GREFFES A STENT TUBULAIRE EXTENSIBLE RADIALEMENT ELUANT LES MEDICAMENTS

DRUG ELUTING RADIALLY EXPANDABLE TUBULAR STENTED GRAFTS

Abrégé français

L'invention porte sur des greffes à stent tubulaire éluant les médicaments, le stent étant recouvert d'un revêtement comprenant un composite constitué d'au moins un polymère bioérodable, acceptable d'un point de vue pharmaceutique, biocompatible et d'au moins une substance thérapeutique. Le polymère peut être un polyester. L'agent thérapeutique peut comprendre des vecteurs d'administration de gènes sélectifs tels que le sirolimus, l'actinomycine D et le paclitaxel. Les greffes à stent tubulaire ont, selon les formes d'exécution, un stent intégré et un stent intérieur, le stent pouvant soit s'autodilater, soit se dilater sous pression. Le stent peut également comprendre une pluralité d'éléments ayant chacun une forme linéaire ondulante créée dans une configuration généralement cylindrique, chaque élément étant raccordé à un élément adjacent par au moins un raccord linéaire. L'invention porte, en outre, sur un procédé de traitement des maladies cardio-vasculaires par implantation de la greffe à stent, et sur un article de fabrication comprenant un matériau de conditionnement et la greffe à stent.

Abrégé anglais

Drug eluting stented tubular grafts wherein the stent is coated with a coat
comprising a composite of at least one biocompatible, pharmaceutically
acceptable, bioerodible polymer and at least one therapeutic substance. The
polymer may be a polyester. The therapeutic agent may include selective gene
delivery vectors, sirolimus, actinomycin-D and paclitaxel. The stented grafts
include an integrally stented embodiment and an internally stented embodiment.
In each embodiment, the stent may be either self-expanding or pressure-
expandable. Further, the stent may comprise a plurality of elements, wherein
each said element comprises an undulating linear shape formed into a generally
cylindrical configuration, and wherein each said element is connected to an
adjacent neighbor element by at least one linear connector. A method for the
treatment of cardiovascular disease by implantation of the stented graft, and
an article of manufacture, comprising packaging material and the stented graft
are also taught.

Revendications

43
Claims :
1. A stented graft that is able to change configuration between a compact
configuration having a first diameter and an expanded configuration having a
greater
diameter, said stented graft comprising,
at least one stent formed in a generally cylindrical shape having an outer
surface and
a hollow bore extending longitudinally therethrough, said stent being able to
change
configuration between a compact configuration wherein said stent has a first
diameter, and an expanded configuration wherein said stent has a greater
diameter
and a plurality of lateral openings;
and,
a flexible, porous, biocompatible tubular elastomer covering having a first
end, a
second end, an outer surface and a hollow bore that extends longitudinally
therethrough to define an inner surface;
wherein said stent is deployed coaxially within said hollow bore of said
covering such
that said inner surface of said tubular covering is in contact with said outer
surface of
said stent;
said stented graft being further characterized in that said tubular elastomer
covering
is a tubular PTFE covering formed of expanded, sintered PTFE tape, said tape
having been helically wound about the outer surface of said stent to create
said
covering thereon and in that
said stent further comprises a coating comprising a composite of at least one
polymer
and at least one therapeutic substance so as to form a drug eluting stented
graft.
2. The drug eluting stented graft of claim 1, wherein said at least one
polymer is a
biocompatible, pharmaceutically acceptable, bioerodible polymer.
3. The drug eluting stented graft of claim 1, wherein said at least one
polymer is a
polyester.
4. The drug eluting stented graft of claim 1, wherein said at least one
therapeutic
agent is selected from the group consisting of antiplatelet agents,
anticoagulant
agents, antimetabolic agents, vasoactive agents, nitric oxide releasing
agents, anti-

