according to
the present invention.
[0027] FIG. 5 is a bar chart showing the effects of oral
resveratrol administration on NF.kappa.B activation in mouse aorta
after carotid artery endothelial denudation according to the
present invention.
[0028] FIG. 6 is a set of bar charts showing the effects of oral
resveratrol administration on vascular nitric oxide production, as
assessed by measurement of its stable metabolite, nitrite, in
aortas of either wildtype mice or ER-deficient mice according to
the present invention.
[0029] FIG. 7 is a bar chart showing the effect of resveratrol on
neointimal area in mice.
[0030] FIG. 8 is a schematic showing the mechanism for
resveratrol-mediated inhibition of VSMC proliferation according to
the present invention.
[0031] FIG. 9 is a bar chart showing the effects of oral
administration with 50 mg/kg resveratrol (RESV), 10 mg/kg quercetin
(QUER), or resveratrol plus quercetin on neointimal areas in mice
subjected to the carotid artery injury procedure. Values represent
means+SEM. ANOVA revealed a significant effect of treatment.
*Denotes significance compared to controls. Neointimal area was
determined by subtracting the luminal area from the area encircled
by the internal elastic lamina.
[0032] FIG. 10 is a bar chart showing the release of tritiated
serotonin from platelets incubated for 3 h with resveratrol or
quercetin and then activated with 5 .mu.M ADP. Values represent
means+/-standard error. ANOVA revealed a significant effect of
treatment. *Denotes significance compared to vehicle.
[0033] FIG. 11 is a bar chart showing the effects of 4 weeks oral
administration of 50 mg/kg resveratrol, 10 mg/kg quercetin or
resveratrol+quercetin on serum thromboxane B2 levels in B6.129 mice
subjected to the carotid artery injury procedure. One-way ANOVA
revealed a significant effect of treatment. *Denotes a significant
change compared to control mice.
[0034] FIG. 12 shows the effects of resveratrol and quercetin on
LPS-induced activation of macrophages, as indicated by increases in
iNOS protein (FIG. 12A) and reactive oxygen species (FIG. 12B).
ANOVA revealed a significant effect of treatment. *Indicates
differences compared to LPS alone.
[0035] FIG. 13 is an isobologram for predicting the synergistic
effects of a resveratrol/quercetin combination on macrophage
activation. Macrophages were incubated with differing dose ratios
of resveratrol:quercetin and were stimulated with LPS. Activation
was assessed as increases in nitric oxide release. The IC.sub.50's
for each dose ratio were calculated using CaluSyn software and were
used to plot the isobologram. The line depicted above indicates the
point at which additive responses are observed (C.sub.i=1). Points
lying above the line indicate antagonism, whereas points below the
line represent synergism.
[0036] FIG. 14 is a scanning electron microscopy images at
1,000.times. (left; FIGS. 14A, 14C, 14E) and 20,000.times.
magnification (right; FIGS. 14B, 14D, 14F). Images FIG. 14A and
FIG. 14B are quercetin containing arbIBS nanoparticles coated using
a closed morphology, while images FIG. 14C and FIG. 14D are coated
using an open morphology. FIG. 14E and FIG. 14F are resveratrol
containing arbIBS nanoparticles coated using a closed morphology.
All polymer applications were by ElectroNanospray.TM. process.
[0037] FIG. 15 is a bar chart showing the Lactate Dehydrogenase
(LDH) cytotoxicity assay from the 48-hour endpoint experiment
expressed as amount released in medium over total LDH.
[0038] FIG. 16 is a set of bar charts showing the effects of
arblBS-coated flats on platelet activation. Bare metal flats coated
using a closed or an open morphology of arbIBS polymer were
incubated in Tyrode's buffer for 48 h at 37.degree. C. Platelets
were isolated and incubated for 1 h with the resulting conditioned
Tyrode's buffer. Basal levels of activation (FIG. 16A), compared to
ADP-stimulated platelet activation (FIG. 16B), were assessed by
enzyme-linked immunosorbent assay for release of platelet-derived
growth factor (PDGF) into the medium. Data are expressed as
means+/-standard error. No significant effects of the
polymer-coated flats were detected for levels of either basal or
ADP-stimulated activation.
[0039] FIG. 17 is a set of bar charts showing the efficacy of
drug-eluting fiats on inhibition of VSMC proliferation. Bare metal
flats coated with resveratrol- (FIG. 17A) or quercetin- (FIG. 17B)
containing arbIBS of either a closed or an open morphology were
incubated in semi-permeable transwell inserts in plates containing
VSMC. The bromodeoxyuridine (BrdU) incorporation assay for cell
proliferation was conducted after 48 h of drug elution. The data
are expressed as percent of control (wells not containing flats).
*Denotes significance compared to controls.
[0040] FIG. 18 shows the release of resveratrol from smooth
(closed) versus particulate (open) matrix arbIBS polymer-coated
bare metal flats. Polymer coated flats were incubated in medium at
37.degree. C. for 28 d. Resveratrol concentration in the medium was
assessed at 2 d intervals using high performance liquid
chromatography. The data are expressed as means+/-standard error
for cumulative release in micromolar concentrations (FIG. 18A)
compared to a percent of total drug loaded (FIG. 18B).
DETAILED DESCRIPTION OF THE INVENTION
Coated Stent Reducing SMC Proliferation and Platelet Activity
[0041] The following description should be viewed in the eyes of
someone who is familiar with the state-of-the-art in this field;
specific technology should not be considered limiting but should be
taken as use of state-of-the-art at a moment in time. The present
invention is capable of embodiments in many different forms.
Preferred embodiments of the invention are disclosed with the
understanding that the present disclosure is to be considered as
exemplifications of the principles of the invention and are not
intended to limit the broad aspects of the invention to the
embodiments illustrated. In the following description, like
reference characters designate like or corresponding parts
throughout the several views. Also in the following description, it
is to be understood that such terms as "forward," "rearward,"
"front," "back," "right," "left," "upwardly," "downwardly," and the
like are words of convenience and are not to be construed as
limiting terms.
[0042] The present invention relates generally to the maintenance
of blow flood through stenotic areas using drug eluting stents
and/or other medical devices; and, to increased length of time of
blood flow without restenosis in these areas.
[0043] Also, the present invention relates to drug-releasing stents
for maintenance of blow flood through stenotic areas and to
increased length of time of blood flow without restenosis.
Preferably the stents and/or other medical devices of the present
invention is/are coated with agents that can include but are not
limited to phytochemicals such as polyphenols. One exemplary
embodiment is a DES coated with a single agent, especially where
that agent is resveratrol, which results in maintenance of blood
flow and decreased restenosis. Additional embodiments would have
multiple agents, preferably resveratrol and quercetin, coating the
stent to maintain blood flow and decrease restenosis.
[0044] According to one embodiment of the present invention, the
resveratrol/quercetin combination will have equal or better
efficacy with fewer side effects compared to rapamycin- or
paclitaxel-coated stents. The resveratrol/quercetin combination
will likely block more pathways involved in restenosis. For
example, the combination should inhibit VSMC proliferation,
platelet activation, and inflammatory responses, and may even
promote endothelial function. None of the currently-used DES
promotes endothelial function or re-endothelialization.
Resveratrol
[0045] The invention, as noted above, involves the administration
of resveratrol to an individual in order to prevent restenosis
and/or the progression or recurrence of coronary heart disease.
[0046] Resveratrol may be administered in natural form, i.e., as
isolated from grape skins, wine or other plant-derived
compositions, or it may be administered as chemically synthesized
in the laboratory (e.g., using the methods of Moreno-Manas et al.,
Jeandet et al., or Goldberg et al. (1994), cited earlier herein),
or as obtained commercially, e.g., from the Sigma Chemical Company
(St. Louis, Mo.).
[0047] The resveratrol active agent may be administered in the form
of a pharmacologically acceptable salt, ester, amide, prodrug or
analog, or as a combination thereof. However, conversion of an
inactive ester, amide, prodrug or analog to an active form must
occur prior to or upon reaching the target tissue or cell. Salts,
esters, amides, prodrugs and analogs of the active agents may be
prepared using standard procedures known to those skilled in the
art of synthetic organic chemistry and described, for example, by
J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and
Structure," 4th Ed. (New York: Wiley-Interscience, 1992). For
example, basic addition salts are prepared from the neutral drug
using conventional means, involving reaction of one or more of the
active agent's free hydroxyl groups with a suitable base.
Generally, the neutral form of the drug is dissolved in a polar
organic solvent such as methanol or ethanol and the base is added
thereto. The resulting salt either precipitates or may be brought
out of solution by addition of a less polar solvent. Suitable bases
for forming basic addition salts include, but are not limited to,
inorganic bases such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
Preparation of esters involves functionalization of hydroxyl groups
which may be present within the molecular structure of the drug.