44
inflammatory agents, antiproliferative agents, antisense agents, pro-
endothelial
agents, anti-migratory agents, antimicrobial agents, selective gene delivery
vectors,
sirolimus, actinomycin-D and paclitaxel.
5. The drug eluting stented graft of claim 4, wherein said selective gene
delivery
vectors are Semliki Forest Virus (SMV) adapted to deliver restenosis
preventing
genes.
6. The drug eluting stented graft of claim 1, wherein:
a multiplicity of discrete, closed cells exists within said at least one
polymer, said cells
having a wall formed and defined by said at least one polymer;
said at least one polymer has the formula:
<IMG>
wherein R1 is a member selected from the group of divalent, trivalent and
tetravalent
radicals consisting of alkylene of 1 to 10 carbons; alkenylene of 2 to 10
carbons;
alkyleneoxy of 2 to 6 carbons; cycloalkylene of 3 to 7 carbons; cycloalkylene
of 3 to 7
carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons,
an
alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons; cycloalkenylene
of 4 to
7 carbons; cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to
7
carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an
alkenyl
of 2 to 7 carbons; arylene; and arylene substituted with an alkyl of 1 to 7
carbons, an
alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons; R2 and R3 are
selected
from the group consisting of alkyl of 1 to 7 carbons; alkenyl of 2 to 7
carbons; alkoxy
of 1 to 7 carbons; alkenyloxy of 2 to 7 carbons; alkylene of 2 to 6 carbons;
alkenylene
of 3 to 6 carbons; alkyleneoxy of 2 to 6 carbons; alkenyleneoxy of 3 to 6
carbons;

45
aryloxy; aralkyleneoxy of 8 to 12 carbons; aralkenyleneoxy of 8 to 12 carbons;
oxa;
OR1O with R1 as defined above; a heterocyclic ring of 5 to 8 carbon and oxygen
atoms formed when R2 and R3 are taken together; a heterocyclic ring of 5 to 8
carbon
and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1
to 7
carbons and an alkenyl of 2 to 7 carbons formed when R2 and R3 are taken
together;
a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R2 and
R3
are taken together; a fused polycyclic ring of 8 to 12 carbon and oxygen atoms
substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and
an alkenyl
of 2 to 7 carbons; and wherein at least one of said R2 and R3 is a member
selected
from the group consisting of alkoxy, alkenyloxy and OR1O with R1 as defined
above;
R2 and R3 when taken together are a member selected from the group of
heterocyclic
and fused polycyclic rings having at least one oxygen atom in the ring; and
wherein n
is greater than 10;
wherein said at least one therapeutic substance dissolved in a
pharmaceutically
acceptable carrier that is a solvent for said at least one therapeutic
substance and a
nonsolvent for said at least one polymer is contained within said multiplicity
of
discrete, closed cells;
so that, when in operation, said at least one polymer is capable of bioeroding
at a
controlled and continuous rate over a prolonged period of time, thereby
releasing
said at least one therapeutic substance at a controlled and continuous rate
over a
prolonged period of time.
7. The drug eluting stented graft of claim 1, wherein said stent comprises a
plurality
of elements, wherein each said element comprises an undulating linear shape
formed into a generally cylindrical configuration having a cylinder axis
generally
aligned on the axis of said hollow bore, and wherein each said element is
connected
to an adjacent neighbor element by at least one linear connector.
8. The drug eluting stented graft of claim 7, wherein said plurality of
elements
comprises a spiral.
9. The drug eluting stented graft of claim 7, wherein at least one said
connector is
substantially circumferentially offset from an adjacent neighbor connector.