The esters are typically acyl-substituted derivatives of free
alcohol groups, i.e., moieties which are derived from carboxylic
acids of the formula RCOOH where R is alkyl, and preferably is
lower alkyl. Esters can be reconverted to the free acids, if
desired, by using conventional hydrogenolysis or hydrolysis
procedures. Preparation of amides and prodrugs can be carried out
in an analogous manner. Other derivatives and analogs of the active
agents may be prepared using standard techniques known to those
skilled in the art of synthetic organic chemistry, or may be
deduced by reference to the pertinent literature (see U.S. Pat. No.
6,022,901).
##STR00001##
[0048] Non-limiting examples of derivatives of cis- and
trans-resveratrol are those in which the hydrogen of one or more of
the compounds' hydroxyl group is replaced to form esters or ethers
(for example, see Formula I). Ether formation examples include, but
are not limited to, the addition of alkyl chains such as methyl and
ethyl groups, as well as conjugated mono- or disaccharides such as
glucose, galactose, maltose, lactose and sucrose. Additional
modifications at the hydroxyl groups might include glucuronidation
or sulfation.
[0049] Esterification products include, but are not limited to,
compounds formed through the addition of amino acid segments such
as RGD or KGD or other compounds resulting from the reaction of the
resveratrol hydroxyl groups with other carboxylic acids.
[0050] Additional derivatives include, but are not limited to,
those compounds that result from the oxidative dimerization of or
functional group addition to the parent resveratrol compound or to
a functionalized resveratrol variant. Examples of these compounds
include materials resulting from the addition of hydroxyl, methoxy
and ethoxy groups at the 4, 2', and 3' positions. Dimerization
results from the reaction of the ethane bond of one resveratrol
molecule with one of the hydroxyl groups on a second resveratrol
molecule resulting in the formation of a fused ring system.
Alkylation at the 4, 2', and 3' positions creates other derivatives
through the addition of groups including, but not limited to,
methyl, ethyl, and propyl, as well as the addition of larger carbon
chains such as 4-methyl-2-pentene, 4-methyl-3-pentene and
isopentadiene.
[0051] Additional derivatives include, but are not limited to,
compounds that arise from the loss of any of the hydroxyl groups of
the parent molecule, addition of hydroxyl groups at alternate
positions, and any compound that may arise from the previously
mentioned reactions to provide a functionalized variant of the
dehydroxylated compound.
Examples of Resveratrol Derivatives
##STR00002##
[0052] Additional Uses for Resveratrol
[0053] Resveratrol may be involved in many pathways of restenosis.
Thus, according to the present invention, resveratrol may address
many if not all targets causing a problem from restenosis. For
instance, it provides anti-inflammatory benefits and promotes
endothelial cell function. Reports have shown that resveratrol
stimulates the growth of endothelial progenitor cells, both in vivo
and in vitro (see J. Gu, et al., 2006, Effects of resveratrol on
endothelial progenitor cells and their contributions to
reendothelialization in intima-injured rats. J Cardiovasc
Pharmacol., 47(5): 711-721). This may be a key step in
re-endothelialization.
[0054] Resveratrol also increases endothelial nitric oxide synthase
activity (see Wallerath T et al., "Resveratrol, a polyphenolic
phytoalexin present in red wine, enhances expression and activity
of endothelial nitric oxide synthase." Circulation. 2002 Sep. 24;
106(13):1652-8.) Further, resveratrol enhances
endothelium-dependent vasorelaxation (Rush J W, Quadrilatero J,
Levy A S, Ford R J. Chronic resveratrol enhances
endothelium-dependent relaxation but does not alter eNOS levels in
aorta of spontaneously hypertensive rats. Exp Biol Med (Maywood).
2007 June; 232(6):814-22). Therefore, utilizing resveratrol in a
DES and/or other medical device according to the present invention
provides a multi-faceted approach to reducing restenosis and
improving blood flow after stent implantation.
Quercetin
[0055] Another exemplary compound for use in the compositions of
the present invention is quercetin or an analog of quercetin.
Quercetin is typically found in plants as glycone or carbohydrate
conjugates. Quercetin itself is an aglycone or aglucon. That is,
quercetin does not possess a carbohydrate moiety in its structure.
Analogs of quercetin include its glycone conjugates include rutin
and thujin. Rutin is also known as quercetin-3-rutinoside. Thujin
is also known as quercitrin, quercetin-3-L-rhamnoside, and
3-rhamnosylquercetin. Onions contain conjugates of quercetin and
the carbohydrate isorhamnetin, including quercetin-3,4'-di-O-beta
glucoside, isorhamnetin-4'-O-beta-glucoside and
quercetin-4'-O-beta-glucoside. Quercetin itself is practically
insoluble in water. The quercetin carbohydrate conjugates have much
greater water solubility then quercetin.
[0056] Quercetin is known chemically as
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one and
3,3',4'5,7-pentahydroxy flavone.
[0057] Quercetin is a phenolic antioxidant and has been shown to
inhibit lipid peroxidation. In vitro and animal studies have shown
that quercetin inhibits degranulation of mast cells, basophils and
neutrophils. Such activities account, in part, for quercetin's
anti-inflammatory and immunomodulating activities. Other in vitro
and animal studies show that quercetin inhibits tyrosine kinase and
reduces the activation of the inflammatory mediator, NF-.kappa.B.
Further activities of quercetin include anti-viral and anti-cancer
activity. Quercetin is further known to inhibit aldose reductase. A
quercetin or an analog thereof for use in the present invention can
be an inhibitor of tyrosine kinases. The most important biologic
activities of quercetin are its inhibition of platelet activation
plus its anti-inflammatory properties, as the interaction of these
two effects can reduce the incidence of thrombogenesis associated
with current generation DES.
[0058] Quercetin inhibits both platelet activation and platelet
aggregation. It enhances platelet-derived nitric oxide to inhibit
the activation of a protein kinase C-dependent NADPH oxidase. In
addition, quercetin inhibits platelet aggregation through its
inhibition of phosphoinositide kinase. Further properties of
quercetin or its analogs that are relevant in the context of the
present invention include: inhibition of cell cycle, inhibition of
smooth muscle cell proliferation and/or migration. Suitable
analogs/derivatives of quercetin include its glycone conjugates
rutin and thujin (See U.S. Patent Application Publication No.
2007/0212386 (Patravale et al.)).
[0059] Quercetin and/or its analogs may be capable of exerting the
above activities when used singly. However, the above properties of
quercetin and/or its analogs may be further enhanced by exploiting
the synergy between quercetin and/or its analogs and further
therapeutic agents (as disclosed herein), such as resveratrol
and/or its derivatives.
[0060] In one embodiment, the combination of polymer and
pharmaceutically active agent comprise a combination of
pharmaceutically active agents. If more than one pharmaceutically
active agent is used, they can be present in combination in the
same layer, or in separate polymer layers. Exemplary combinations
include resveratrol plus quercetin separately or in combination in
one or more coatings and resveratrol or quercetin alone or in
combination in one or more coatings.
##STR00003##
[0061] Exemplary derivatives of quercetin are those in which the
hydrogen of one or more of the compounds' hydroxyl groups, most
commonly the 3 hydroxyl is replaced to form esters or ethers (see
for example Formula VII). Ether formation examples include, but are
not limited to, the addition of alkyl chains such as methyl and
ethyl groups, as well as deoxy sugars such as fucose and rhamnose.
Esterification products include, but are not limited to; compounds
formed through the reaction of carboxylic acid containing materials
such as acetic acid, propionic acid and palmitic acid. Urethane
derivatives of quercetin include, but are not limited to; amino
acid ester carbamates formed by the addition of materials such as
benzyl 2-isocyanatoacetate and (S)-methyl
2-isocyanatopropanoate.
[0062] Additional quercetin derivatives include, but are not
limited to, compounds that can be described as metabolites formed
by the addition of sugar-like derivatives such as glucuronyl groups
at any of the hydroxyl positions. Examples of these metabolites
include 7-O-glucuronyl-quercetin and 3'-O-glucuronyl-quercetin.
[0063] Additional derivatives include, but are not limited to,
compounds that arise from the loss of any of the hydroxyl groups of
the parent molecule, addition of hydroxyl groups at alternate
positions, and any compound that may arise from the previously
mentioned reactions to provide a functionalized variant of the
dehydroxylated compound.
[0064] Examples of Quercetin Derivatives
##STR00004##
Resveratrol and Quercetin
[0065] In an exemplary embodiment, resveratrol plus a small
concentration of quercetin are incorporated onto a DES and/or other
medical device to maintain blow flood through stenotic areas using
stents; and, to increased length of time of blood flow without
restenosis in these areas.
[0066] For more information on the use of resveratrol in the
treatment of restenosis through methods other than drug-eluting
stents, see U.S. Pat. No. 6,022,901, to David William Goodman,
titled "Administration of resveratrol to prevent or treat
restenosis following coronary intervention", which is herein
incorporated by reference in its entirety.