46
10. The drug eluting stented graft of claim 9, wherein said circumferentially
offset
connectors form a helical array.
11. The drug eluting stented graft of claim 7, wherein at least one said
connector is
not substantially circumferentially offset from an adjacent neighbor
connector.
12. The drug eluting stented graft of claim 7, wherein said undulating linear
shape is
a generally zigzag shape comprising a plurality of zigs having tips and a
plurality of
zags having tips, wherein said tip of each said zig of each element and the
nearest
said tip of each said zig of an adjacent neighbor element generally lie in a
plane
passing through the axis of said hollow bore, and wherein said tip of at least
one said
zig of each element and at least one said nearest said tip of a zig of an
adjacent
neighbor are connected by one said linear connector.
13. The drug eluting stented graft of claim 7, wherein said undulating linear
shape is
a sinusoidal shape having a plurality of peaks and a plurality of valleys,
wherein each
said peak of each element and each said valley of an adjacent neighbor lie
generally
in a common plane passing through the axis of said hollow bore, and wherein at
least
one said peak of each element and said valley of an adjacent neighbor lying
generally in said common plane are connected by one said linear connector.
14. The drug eluting stented graft of claim 7, wherein each said linear
connector has
a length dimension generally parallel to the axis of said hollow bore, and a
width and
depth dimension, and wherein said length dimension is greater than said width
dimension and said length dimension is greater than said depth dimension.
15. The drug eluting stented graft of claim 14, wherein said length dimension
is about
3 to 10 times greater than said width dimension, and said length dimension is
about 3
to 10 times greater than said depth dimension.
16. The drug eluting stented graft according to claim 1, wherein said stent
and said
elastomer are anchored to each other by means for anchoring.
17. The tubular drug eluting stented graft according to claim 16, wherein said
means

47
for anchoring comprise protrusions of said covering that fixedly protrude into
said
lateral openings in said stent.
18. The drug eluting stented graft of claim 1 wherein said tape has a width of
less
than about 1 inch.
19. The drug eluting stented graft of claim 1 wherein said tape has a
thickness of less
than 0.015 inch and wherein said tape is wound about said stent in overlapping
fashion, such that said elastomer covering comprises 1 to 10 layers of said
tape.
20. The drug eluting stented graft of claim 1 wherein said tape has a width of
0.5
inches, and wherein said tape is helically wrapped such that 6-8 revolutions
of tape
are applied per longitudinal inch of said drug eluting stented graft.
21. The drug eluting stented graft of claim 1 wherein said tape is helically
wrapped
alternately in a first direction and then in the opposite direction.
22. The drug eluting stented graft of claim 21 further comprising 8 layers of
said tape.
23. The drug eluting stented graft of claim 1 wherein said stent is a self-
expanding
stent.
24. The drug eluting stented graft of claim 23 wherein said self-expanding
stent
comprises a shape memory alloy that is able to change between a first and a
second
crystalline state, wherein said stent assumes a radially expanded
configuration when
said shape memory alloy is in said first crystalline state, and a radially
compact
configuration when said shape memory alloy is in said second crystalline
state.
25. The drug eluting stented graft of claim 1 wherein said stent is a pressure-
expandable stent.
26. The drug eluting stented graft of claim 1 wherein said stent is formed of
a metal
alloy comprising at least two elements selected from the group consisting of
iron,
cobalt, chromium, nickel, titanium, niobium, and molybdenum.

48
27. The drug eluting stented graft of claim 24 wherein said shape memory alloy
comprises at least about 51% to about 59% nickel and the remainder comprising
titanium.
28. The drug eluting stented graft of claim 24 wherein said shape memory alloy
comprises about 0.25% chromium, at least about 51% to about 59% nickel, and
the
remainder comprising titanium.
29. The drug eluting stented graft of claim 1 wherein said covering has a
thickness of
less than 0.1 inch.
30. The drug eluting stented graft of claim 1 wherein said PTFE tape has a
thickness
of less than 0.015 inches, said tape being wrapped about said stent in
overlapping
fashion so as to form said covering.
31. The drug eluting stented graft of claim 1 wherein said PTFE tape has a
density of
less than 1.6 g/cc.
32. The drug eluting stented graft of claim 1 wherein said covering has a
thickness of
less than 0.1 inch and said PTFE tape has a density of less than 1.6 g/cc.
33. An article of manufacture, comprising packaging material and the drug
eluting
stented graft of claim 1 contained within the packaging material, wherein said
drug
eluting stented graft is effective for implantation in a patient afflicted
with
cardiovascular disease, and the packaging material comprises a label that
indicates
that said device is effective for said implantation.
34. A tubular stented graft which is alternately deployable in a radially
compact
configuration having a first diameter and a radially expanded configuration
having a
second diameter, said stented graft comprising:
a stent comprising:
at least one member formed in a generally cylindrical shape having an outer
surface
and a hollow bore which extends longitudinally therethrough to define an inner

49
surface;
said stent being initially radially collapsible to a diameter which is
substantially equal
to said first diameter of the stented graft, and subsequently radially
expandable to a
diameter which is substantially equal to said second diameter of the stented
graft;
and,
a plurality of lateral openings existing in said stent when said stent is at
its radially
expanded second diameter;
a continuous, tubular PTFE covering formed on said stent, said PTFE covering
comprising:
a tubular inner base graft formed of expanded, sintered PTFE, said tubular
base graft
having an outer surface and an inner surface, said tubular base graft being
deployed
coaxially within the hollow bore of said stent such that the outer surface of
the tubular
base graft is in contact with the inner surface of the stent, and the inner
surface of
said tubular base graft thereby defining a luminal passageway through the
stented
graft; and,
a tubular outer layer formed of expanded, sintered PTFE tape which has a width
of
less than about 1 inch, said tape having been helically wound about the outer
surface
of said stent to create said tubular outer layer thereon, such that said stent
is
captured between said outer layer and said tubular base graft;
said tubular outer layer being attached to said tubular base graft, through
said lateral
openings in said stent, to thereby form an integrally stented, continuous PTFE
tube
which is alternately disposable in said radially compact configuration of said
first
diameter and said radially expanded configuration of said second diameter;
said
stented graft being further characterized in that said stent comprising a
composite of
at least one polymer and at least one therapeutic substance so as to form a
drug
eluting stented graft.
35. The drug eluting stented graft of claim 34, wherein said at least one
polymer is a
biocompatible, pharmaceutically acceptable, bioerodible polymer.
36. The drug eluting stented graft of claim 34, wherein said at least one
polymer is a
polyester.
37. The drug eluting stented graft of claim 34, wherein said at least one
therapeutic

50
agent is selected from the group consisting of antiplatelet agents,
anticoagulant
agents, antimetabolic agents, antisense agents, vasoactive agents, nitric
oxide
releasing agents, anti-inflammatory agents, antiproliferative agents, pro-
endothelial
agents, anti-migratory agents, antimicrobial agents, selective gene delivery
vectors,
sirolimus, actinomycin-D and paclitaxel.
38. The drug eluting stented graft of claim 37, wherein said selective gene
delivery
vectors are Semliki Forest Virus (SMV) adapted to deliver restenosis
preventing
genes.
39. The drug eluting stented graft of claim 34, wherein:
a multiplicity of discrete, closed cells exists within said at least one
polymer, said cells
having a wall formed and defined by said at least one polymer;
said at least one polymer has the formula:
<IMG>
wherein R1 is a member selected from the group of divalent, trivalent and
tetravalent
radicals consisting of alkylene of 1 to 10 carbons; alkenylene of 2 to 10
carbons;
alkyleneoxy of 2 to 6 carbons; cycloalkylene of 3 to 7 carbons; cycloalkylene
of 3 to 7
carbons substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons,
an
alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons; cycloalkenylene
of 4 to
7 carbons; cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to
7
carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an
alkenyl
of 2 to 7 carbons; arylene; and arylene substituted with an alkyl of 1 to 7
carbons, an
alkoxy of 1 to 7 carbons, and an alkenyl of 2 to 7 carbons; R2 and R3 are
selected
from the group consisting of alkyl of 1 to 7 carbons; alkenyl of 2 to 7
carbons; alkoxy