[0067] Resveratrol is a polyphenol that has been linked to the
reported cardioprotection of red wine consumption. The reported
cardioprotective effects of red wine consumption was prompted by
epidemiological studies documenting the "French Paradox," a term
coined to describe the reduced incidence of death due to CHD in
areas of southwest France. Inhabitants of this area exhibit
increased serum cholesterol and blood pressure and eat more lard
and butter than do Americans, yet suffer 40% fewer deaths due to
CHD than other western societies. This paradoxical effect is
attributed to their daily consumption of red wine. While
epidemiological studies suggest a decreased risk of CHD in
populations regularly consuming alcohol, considerable data indicate
that wine provides greater protection as compared to other
alcoholic beverages.
[0068] Resveratrol is a phytoalexin polyphenol found in foods such
as grapes, mulberries, peanuts, and grapevine. Within the grape
itself, resveratrol is most abundant in the skin (ca. 50-100
.mu.g/gm. One fluid ounce of red wine provides .sup..about.160
.mu.g resveratrol. The rapid conjugation of resveratrol to form
glucuronides and sulfates has been argued as evidence that orally
administered resveratrol concentrations cannot approach
therapeutically useful levels. However, immediately after
consumption, resveratrol can be measured in the plasma, heart,
liver, and kidney. Chronic consumption further increases levels of
resveratrol in tissues such as the heart and liver.
[0069] Quercetin is also a polyphenol present in red wine and it is
likewise reported to exert protection against atherosclerosis. From
a pharmacological point of view, an exemplary drug combination of
the present invention, resveratrol and quercetin, appears
reasonable, red wine is actually a combination of low levels of
many bioactive polyphenols that act synergistically to exert the
effects observed clinically for chronic red wine consumption.
[0070] Prior reports by other laboratories have indicated that
resveratrol acts through a variety of mechanisms to promote
vascular health. As an antioxidant polyphenol, it limits the
oxidation of low-density lipoprotein, thus inhibiting fatty streak
formation. It furthermore exhibits anti-inflammatory effects
through an inhibition of NF.kappa.B activation. Several labs have
demonstrated that resveratrol promotes endothelial function by
increasing eNOS activity, and a recent report suggests that the
mechanism for this effect is an increase in eNOS phosphorylation.
Resveratrol also promotes endothelial protection against oxidant
injury, likely via an inhibition of the activation of NADPH
oxidase. Finally, resveratrol inhibits adhesion of inflammatory
cells to the vascular endothelium by inhibiting the expression of
adhesion molecules.
[0071] Prior reports demonstrate resveratrol's efficacy in
inhibiting proliferation of vascular smooth muscle cells (VSMC).
For example, in VSMC stimulated with the mitogens endothelin-1 and
platelet-derived growth factor, resveratrol inhibited cell cycle
traverse, and in coronary artery smooth muscle, resveratrol
inhibited endothelin-1-induced map kinase stimulation.
[0072] The mechanisms for these effects are due in part to a
resveratrol-mediated ER activation that culminates in an
upregulation of tetrahydrobiopterin (BH.sub.4) biosynthesis. The
inventors have demonstrated that the resulting increase in levels
of BH.sub.4, a known NOS cofactor, promoted an elevation in NO
concentration that culminated in cell cycle arrest. Effects on NO
concentration are dependent upon an increase in inducible nitric
oxide synthase (iNOS) activity, but not its expression. In addition
to this novel ER-dependent pathway, the current invention also
shows that resveratrol inhibits NF.kappa.B activation very
potently.
[0073] Thus, according to the present invention, resveratrol exerts
pleiotropic effects on VSMC proliferation, enhancing NO production
through an ER-dependent pathway, but also inhibits NF.kappa.B
activation through an ER-independent pathway. It is the
cooperativity between these two pathways that accounts for the
observed effects on VSMC proliferation.
[0074] Quercetin is an inhibitor of both platelet and NF.kappa.B
activation. The addition of quercetin to the DES of the present
invention should potentiate the effects of resveratrol on VSMC
proliferation by boosting the inhibitory effects on NF.kappa.B
activation. Further, strong inhibition NF.kappa.B should also
potentiate resveratrol-mediated inhibition of the inflammatory
component of restenosis. Addition of quercetin should also limit
platelet activation, which is a part of the inflammatory response
to balloon angioplasty and stent implantation that leads to
restenosis. Alternatively, another agent or agents which inhibit
platelet activation and/or aggregation could be utilized in place
of quercetin with resveratrol. Such alternative options include,
but are not limited to, aspirin, ticlopidine, clopidogrel,
dipyridamole, and the like.
[0075] Resveratrol has same binding site as estradiol and behaves
as an ER-alpha agonist, however, it has a lower binding affinity
than estradiol. This provides protection against estrogenic side
effects, such as alteration of the female menstrual cycle and
feminization side-effects in males.
Alternative Drug Delivery Mechanisms
[0076] Oral dosing of resveratrol is described in U.S. Pat. Nos.
6,022,901 and 6,211,247 to David William Goodman titled
"Administration of resveratrol to prevent or treat restenosis
following coronary intervention", which are herein incorporated by
reference in their entirety. However, positive effects from oral
dosing studies in animal models would require humans to ingest
.sup..about.3 g/day in a 60 kg human. Therefore, a drug releasing
stent and/or other medical device should work better than oral
dosage because of its localized targets. Regardless, the present
invention contemplates oral delivery of a therapeutic amount of
both resveratrol and quercetin to prevent or treat restenosis.
Devices
[0077] In one embodiment, the device treats narrowing or
obstruction of a body passageway in a subject in need thereof. In
another embodiment, the method comprises inserting the device into
the passageway, the device comprising a generally tubular
structure, the surface of the structure being coated with a
composition disclosed herein, such that the passageway is expanded.
In the method, the body passageway may be selected from arteries,
veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal
passages, sinuses, eustachian tubes, the external auditory canal,
oral cavities, the esophagus, the stomach, the duodenum, the small
intestine, the large intestine, biliary tracts, the ureter, the
bladder, the urethra, the fallopian tubes, uterus, vagina, the
vasdeferens, and the ventricular system.
[0078] Exemplary devices include, but are not limited to, stents,
balloon components of balloon catheters, catheters, guidewires,
sutures, staples, anastomosis devices, vertebral disks, bone pins,
suture anchors, hemostatic barriers, clamps, screws, plates, clips,
vascular implants, urological implants, tissue adhesives and
sealants, tissue scaffolds, bone substitutes, intraluminal devices,
and vascular supports. For example, the device can be a
cardiovascular device, such as venous catheters, venous ports,
tunneled venous catheters, chronic infusion lines or ports,
including hepatic artery infusion catheters, pacemakers and pace
maker leads, and implantable defibrillators. Alternatively, the
device can be a neurologic/neurosurgical device such as ventricular
peritoneal shunts, ventricular atrial shunts, nerve stimulator
devices, dural patches and implants to prevent epidural fibrosis
post-laminectomy, and devices for continuous subarachnoid
infusions. The device can be a gastrointestinal device, such as
chronic indwelling catheters, feeding tubes, portosystemic shunts,
shunts for ascites, peritoneal implants for drug delivery,
peritoneal dialysis catheters, and suspensions or solid implants to
prevent surgical adhesions. In another example, the device can be a
genitourinary device, such as uterine implants, including
intrauterine devices (IUDs) and devices to prevent endometrial
hyperplasia, fallopian tubal implants, including reversible
sterilization devices, fallopian tubal stents, artificial
sphincters and periurethral implants for incontinence, ureteric
stents, chronic indwelling catheters, bladder augmentations, or
wraps or splints for vasovasostomy, central venous catheters.
[0079] Other exemplary devices include, but are not limited to,
prosthetic heart valves, vascular grafts opthalmologic implants
(e.g., multino implants and other implants for neovascular
glaucoma, drug eluting contact lenses for pterygiums, splints for
failed dacrocystalrhinostomy, drug eluting contact lenses for
corneal neovascularity, implants for diabetic retinopathy, drug
eluting contact lenses for corneal injury or high risk corneal
transplants), otolaryngology devices (e.g., ossicular implants,
Eustachian tube splints or stents for glue ear or chronic otitis as
an alternative to transtempanic drains), plastic surgery implants
(e.g., breast implants or chin implants), and catheter cuffs and
orthopedic implants (e.g., cemented orthopedic prostheses).
[0080] Another exemplary device according to the invention is a
stent, such as a stent comprising a generally tubular structure. A
stent is commonly used as a tubular structure disposed inside the
lumen of a duct to relieve an obstruction. Commonly, stents are
inserted into the lumen in a non-expanded form and are then
expanded autonomously, or with the aid of a second device in situ.
A typical method of expansion occurs through the use of a
catheter-mounted angioplasty balloon which is inflated within the
stenosed vessel or body passageway in order to shear and disrupt
the obstructions associated with the wall components of the vessel
and to obtain an enlarged lumen.
[0081] An exemplary stent is a stent for treating narrowing or
obstruction of a body passageway in a human or animal in need
thereof. "Body passageway" as used herein refers to any of number
of passageways, tubes, pipes, tracts, canals, sinuses or conduits
which have an inner lumen and allow the flow of materials within
the body. Representative examples of body passageways include
arteries and veins, lacrimal ducts, the trachea, bronchi,
bronchiole, nasal passages (including the sinuses) and other
airways, eustachian tubes, the external auditory canal, oral
cavities, the esophagus, the stomach, the duodenum, the small
intestine, the large intestine, biliary tracts, the ureter, the
bladder, the urethra, the fallopian tubes, uterus, vagina and other
passageways of the female reproductive tract, the vasdeferens and
other passageways of the male reproductive tract, and the
ventricular system (cerebrospinal fluid) of the brain and the
spinal cord. Exemplary devices of the invention are for these
above-mentioned body passageways, such as stents, e.g., vascular
stents. There is a multiplicity of different vascular stents known
in the art that may be utilized following percutaneous transluminal
coronary angioplasty.
[0082] Any number of stents may be utilized in accordance with the
present invention and the invention is not limited to the specific
stents that are described in exemplary embodiments of the present
invention. The skilled artisan will recognize that any number of
stents may be utilized in connection with the present invention. In
addition, as stated above, other medical devices may be utilized,
such as e.g., orthopedic implants.
[0083] Examples in patent literature disclosing stents which have
been applied in PTCA procedures include stents illustrated in U.S.
Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued
to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor, and
U.S. Patent Application Publication No. 20050186248 (Hossainy).
[0084] According to one embodiment of the present invention, the
stent has expandable radial struts (FIG. 1). The number of struts
and cells may vary with the size of the stent, also. For a detailed
description of such a stent, please see U.S. Pat. No. 5,843,172 to
John Y. Yan, titled "Porous medicated stent", which is herein
incorporated by reference in its entirety. For other examples such
a stent, please see U.S. Pat. No. 6,083,257 to Alistair Stewart
Taylor, Peter William Stratford, Yiannakis Petrou Yianni, and
Matthew John Woodroffe titled "Braided Stent", which is herein
incorporated by reference in its entirety; and, U.S. Pat. No.
6,471,979, to Gishel New, Jeffrey W. Moses, Nicholas Kipshidze,
Gary S. Roubin, and Martin B. Leon, titled "Apparatus and method
for delivering compounds to a living organism", which is herein
incorporated by reference in its entirety. The stents and/or other
medical devices may be prepared by an initial dip coating with a
silane ester primer, followed by sequential layering of a
biocompatible polymer preparation containing 5-20% resveratrol,
which will likewise be accomplished by a dip-coating technique; the
biocompatible polymer preparation can be a hydrophilic
polyurethane. An additional layer of polymer can be placed over the
final layer of drug coating for a more controlled drug delivery.
All of the described techniques for stent construction, with the
exception of the resveratrol/quercetin formulation, are well-known
to the art.
Drug Eluting Balloon Catheters and Other Devices
[0085] The invention also provides a drug coated balloon in for
example, a catheter, particularly where the drug has
anti-inflammatory, anti proliferative or anti-thrombotic capability
or can prevent collagen induced platelet aggregation.
[0086] The catheter balloon is typically coated with layers one or
more of the polymers disclosed elsewhere in this specification
particularly where the drug is sequestered within one or more of
the polymer coating materials. Preferred polymer coating materials
include Poly L-Lactide polymer (PLLA), poly(lactide-co-glycolide)
(PLGA), poly(l-lactide-co-trimethylene carbonate),
poly(d,l-lactide-co-trimethylene carbonate), polyvinyl alcohol
(PVA) and polyalkylene glycols (PAG) such as polyethylene glycol
(PEG), albumin, gelatin, starch, cellulose, dextrans,
polysaccharides, fibrinogen, poly(D,L lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(hydroxybutyrate), poly(alkylcarbonate), poly(orthoesters) and
any of the polymers disclosed herein for use in covalent binding of
drugs having a nucleophilic group (e.g. hydroxyl or amino)
available for reaction with a complementary electrophilic group of
the polymer material. The selected polymer coatings can be mixed,
combined or covalently bound to the selected bioactive drug in any
desired concentration of selected drug. Two or more polymers can be
combined with each other to form a polymer matrix. The balloon can
contain multiple coatings or layers of such polymers, at least one
of the layers or coatings containing a selected drug.
[0087] Other polymer materials may be used alone or together with
any of the foregoing polymers as disclosed for example in Patent
Cooperation Treaty application PCT/IN02/00173 03018082, the
disclosure of which is incorporated herein by reference as if fully
set forth herein.
[0088] The drug or drugs that is/are selected for inclusion in the
coating on the stents and/or other medical devices may or may not
be covalently bound to the coating polymer. Examples of the drug or
drugs which may be included in the coating, include but are not
limited to, resveratrol and quercetin for use in/on a coating on a
balloon catheter. Any other of the drugs described in this
specification can alternatively be used depending on the treatment
desired.
[0089] Dip coating techniques may be used for coating the surface
of a balloon although other methods may also be employed such as
spray coating. Coating is typically comprised of a single layer but
may also comprise multiple layers depending on the content and
release profile of drug contained in the coating. The surface may
also be coated with micro or nanoformulations of the active agents.
These may be pure active agent nanoparticles adhered to the surface
or released from beneath a polymeric film or active agents
encapsulated in polymeric micro- or nanospheres or other carriers
such as liposomes. Polymeric capsules may either be rupturable to
release their contents, may release the active agents after
enzymatic or hydrolytic break down or release the active agents by
diffusion release formulations.
[0090] Coated balloons are useful in revascularization,
catheterization, balloon expansion and stent delivery procedures
and methods described herein. In a stent delivery procedure for
example, a drug coated balloon according to the invention may also
incidentally deliver drugs to vessel areas that are not situated at
the localized situs of implant of a stent. Such incidental delivery
of drug from the surface of the balloon is of particular utility
for small and tortuous vessel passages leading up to the site of
interest. Furthermore, healing and re-endothelialization of stent
struts that do not carry antiproliferative agents can be
facilitated by the use of drug coated balloons.
[0091] On pressurized contact of the surface of the balloon with a
blood vessel wall either as a result of stent delivery or
otherwise, the drug containing polymer coating will adhere to the
blood vessel wall surface and release the drug either over a very
short period of time, e.g. less than about 45 seconds, or over a
longer period of time as described below, e.g. over less than about
8 minutes, depending on the selection of the coating material(s),
whether the drug is covalently bound, the miscibility/affinity of
the drug for the coating material and the concentration of the
selected drug in the coating.
[0092] As a specific example, the surface of a stent, catheter
balloon, or other medical device is coated with 0.1 to 15 .mu.g of
resveratrol and/or quercetin per square millimeter of device
surface to enable immediate release of the drug on inflation. The
coating resulted in a very slight increase in profile but no
recognizable change in flexibility. The release profile for
compound or compounds in the coating on the surface of a stent,
catheter balloon, and/or other medical device, is in a time period
of between about 20 and about 40 seconds, about 1 min to 100
minutes, about 1 hour to 20 hours, about 1 day to 1 month, about 1
day to 10 days, about 1 day to about 30 days, about 1 day to about
2 months, about 1 day to about 6 months, about 1 day to about 6
months, about 1 day to about 1 year. Non limiting examples of
delayed profile coating release an active agent and/or agents over
a period of at least one month, at least two months, at least six
months, or at least one year, after implantation.
Polymers
[0093] The invention is directed to thin coatings for medical
devices, more specifically an implantable medical device, for
example a stent and/or other medical device. In accordance to one
embodiment, the invention is specifically directed to a coating for
a stent. The stent can be a self-expandable stent or a radially
expandable stent. In others embodiments, the stent can have a coil
configuration or be made from a wire or fiber-type body. The stent
body can be made from a metallic material, polymeric material, or a
combination of metallic or polymeric material. The combination can
be in a layered, disbursed, blended or conjugated form. In some
embodiments, the metal or polymer can be biodegradable such that
the stent is intended to remain at the implantation site for a
temporary duration of time. Biodegradable, bioerodable,
bioabsorbable, etc. are terms which are used interchangeably unless
otherwise specifically intended. The stent may have, for example, a
polymer body made from one or a combination of polymers. In some
embodiments, the stent is from about 5 mm in length to about 40 mm
in length. In some embodiments, the stent is at least 40 mm in
length. See U.S. Patent Application Publication No. 2007/0299511
(Gale).
[0094] A thin coating may be disposed on the surface of the
structural element or strut. The coating can be deposited on the
outer surface, inner surface and the side walls of the strut. In
some embodiments, the coating is exclusively on the outer surface,
and not the inner surface or the side walls. In some embodiments,
the coating can be on the outer surface and at least a portion of
the sidewalls of the strut. In one embodiment, the thickness of the
coating is about 1 to 100 microns. In an exemplary embodiment, the
thickness of the coating can be at any range between about 5 and 20
microns. In an exemplary embodiment, the thickness of the coating
can be, for example, about 5, about 10, about 15, or about 20
microns.