51
of 1 to 7 carbons; alkenyloxy of 2 to 7 carbons; alkylene of 2 to 6 carbons;
alkenylene
of 3 to 6 carbons; alkyleneoxy of 2 to 6 carbons; alkenyleneoxy of 3 to 6
carbons;
aryloxy; aralkyleneoxy of 8 to 12 carbons; aralkenyleneoxy of 8 to 12 carbons;
oxa;
OR1O with R1 as defined above; a heterocyclic ring of 5 to 8 carbon and oxygen
atoms formed when R2 and R3 are taken together; a heterocyclic ring of 5 to 8
carbon
and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1
to 7
carbons and an alkenyl of 2 to 7 carbons formed when R2 and R3 are taken
together;
a fused polycyclic ring of 8 to 12 carbon and oxygen atoms formed when R2 and
R3
are taken together; a fused polycyclic ring of 8 to 12 carbon and oxygen atoms
substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons and
an alkenyl
of 2 to 7 carbons; and wherein at least one of said R2 and R3 is a member
selected
from the group consisting of alkoxy, alkenyloxy and OR1O with R1 as defined
above;
R2 and R3 when taken together are a member selected from the group of
heterocyclic
and fused polycyclic rings having at least one oxygen atom in the ring; and
wherein n
is greater than 10;
wherein said at least one therapeutic substance dissolved in a
pharmaceutically
acceptable carrier that is a solvent for said at least one therapeutic
substance and a
nonsolvent for said at least one polymer is contained within said multiplicity
of
discrete, closed cells;
so that, when in operation, said at least one polymer is capable of bioeroding
at a
controlled and continuous rate over a prolonged period of time, thereby
releasing
said at least one therapeutic substance at a controlled and continuous rate
over a
prolonged period of time.
40.The drug eluting stented graft of claim 34, wherein said stent comprises a
plurality
of elements, wherein each said element comprises an undulating linear shape
formed into a generally cylindrical configuration having a cylinder axis
generally
aligned on the axis of said hollow bore, and wherein each said element is
connected
to an adjacent neighbor element by at least one linear connector.
41.The drug eluting stented graft of claim 40, wherein said plurality of
elements
comprises a spiral.
42.The drug eluting stented graft of claim 40, wherein at least one said
connector is

52
substantially circumferentially offset from an adjacent neighbor connector.
43. The drug eluting stented graft of claim 42, wherein said circumferentially
offset
connectors form a helical array.
44. The drug eluting stented graft of claim 40, wherein at least one said
connector is
not substantially circumferentially offset from an adjacent neighbor
connector.
45. The drug eluting stented graft of claim 40, wherein said undulating linear
shape is
a generally zigzag shape comprising a plurality of zigs having tips and a
plurality of
zags having tips, wherein said tip of each said zig of each element and the
nearest
said tip of each said zig of an adjacent neighbor element generally lie in a
plane
passing through the axis of said hollow bore, and wherein said tip of at least
one said
zig of each element and at least one said nearest said tip of a zig of an
adjacent
neighbor are connected by one said linear connector.
46. The drug eluting stented graft of claim 40, wherein said undulating linear
shape is
a sinusoidal shape having a plurality of peaks and a plurality of valleys,
wherein each
said peak of each element and each said valley of an adjacent neighbor
generally lie
in a plane passing through the axis of said hollow bore, and wherein at least
one said
peak of each element and said valley of an adjacent neighbor lying generally
in said
plane are connected by one said linear connector.
47. The drug eluting stented graft of claim 40, wherein each said linear
connector has
a length dimension generally parallel to the axis of said hollow bore, and a
width and
depth dimension, and wherein said length dimension is greater than said width
dimension and said length dimension is greater than said depth dimension.
48. The drug eluting stented graft of claim 47, wherein said length dimension
is about
3 to 10 times greater than said width dimension, and said length dimension is
about 3
to 10 times greater than said depth dimension.
49.The drug eluting stented graft of claim 34 wherein said tape has a width of
less
than about 1 inch.

53
50. The drug eluting stented graft of claim 34 wherein said tape has a
thickness of
less than 0.015 inch and wherein said tape is wound about said stent in
overlapping
fashion, such that said elastomer covering comprises 1 to 10 layers of said
tape.
51.The drug eluting stented graft of claim 34 wherein said tape has a width of
0.5
inches, and wherein said tape is helically wrapped such that 6-8 revolutions
of tape
are applied per longitudinal inch of said drug eluting stented graft.
52. The drug eluting stented graft of claim 34 wherein said tape is helically
wrapped
alternately in a first direction and then in the opposite direction.
53. The drug eluting stented graft of claim 52 further comprising 8 layers of
said tape.
54.The drug eluting stented graft of claim 34 wherein said stent is a self-
expanding
stent.
55. The drug eluting stented graft of claim 54, wherein said self-expanding
stent
comprises a shape memory alloy that is able change between a first and a
second
crystalline state, wherein said stent assumes a radially expanded
configuration when
said shape memory alloy is in said first crystalline state, and a radially
compact
configuration when said shape memory alloy is in said second crystalline
state.
56.The drug eluting stented graft of claim 34 wherein said stent is a pressure-
expandable stent.
57. The drug eluting stented graft of claim 54 wherein said stent is formed of
a metal
alloy comprising at least two elements selected from the group consisting of
iron,
cobalt, chromium, nickel, titanium, niobium, and molybdenum.
58. The drug eluting stented graft of claim 55 wherein said shape memory alloy
comprises at least about 51% to about 59% nickel and the remainder comprising
titanium.