[0095] In some embodiments, the coating is a pure drug or
therapeutic substance layer. In some embodiments, the coating is a
combination of more than one drug or therapeutic substance without
any polymers. In some embodiments the coating can be a combination
of at least one polymer and at least one drug or therapeutic
substance. Combination is defined as blending, mixing, dispersing,
conjugating, and/or bonding of the drug/therapeutic substance to
the polymer. The coating polymer can be the same as or different
than a polymer from which the stent is made. At least one of the
polymers for the coating can be the same or different than at least
one of the polymers of the stent structure.
[0096] In some embodiments, the coating can include a primer layer
and/or a topcoat layers or sub-layers. The primer layer will be
beneath the drug/therapeutic substance layer and the topcoat layer
above it. Both the primer layer and the topcoat layer can be
without any drugs/therapeutic substances. In some embodiments, some
drug may incidentally migrate into the primer layer or region. The
topcoat layer reduces the rate of release of the drug and/or
provides for biobeneficial properties.
[0097] The thin coating can be deposited by spray application,
electrostatic application, "ink-jet"-type application, plasma
deposition and the like. These processes are known in the art. A
coating composition including polymer(s), solvent(s), and
optionally drug(s)/therapeutic substance(s) can be used, for
example. In some embodiments, the amount of solvent included in the
composition can be low so as to allow for formation of the thin
coating. In some embodiments, the method of coating may include
modifying at least one process parameter of the spraying so that a
weight percent of solvent in coating material applied on the
polymeric surface is less than about 30 wt %, 20 wt %, 15 wt %, or
more narrowly, 10 wt %.
[0098] The stent or the coating can be made from a material
including, but are not limited to,
poly(N-acetylglucosamine)(Chitin), Chitosan, poly(hydroxyvalerate),
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polyorthoester, polyanrhydride,
poly(glycolic acid), poly(glycQlide), poly(L-lactic acid),
poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),
poly(caprolactone), poly(trimethylene carbonate), polyester amide,
poly(glycolic acid-co-trimethylene carbonate),
co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes,
biomolecules (such as fibrin, fibrinogen, cellulose, starch,
collagen and hyaluronic acid), polyurethanes, silicones,
polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin
copolymers, acrylic polymers and copolymers other than
polyacrylates, vinyl halide polymers and copolymers (such as
polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl
ether), polyvinylidene halides (such as polyvinylidene chloride),
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as
polystyrene), polyvinyl esters (such as polyvinyl acetate),
acrylonitrile-styrene copolymers, ABS resins, polyamides (such as
Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes,
polyimides, polyethers, polyurethanes, rayon, rayon-triacetate,
cellulose, cellulose acetate, cellulose butyrate, cellulose acetate
butyrate, cellophane, cellulose nitrate, cellulose propionate,
cellulose ethers, and carboxymethyl cellulose. Another type of
polymer based on poly(lactic acid) that can be used includes graft
copolymers, and block copolymers, such as AB block-copolymers
("diblock-copolymers") or ABA block-copolymers
("triblock-copolymers"), or mixtures thereof.
[0099] Additional representative examples of polymers that may be
especially well suited for use in fabricating or coating the stent
include ethylene vinyl alcohol copolymer (commonly known by the
generic name EVOH or by the trade name EVAL), poly(butyl
methacrylate), poly(vinylidene fluoride-co-hexafluororpropene)
(e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare,
N.J.), polyvinylidene fluoride (otherwise known as KYNAR, available
from ATOFINA Chemicals, Philadelphia, Pa.), ethylene-vinyl acetate
copolymers, and polyethylene glycol.
[0100] The stent can also be made from the following metallic
materials or alloys: cobalt chromium alloy (ELGILOY), stainless
steel (316L), "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum,
nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or
combinations thereof. "MP35N" and "MP20N" are trade names for
alloys of cobalt, nickel, chromium and molybdenum available from
standard Press Steel Co., Jenkintown, Pa. "MP35N" consists of 35%
cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N"
consists of 50% cobalt, 20% nickel, 20% chromium, and 10%
molybdenum.
[0101] The coating can be made from the following materials:
poly(ester amide), polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and
poly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such as
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate) and copolymers including any of the
3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein
or blends thereof, poly(D,L-lactide), poly(L-lactide),
polyglycolide, poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide), polycaprolactone,
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(anhydrides),
poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine
ester) and derivatives thereof, poly(imino carbonates),
poly(glycolic acid-co-trimethylene carbonate), polyphosphoester,
polyphosphoester urethane, poly(amino acids), polycyanoacrylates,
poly(trimethylene carbonate), poly(iminocarbonate), polyurethanes,
polyphosphazenes, silicones, polyesters, polyolefins,
polyisobutylene and ethylene-alphaolefin copolymers, acrylic
polymers and copolymers, vinyl halide polymers and copolymers, such
as polyvinyl chloride, polyvinyl ethers, such as polyvinyl methyl
ether, polyvinylidene halides, such as polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, such as
polystyrene, polyvinyl esters, such as polyvinyl acetate,
copolymers of vinyl monomers with each other and olefins, such as
ethylene-methyl methacrylate copolymers, acrylonitrile-styrene
copolymers, ABS resins, and ethylene-vinyl acetate copolymers,
polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,
polycarbonates, polyoxymethylenes, polyimides, polyethers,
poly(glyceryl sebacate), poly(propylene fumarate), poly(n-butyl
methacrylate), poly(sec-butyl methacrylate), poly(isobutyl
methacrylate), poly(tert-butyl methacrylate), poly(n-propyl
methacrylate), poly(isopropyl methacrylate), poly(ethyl
methacrylate), poly(methyl methacrylate), epoxy resins,
polyurethanes, rayon, rayon-triacetate, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers,
carboxymethyl cellulose, polyethers such as poly(ethylene glycol)
(PEG), copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxides
such as poly(ethylene oxide), poly(propylene oxide), poly(ether
ester), polyalkylene oxalates, polyphosphazenes, phosphoryl
choline, choline, poly(aspirin), polymers and co-polymers of
hydroxyl bearing monomers such as HEMA, hydroxypropyl methacrylate
(HPMA), hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG
methacrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and
n-vinyl pyrrolidone (VP), carboxylic acid bearing monomers such as
methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,
alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA),
poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,
polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,
poly(methyl methacrylate)-PEG (PMMA-PEG),
polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene
fluoride)-PEG (PVDF-PEG), PLURONIC.TM. surfactants (polypropylene
oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), biomolecules such as collagen,
chitosan, alginate, fibrin, fibrinogen, cellulose, starch,
collagen, dextran, dextrin, fragments and derivatives of hyaluronic
acid, heparin, fragments and derivatives of heparin, glycosamino
glycan (GAG), GAG derivatives, polysaccharide, elastin, chitosan,
alginate, or combinations thereof. In some embodiments, the
substrate coating described herein can exclude any one of the
aforementioned polymers.
[0102] As used herein, the terms poly(D,L-lactide),
poly(L-lactide), poly(D,L-lactide-co-glycolide), and
poly(L-lactide-co-glycolide) can be used interchangeably with the
terms poly(D,L-lactic acid), poly(L-lactic acid), poly(D,L-lactic
acid-co-glycolic acid), or poly(L-lactic acid-co-glycolic acid),
respectively.
[0103] In some embodiments, the coating preferably includes a
fluoropolymer such as a Solef.TM. polymer (e.g., PVDF-HFP).
[0104] In some embodiments, the coating can be made from or further
include a biobeneficial material. The biobeneficial material can be
polymeric or non-polymeric. The biobeneficial material is
preferably substantially non-toxic, non-antigenic and
non-immunogenic. A biobeneficial material is one that enhances the
biocompatibility of a device by being non-fouling, hemocompatible,
actively non-thrombogenic, or anti-inflammatory, all without
depending on the release of a pharmaceutically active agent.
[0105] Representative biobeneficial materials include, but are not
limited to, polyethers such as poly(ethylene glycol),
copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxides such as
poly(ethylene oxide), poly(propylene oxide), poly(ether ester),
polyalkylene oxalates, polyphosphazenes, phosphoryl choline,
choline, poly(aspirin), polymers and co-polymers of hydroxyl
bearing monomers such as hydroxyethyl methacrylate (HEMA),
hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide,
poly(ethylene glycol) acrylate (PEGA), PEG methacrylate,
2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl
pyrrolidone (VP), carboxylic acid bearing monomers such as
methacrylic acid (MA), acrylic acid (AA), alkoxymethacrylate,
alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA),
poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,
polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,
poly(methyl methacrylate)-PEG (PMMA-PEG),
polydimethylsiloxane-co-PEG (PDMS-PEG), poly(vinylidene
fluoride)-PEG (PVDF-PEG), PLURONIC.TM. surfactants (polypropylene
oxide-co-polyethylene glycol), poly(tetramethylene glycol), hydroxy
functional poly(vinyl pyrrolidone), biomolecules such as fibrin,
fibrinogen, cellulose, starch, collagen, dextran, dextrin,
hyaluronic acid, fragments and derivatives of hyaluronic acid,
heparin, fragments and derivatives of heparin, glycosamino glycan
(GAG), GAG derivatives, polysaccharide, elastin, chitosan,
alginate, silicones, PolyActive.TM., and combinations thereof.
[0106] The term PolyActive.TM. refers to a block copolymer having
flexible poly(ethylene glycol) and poly(butylene terephthalate)
blocks (PEGT/PBT). PolyActive.TM. is intended to include AB, ABA,
BAB copolymers having such segments of PEG and PBT (e.g.,
poly(ethylene glycol)-block-poly(butyleneterephthalate)-block
poly(ethylene glycol) (PEG-PBT-PEG).
[0107] In a preferred embodiment, the biobeneficial material can be
a polyether such as poly(ethylene glycol) (PEG) or polyalkylene
oxide.
Dosages
[0108] On-device dosages of at least one pharmaceutically active
agent or agents may be determined by means known in the art.
Typically, the dosage is dependent upon the particular drug
employed and medical condition being treated to achieve a
therapeutic result. In one embodiment, the amount of drug
represents about 0.001 percent to about seventy percent of the
total coating weight, or about 0.01 percent to about sixty percent
of the total coating weight. In one embodiment, the weight percent
of the therapeutic agents in the carrier or polymer coating is 1%
to 50%, 2% to 45, 5% to 40, or 10 to 35%. In another embodiment, it
is possible that the drug may represent as little as 0.0001 percent
to the total coating weight. In another embodiment, the amount of
selected drugs loaded onto a 16 mm long stent range from about 30
to about 105 micrograms per coating layer.
[0109] In an exemplary embodiment, the dosage or concentration of,
e.g., resveratrol and/or quercetin based on surface area on a
typical coronary stent and/or other medical device can range from
about 0.1 to about 5 .mu.g/mm.sup.2, or more than about 0.7
.mu.g/mm.sup.2 (at lower dosage restenosis rates are higher), or
less than about 3.0 .mu.g/mm.sup.2 (higher will be cytotoxic), or
ranging from 1.0 and 1.8 .mu.g/mm.sup.2, and or about 1.4
.mu.g/mm.sup.2. In an exemplary embodiment, the dosage or
concentration of, e.g., resveratrol and/or quercetin based on
surface area on a typical coronary stent and/or other medical
device can range from about 0.5 .mu.g/mm.sup.2 to about 35
.mu.g/mm.sup.2. In an exemplary embodiment, the dosage or
concentration of, e.g., resveratrol and/or quercetin based on
surface area on a typical coronary stent and/or other medical
device can range from about 1 .mu.g/mm.sup.2 to about 100
.mu.g/mm.sup.2. In an exemplary embodiment, the dosage or
concentration of, e.g., resveratrol and/or quercetin based on
surface area on a typical coronary stent and/or other medical
device can range from about 1 .mu.g/mm.sup.2 to about 2
.mu.g/mm.sup.2. In an exemplary embodiment, the dosage or
concentration of, e.g., resveratrol and/or quercetin based on
surface area on a typical coronary stent and/or other medical
device can range from about 1 .mu.g/mm.sup.2 to about 5
.mu.g/mm.sup.2. In an exemplary embodiment, for a typical series of
coronary stent varying in length from 8.00 to 39.00 mm, the total
resveratrol and/or quercetin content will vary from 35 .mu.g to 250
.mu.g. Suitable dosaging for drug-eluting stents is further
described in U.S. Pat. No. 6,908,622, the disclosure of which is
incorporated herein by reference.
[0110] The dosage or concentration of e.g. resveratrol and/or
quercetin based on surface area on a typical coronary stent may be
is 0.1 and 5 .mu.g/mm.sup.2 In another embodiment, the dosage is
more than about 0.7 .mu.g/mm.sup.2 (at lower dosage restenosis
rates are higher) and less than about 3.0 .mu.g/mm.sup.2, such as
ranging from 1.0 and 1.8 .mu.g/mm.sup.2, e.g., about 1.4
.mu.g/mm.sup.2. Typically, the amount of resveratrol and/or
quercetin will increase linearly with the length of the stent. For
example, for a typical series of coronary stent varying in length
from 8.00 to 39.00 mm, the total resveratrol and/or quercetin
content will vary from 35 .mu.g to 250 .mu.g.
[0111] The dosage or concentration of a flavonoid or derivative
thereof based on surface area on a stent (e.g. a typical coronal
stent) may be is 0.1 and 40 .mu.g/mm.sup.2. In one embodiment, the
dosage of a flavonoid or derivative thereof based on surface area
of a device of the invention is more than about 0.2, 0.5, 1.0, 2.0,
5.0 or 10 .mu.g/mm.sup.2. In another embodiment, the dosage of a
flavonoid or derivative thereof based on surface area of a device
of the invention is less than about 30.0, 20.0, 15.0, 10.0, 5.0,
3.0 or 2.0 .mu.g/mm.sup.2. Generally, the amount of the flavonoid
or derivative thereof will increase linearly with the length of the
stent. For example, for a typical series of coronary stent varying
in length from 8.00 to 39.00 mm, the total flavonoid (or derivative
thereof) content will vary from 28 .mu.g to 3500 .mu.g.
Method of Treatment
[0112] In one embodiment, the implantable devices disclosed herein
are implanted in a subject in need thereof to achieve a therapeutic
effect, e.g., therapeutic treatment and/or
prophylactic/preventative measures. Those in need of treatment may
include individuals already having a particular medical disease as
well as those at risk for the disease (e.g., those who are likely
to ultimately acquire the disorder). A therapeutic method can also
result in the prevention or amelioration of symptoms, or an
otherwise desired biological outcome, and may be evaluated by
improved clinical signs, delayed onset of disease, reduced/elevated
levels of lymphocytes and/or antibodies.
[0113] In one embodiment, the method is used for treating at least
one disease or condition associated with vascular injury or
angioplasty. Angioplasty may be performed as part of
"revascularization" treatment for "artherosclerosis," which as used
herein means diseases in which plaque, made up of cholesterol,
fats, calcium, and scar tissue, builds up in the wall of blood
vessels, narrowing the lumen and interfering with blood flow.
"Revascularization," as used herein means any treatment that
re-establishes brisk blood flow through a narrowed artery,
including bypass surgery, angioplasty, stenting, and other
interventional procedures. Secondary complications following
revascularization may include restenosis, neointima, neointimal
hyperplasia and thrombosis. "Restenosis," as used herein is defined
as the re-narrowing of an artery in the same location of a previous
treatment; clinical restenosis is the manifestation of an ischemic
event, usually in the form of recurrent angina. "Neointima," as
used herein is defined as the scar tissue made up of cells and cell
secretions that often forms as a result of vessel injury following
angioplasty or stent placement as part of the natural healing
process. "Neointimal hyperplasia," as used herein means excessive
growth of smooth muscle cells from the inner lining of the artery.
After angioplasty and/or stenting, excessive growth of these cells
can narrow the artery again. "Thrombosis," as used herein means the
formation of a blood clot within a blood vessel or the heart cavity
itself and a "thrombus" is a blood clot.
[0114] Three pathophysiological phases can be distinguished
subsequent to revascularization. Stage I, the thrombotic phase
(days 0-3 after revascularization). This stage consists of rapid
thrombus formation. The initial response to arterial injury is
explosive activation, adhesion, aggregation, and platelet
deposition. The platelet thrombus may frequently be large and can
grow large enough to occlude the vessel, as occurs in myocardial
infarction. Within 24 hours, fibrin-rich thrombus accumulates
around the platelet site. Two morphologic features are prominent:
1) platelet/fibrin, and 2) fibrin/red cell thrombus. The platelets
are densely clumped at the injury site, with the fibrin/red cell
thrombus attached to the platelet mass.
[0115] Stage II, the recruitment phase (days 3-8). The thrombus at
arterial injury sites develops an endothelial cell layer. Shortly
after the endothelial cells appear, an intense cellular
infiltration occurs. The infiltration is principally monocytes that
become macrophages as they leave the bloodstream and migrate into
the subendothelial mural thrombus. Lymphocytes also are present,
and both types of cells demarginate from the bloodstream. This
infiltrate develops from the luminal side of the injured artery,
and the cells migrate progressively deeper into the mural
thrombus.
[0116] Stage III, the proliferative phase: (day 8 to final
healing). Actin-positive cells colonize the residual thrombus from
the lumen, forming a "cap" across the top of the mural thrombus in
this final stage. The cells progressively proliferate toward the
injured media, resorbing thrombus until it is completely gone and
replaced by neointimal cells. At this time the healing is complete.
In the pig this process requires 21-40 days, depending on residual
thrombus thickness. Smooth muscle cell migration and proliferation
into the degenerated thrombus increases neointimal volume,
appearing greater than that of thrombus alone. The smooth muscle
cells migrate from sites distant to the injury location, and the
resorbing thrombus becomes a bioabsorbable "proliferation matrix"
for neointimal cells to migrate and replicate. The thrombus is
colonized at progressively deeper levels until neointimal healing
is complete.