54
59. The drug eluting stented graft of claim 55 wherein said shape memory alloy
comprises about 0.25% chromium, at least about 51% to about 59% nickel, and
the
remainder comprising titanium.
60.The drug eluting stented graft of claim 34 wherein said covering has a
thickness of
less than 0.1 inch.
61.The drug eluting stented graft of claim 34 wherein said PTFE tape has a
thickness
of less than 0.015 inches, said tape being wrapped about said stent in
overlapping
fashion so as to form said covering.
62. The drug eluting stented graft of claim 34 wherein said PTFE tape has a
density
of less than 1.6 g/cc.
63. The drug eluting stented graft of claim 34 wherein said covering has a
thickness
of less than 0.1 inch and the PTFE tape has a density of less than 1.6 g/cc.
64. An article of manufacture, comprising packaging material and the drug
eluting
stented graft of claim 34 contained within the packaging material, wherein
said drug
eluting stented graft is effective for implantation in a patient afflicted
with
cardiovascular disease, and the packaging material comprises a label that
indicates
that said device is effective for said implantation.

Description

CA 02465517 2010-01-20
1
Drug eluting radially expandable tubular stented grafts
BACKGROUND ART
This invention pertains generally to medical devices and their methods of
manufacture, and more particularly to drug eluting tubular grafts having
radially
expandable stents for implantation in a cavities or passageways (e.g., ducts
or
blood vessels) of the body, wherein the stents have polymer coats that possess
the
capability to release drugs.
A. Stents
The prior art includes a number of radially expandable stents which may be
initially deployed in a radially collapsed state suitable for transluminal
insertion
via a delivery catheter, and subsequently transitioned to a radially expanded
state
whereby the stent will contact and engage the surrounding wall or the
anatomical
duct or body cavity within which the stent has been positioned. Such stents
have
been used to support and maintain the patency of blood vessel lumens (e.g., as
an
adjuvant to balloon angioplasty) and to structurally support and/or anchor
other
apparatus, such as a tubular endovascular grafts, at desired locations within
a body
cavity or passageway. For example, they may be used to anchor a tubular
endovascular graft within a blood vessel such that the graft forms an internal
conduit through an aneurysm or site of traumatic injury to the blood vessel
wall.
Many stents of the prior art have been formed of individual member(s) such as
wire, plastic, metal strips, or mesh that have been bent, woven, interlaced or
otherwise fabricated into a generally cylindrical

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configuration. These stents of the prior art have generally been classified
into two major categories: a) "self-expanding" stents, and b) "pressure
expandable" stents. Some examples of stents of the prior art include those
described in United States Patent Nos. 5,405,377 (Cragg); 5,882,335
(Leone, et al.; 6,017,362 (Lau); 6,066,168 (Lau); 6,086,604 (Fischell et al.)
and 6,117,165 (Becker).
i) Self-expanding Stents
Self-expanding stents are typically formed of spring metal, shape
memory alloy, or other material that is resiliently biased toward its fully
radially expanded configuration or is otherwise capable of self-expanding
to its fully radially expanded configuration without need for the exertion of
outwardly directed radial force upon the stent by an extraneous expansion
apparatus (e.g., a balloon or mechanical expander tool). Such self-
expanding stents may be initially radially compressed and loaded into a
small diameter delivery catheter or alternatively mounted upon the outer
surface of a delivery catheter equipped with a means for restraining or
maintaining the stent in its radially compressed state. Thereafter, the
delivery catheter is inserted into the body and is advanced to a position
wherein the stent is located at or near the site at which it is to be
implanted. Thereafter, the stent is expelled from the delivery catheter and
allowed to self-expand to its full radial diameter. Expansion of the stent
causes the stent to frictionally engage the surrounding wall of the body
cavity or passageway in which it has been positioned. The delivery
catheter is then extracted, leaving the self-expanded stent at its intended
site of implantation. Some examples of self-expanding stents of the prior
art include those described in United States Patent Nos. 4, 655, 771
(Wallsten et al.); 4,954,126 (Wallsten): 5, 061, 275 (Wallsten et al.);