[0117] In one embodiment, the method of the invention can be used
to treat these conditions subsequent to revascularization, such as
those conditions subsequent to any of the three stages described
above, e.g., activation, adhesion, aggregation, platelet
deposition, thrombosis, platelet aggregation, proliferation, and
neointima.
[0118] In one embodiment, the active agent and/or agents are for
the prevention or treatment of restenosis subsequent to
angioplasty, such as the inhibition of neointimal hyperplasia
subsequent to angioplasty.
[0119] In one embodiment, the methods of the invention are directed
to the prevention of acute, subacute and chronic secondary
complications associated with angioplasty. Such secondary
complications subsequent to and/or associated with angioplasty are
defined herein above and include, e.g., restenosis, neointima,
neointimal hyperplasia, thrombosis and inflammation.
[0120] In one embodiment, the methods disclosed herein are directed
to treating undesired cell proliferation, which is often a
component of many disease processes. Undesired cell growth can be a
component of restenosis, the recurrence of stenosis or artery
stricture after corrective surgery. Restenosis occurs after
coronary artery bypass (CAB), endarterectomy, heart
transplantation, or after angioplasty, atherectomy, laser ablation
or stenting. Restenosis is the result of injury to the blood vessel
wall during the lumen opening procedure. In some patients, the
injury initiates a repair response that is characterized by smooth
muscle cell proliferation referred to as "hyperplasia" in the
region traumatized by the angioplasty. This proliferation of smooth
muscle cells re-narrows the lumen that was opened by the
angioplasty within a few weeks to a few months, thereby
necessitating a repeat angioplasty or other procedure to alleviate
the restenosis.
[0121] The therapeutic compounds disclosed herein will be delivered
locally to reduce side effects from high dose systemic delivery.
The local delivery options can include release from a drug eluting
stent, delivery by a drug eluting balloon or local
delivery/activation by remote techniques. The latter could include
systemic delivery of nanocomposite particles into the circulation
coupled by remote capture or release of the therapeutic agents by
acoustic, electrical, magnetic or optical energy sources. (e.g.,
carotid or other peripheral vesselendarterectomy, vascular bypass,
stent or prosthetic graft procedure). For example, a coated stent
or device as disclosed herein may be implanted at the vascular site
of interest for controlled release of the pharmaceutically active
agents over a desired time period.
Method of Making a Coated Drug Eluting Stent or Balloon
Catheter
[0122] The practice of coating implantable medical devices with a
synthetic or biological active or inactive agent is known. Numerous
processes have been proposed for the application of such a coating.
Soaking or dipping the implantable device in a bath of liquid
medication is suggested by U.S. Pat. No. 5,922,393 to Jayaraman,
soaking in an agitated bath, U.S. Pat. No. 6,129,658 to Delfino et
al. Devices introducing heat and/or ultrasonic energy in
conjunction with the medicated bath are disclosed in U.S. Pat. No.
5,891,507 to Jayaraman and U.S. Pat. No. 6,245,104 to Alt. The
device of U.S. Pat. No. 6,214,115 to Taylor et al. suggests
spraying the medication by way of pressurized nozzles, see U.S.
Patent Application No. 2006/0156976 (Shekalim).
[0123] Initially such coatings were applied at the time of
manufacture. Wrapping the implantable device with medicated
conformal film is disclosed in U.S. Pat. No. 6,309,380 BI to Larson
et al. Dipping or soaking in a medicated bath just prior to
implantation are suggested in U.S. Pat. No. 5,871,436 to Eury, U.S.
Pat. No. 6,730,120 to Berg et al., and U.S. Pat. No. 6,1171,232 to
Papandreou et al. U.S. Pat. No. 6,395,326 BI to Wu provides a
bathing chamber for use with specific implantable device such as
the stent deployed on the balloon of a catheter.
[0124] Each of the methods and devices intended for use just prior
to implantation, listed above, deposit the coating material onto
any and all surfaces that are exposed to the coating. This may
result in depositing coating material on surfaces on which the
coating is unwanted or undesirable. Further, the coating may crack
or break away when the implantable is removed from the implantation
apparatus. An example of this would be a stent deployed on a
catheter balloon. As the balloon is inflated and the stent is
expanded into position, the coating may crack along the interface
between the stent and the balloon. These cracks may lead to a
breaking away of a portion of the coating from the stent itself.
Similar problems can occur in cases where the coating technique
fails to prevent inadvertent overlapping with the edges (e.g.,
internal surfaces along the edges) of various devices (e.g., struts
of stents). This, in turn, may affect the medicinal effectiveness
of the coating, and negatively affect the entire medical
procedure.
[0125] It is known to use Ink-Jet technology to apply a liquid to
selected portion of a surface. In the paper "Applications of
Ink-Jet Printing Technology to BioMEMS and Microfluidic Systems,"
presented at the SPIC Conference on Microfluidics and BioMEMS,
October, 01, the authors, Patrick Cooley, David Wallace, and Bogdan
Antohe provide a fairly detailed description of Ink-Jet technology
and the range of its medically related applications
(www.microfab.compapers/papers_pdf/spie
biomems_O1_reprint.pdf).
[0126] The present invention incorporates at least one compound
coated onto a vascular stent and/or other medical device. For a
detailed description of such a stent and/or other medical device
and how it may be coated, please see U.S. Pat. No. 7,247,338, to
David Y. H. Pui and Da-Ren Chen, titled "Coating medical devices",
which is herein incorporated by reference in its entirety. For
other examples of how such a stent may be coated, please see U.S.
Pat. No. 6,093,557, to David Y. H. Pui and Da-Ren Chen, titled
"Electrospraying apparatus and method for introducing material into
cells," U.S. Pat. No. 6,399,362 to David Y. H. Pui and Da-Ren Chen,
titled "Electrospraying apparatus and method for introducing
material into cells," U.S. Pat. No. 6,746,869 to David Y. H. Pui
and Da-Ren Chen, titled "Electrospraying Apparatus and Method for
Coating Particles," and U.S. Pat. No. 6,764,720, to David Y. H. Pui
and Da-Ren Chen, titled "High mass throughput particle generation
using multiple nozzle spraying" which are herein incorporated by
reference in their entirety.
[0127] Preferably the method of making a coated stent according to
the present invention incorporates a ElectroNanospray.TM. process
for creating the coating because of its uniformity of drug
coverage, even coating, and lack of pooling and webbing.
Additionally, its use of a dual capillary co-axial nozzle allows
for the delivery of multiple agents, as is included in this
invention. However, the present invention is not limited to this
technology for coating. Another technology, which is not limiting,
that could be used is the presence of multiple polymers for
support.
[0128] All coating processes are to be optimized according to the
present invention for variables including the photosensitivity of
resveratrol and quercetin, the levels of resveratrol required for
eliciting efficacious results, synergistic effects between the two
drugs that result in differing levels of drug loading, and
necessary processing steps to decrease or eliminate the possible
oxidation of said compounds.
[0129] The invention will be illustrated in more detail with
reference to the following Examples, but it should be understood
that the present invention is not deemed to be limited thereto.
EXAMPLES
Example 1
[0130] Determining whether quercetin potentiates the vascular
protective effects of resveratrol in vivo, utilizing a mouse
carotid artery injury model. Female B6.129 mice were administered a
high fat diet, in some cases mixed together with 50 mg/kg
resveratrol (RESV), 10 mg/kg quercetin (QUER), or resveratrol plus
quercetin, for 2 weeks. The carotid artery injury procedure was
conducted and the animals were fed the high fat diet plus
polyphenols for an additional two weeks. The animals were then
sacrificed, and the carotid arteries were excised and assessed for
neointimal areas. The results indicate that oral treatment with
resveratrol dramatically reduced neointimal area. Though treatment
with quercetin alone exhibited no significant effect, it
potentiated the effects of resveratrol when the two polyphenols
were administered in combination.
Example 2
[0131] Effects of resveratrol/quercetin combination on platelet
activation. Prior reports suggest the efficacy of quercetin, and to
some extent, resveratrol, in reducing platelet activation and
aggregation. Thus, the addition of quercetin to the drug eluting
stent should make the described invention preferable to current
generation DES and/or other medical devices that have the undesired
side effect of thrombogenesis. To determine the efficacy of these
compounds in reducing platelet activation, platelets isolated from
healthy, male donors were incubated with resveratrol, quercetin, or
resveratrol plus quercetin. The doses were selected based on prior
studies. In experiments examining effects on VSMC proliferation,
resveratrol's EC.sub.50 for inhibiting DNA synthesis was 18 .mu.M,
while its EC.sub.50 for reducing numbers of cells was 25 .mu.M.
Cells were treated with the lower dose, 18 .mu.M resveratrol, and
added to this 10 and 15 .mu.M quercetin, doses about half its
reported EC.sub.50 for reducing VSMC proliferation. Doses of each
that were slightly below their maximal effective doses were
utilized, so as to be able to discern the additive or synergistic
effects of the drugs. The polyphenol treatments exhibited dramatic
effects on platelet activation. Treatment with 18 .mu.M resveratrol
reduced serotonin release by .sup..about.60%, and incubation with
10-15 .mu.M quercetin reduced serotonin release by 40-50% (FIG.
10). Cotreatment with 18 .mu.M resveratrol plus 10 .sup..about.M
quercetin reduced the activation by 65% compared to controls, and
cotreatment with 15 .mu.M quercetin reduced activation by 80%.
Thus, these experiments demonstrate that quercetin potentiated the
effects of resveratrol on platelet activation.
Example 3
[0132] In vivo experiments determining the efficacy of combined
treatment with resveratrol/quercetin in reducing platelet
activation. To confirm the in vitro experiments in an in vivo
rodent model, the effects of oral administration of 50 mg/kg
resveratrol were compared to treatment with resveratrol plus 10
mg/kg quercetin in the mouse carotid artery injury model. Plasma
levels of thromboxane B.sub.2 (TBX.sub.2), a known marker for
platelet activation, were assessed. Though resveratrol treatment
alone had no significant effect on plasma TXB2 levels (FIG. 11),
treatment with quercetin alone reduced TXB.sub.2 levels by 40%, and
treatment with quercetin plus resveratrol reduced TXB.sub.2 by 70%.
Thus, treatment with a resveratrol/quercetin combination induces
additive and synergistic effects on platelet activation in
vivo.
Example 4
[0133] Effects of resveratrol/quercetin combination on the
activation of inflammatory cells. Resveratrol is well-known to
inhibit inflammatory responses via inhibition of NF.kappa.B
activation. To test the efficacy of a resveratrol/quercetin
combination in inhibiting the activation of macrophages, effects of
polyphenol treatments either alone or in combination with quercetin
were assessed in cultures of lipopolysaccharide (LPS) stimulated
macrophages. Macrophage activation was determined by increases in
protein levels of inducible nitric oxide synthase (iNOS) and by
levels of reactive oxygen species (ROS). Treatment with 18 .mu.M
resveratrol reduced iNOS protein levels by .sup..about.25%, in
agreement with prior reports documenting the anti-inflammatory
activity of resveratrol (FIG. 12). However, quercetin more potently
diminished macrophage activation, reducing iNOS protein by
.sup..about.75 and 90% at 10 and 15 .mu.M, respectively. In
addition, the combination of 18 .mu.M resveratrol plus 10-15 .mu.M
quercetin virtually abolished all macrophage activation. The data
for ROS production were similar. This compilation of data thus
demonstrates the efficacy of the drug combination in inhibiting the
activation of inflammatory cells.
Example 5
[0134] Isobolograms for the determination of synergistic dose
ratios for a resveratrol/quercetin combination. To determine the
dose ratios for achieving maximal synergistic effects, activation
in LPS-stimulated cells macrophages incubated with constant dose
ratios of resveratrol and quercetin was measured. The IC.sub.50 for
each dose ratio was calculated using CalcuSyn software, and these
concentrations were used to construct an isobologram (FIG. 13).
Dose ratios exhibiting synergism were 1:5, 1:2, and 1:1
resveratrol:quercetin. These dose ratios exhibited combination
indices (CI values) of .sup..about.0.5. Briefly, CI=1 denotes
additive effects, CI>1 denotes antagonism, and CI<1 indicates
synergism. As an example of the synergistic effects of the
resveratrol/quercetin combination, the IC.sub.50's for individual
treatments of resveratrol and quercetin were 3.5 and 2.4 .mu.M,
respectively. However, when the drugs were administered at a 1:1
dose ratio, 50% inhibition could be achieved at 0.9 .mu.M
concentrations of each compound.
Example 6
[0135] Development of drug eluting stent models for in vitro
analysis of efficacy. For the purposes of modeling DES release and
biocompatibility in an inexpensive in vitro system, stainless steel
flat surfaces coated with drug-containing polymer were utilized.
The bare metal flats (0.2''.times.0.3'') were coated with a
polyisobutylene-polystyrene triblock copolymers containing the
active agents with two distinct surface morphologies-smooth and
nanoparticulate (high surface area) matrices. The
ElectroNanospray.TM. process for depositing drug-containing
nanoparticles, typically 50-300 nm in diameter, was utilized so as
to achieve uniformity of drug coverage, even coating, and lack of
pooling. Differences in coating morphologies can culminate in
differences in drug release characteristics. Initial
biocompatibility testing on both conformations was conducted. Each
coating type was loaded with two concentrations of either
resveratrol or quercetin.
[0136] The coating process needs to be able to minimize variation
so that each flat, and eventually each stent, releases the target
amount of drug at a desired rate. FIG. 14 illustrates scanning
electron microscopy (SEM) images of drug-containing polymer applied
using the ElectroNanospray.TM. process. FIG. 14 furthermore
compares polyisobutylene-polystyrene triblock copolymer surfaces of
both open and closed morphologies containing resveratrol and
quercetin nanoparticles. These images display a uniform coating
with either smooth (closed) or rough (open) surfaces.
Example 7
[0137] Biocompatibility is an important concern when developing an
implantable therapeutic. In order to assess cytotoxicity of the
polymer, the bare metal flats or flats coated with polymer only
were incubated with vascular smooth muscle cells (VSMC) for 48
hours. During the experiment, the flats were separated from the
cells using a 0.4 .mu.m semi-permeable transwell insert. To assess
cytotoxicity, medium collected after this incubation was assayed
for lactate dehydrogenase (LDH), a known marker for cytotoxicity,
as LDH is released from the cell when it becomes injured or
"leaky." Neither bare metal flats nor flats coated with
polyisobutylene-polystyrene triblock copolymer of either morphology
had any effect on LDH release compared to VSMC incubated without
flats (FIG. 15). Thus, this preliminary experiment suggests that
the polymer-coated flats exhibit no cytoxicity to VSMC.
[0138] While platelet activation is also an important factor in
restenosis, polymers that promote platelet activation would
likewise be undesirable for use in a drug eluting stent. To test
the effects of the polymer-coated flats on platelet activation,
bare metal flats coated with polyisobutylene-polystyrene triblock
copolymer using a closed compared to an open morphology were
incubated for 48 h in medium. Platelets were then isolated from
healthy, male donors and were incubated with the resulting
conditioned medium. Platelet activation was assessed as
platelet-derived growth factor (PDGF) release in either a basal
(FIG. 16 a) or ADP-stimulated (FIG. 16 b) condition. Results
indicated no significant effects of the polyisobutylene-polystyrene
triblock copolymer coated flats of either morphology.
Example 8
[0139] Another major goal in the development of a drug-eluting
polymer is to ensure that the system can release an adequate amount
of drug to inhibit local smooth muscle cell proliferation. The
polyisobutylene-polystyrene triblock copolymers coated flats
containing resveratrol or quercetin were incubated in
semi-permeable transwell inserts in plates containing VSMC. After
48 hours of drug elution, resveratrol coated in a smooth (closed)
matrix polyisobutylene-polystyrene triblock copolymer significantly
inhibited proliferation at the 100 .mu.g/cm.sup.2 loading
concentration. Quercetin significantly inhibited proliferation in
flats coated at 75 .mu.g/cm.sup.2, in either the particulate (open)
or the smooth (closed) polyisobutylene-polystyrene triblock
copolymer matrices. Data supporting these results are shown in FIG.
17.
[0140] Determination of resveratrol release was performed using
reversed phase high performance liquid chromatography (HPLC)
coupled to a 4-channel Coularray electrochemical detector run at
590, 660, 730, and 800 mV. Results indicate that resveratrol
release from the 100 mg/cm.sup.2 coated flat was approximately
4-fold greater than from the 50 mg/cm.sup.2-coated flat, regardless
of the morphology (FIG. 18). Slight, though insignificant effects
of the morphology on drug release were observed, with the closed
matrix trending toward a greater release profile compared to the
open matrix. Importantly, the flats eluted low micromolar
concentrations of resveratrol that are in a range that exhibits
efficacy in our in vitro tests. Also important is that at 28 days,
only 5-10% of the total drug loaded onto the flats had eluted,
suggesting that in stents coating in a similar manner, sufficient
drug should remain in the coating to achieve efficacy over several
months after stent placement. Polymer deposition via the
ElectroNanospray.TM. process creates a textured surface with no
noticeable defects or voids. This texture provides high surface
area for the biostable polymer to be in contact with the
surrounding environment. This is important because exposure to new
drug-containing polymer through degradation does not occur in this
system as it would with biodegradable polymers. Cytotoxicity and
proliferation data on the polymer-only samples provide evidence
that the polyisobutylene-polystyrene triblock copolymer is
biocompatible. Establishing biocompatibility is a critical step in
the development of the stent models. Proliferation data from
drug-containing polyisobutylene-polystyrene triblock copolymer
(FIG. 17) suggests that quercetin is releasing faster than
resveratrol from the polymer within the first 48 hours.
[0141] While the invention has been described in detail and with
reference to specific examples thereof, it will be apparent to one
skilled in the art that various changes and modifications can be
made therein without departing from the spirit and scope
thereof.
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