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4,580,568 (Gianturco); 4,830,003 (Wolf et al.); 5,035,706 (Gianturco et al.)
and 5,330,400 (Song).
ii) Pressure-Expandable Stents
Pressure-expandable stents of the prior art are typically formed of
metal wire, metal strips, or other malleable or plastically deformable
material, fabricated into a generally cylindrical configuration. The
pressure-expandable stent is initially disposed in a collapsed configuration
having a diameter that is smaller than the desired final diameter of the
stent when implanted in the blood vessel. The collapsed stent is first
loaded into or mounted upon a small diameter delivery catheter. The
delivery catheter is then advanced to its desired location within the
vasculature, and a balloon or other stent-expansion apparatus (which may
be formed integrally of or incorporated into the delivery catheter) is
utilized
to exert outward radial force on the stent, thereby radially expanding and
plastically deforming the stent to its intended operative diameter whereby
the stent frictionally engages the surrounding blood vessel wall. The
material of the stent undergoes plastic deformation during the pressure-
expansion process. Such plastic deformation of the stent material causes
the stent to remain in its radially expanded operative configuration. The
balloon or other expansion apparatus is then deflated/collapsed and is
withdrawn from the body separately from, or as part of, the delivery
catheter, leaving the pressure-expanded stent at its intended site of
implantation.
Some examples of pressure-expandable stents of the prior art
include those described in United States Patent Nos. 5,135,536 (Hillstead);
5,161,547 (Tower); 5,292,331 (Boneau); 5,304,200 (Spaulding) and
4,733,665 (Palmaz).

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iv. Drug eluting stents
In spite of the availability of the various stents of the prior art, a
continuing need in the stented graft art is for a stented graft capable of
providing drug therapy after implantation. The specific drug needed by
patients who are being treated by the implantation of stented grafts varies
with the type of pathology being treated-for example, whether
cardiovascular, hepatic, or gastrointestinal. In the case of cardiovascular
pathologies, it is pertinent that restenosis is observed in up to 50% of
patients involved in angioplasty procedures. Restenosis refers to the
reclosure of vessels by cellular or other invasion following vessel-clearing
procedures. Restenosis is actually a natural healing process involving
elements of the clotting cascade and later uncontrolled migration and
proliferation of smooth muscle cells (SMC). The ultimate result is stenosis
of the vessel-a return to the condition for which the treatment was
initiated. Such cellular invasion is also a major problem in hepatic stenting
procedures.
One of the original reasons for the use of stents in angioplasty was
to minimize the impact of restenosis. Disappointingly, stents have been
found not only to cause undesirable local thrombosis, but also to be
ineffective in countering the effects of SMC migration and consequent
restenosis. The consensus of medical opinion as of late 2001 is that it is
unlikely that a single physiological process is responsible for restenosis,
and thus it may be necessary to have different approaches for different
clinical scenarios.
To address the restenosis problem, it has been proposed to provide
therapeutic substances to the vascular wall. Although this could be done
by means of systemic administration, for example orally or by injection, this
route of administration subjects the patient to the general systemic effects
of the drug. Such general systemic effects would include the possibility of

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systemic toxicity. By contrast, it has been proposed to administer the
drugs locally by means of drug eluting stents. Here, ideally only the
specific vasculature at issue would be affected by the action of the drug,
whereas the general tissues of the patient would only be subjected to
5 extremely small doses of the drug. Pertinent therapeutic substances
include antiplatelet agents, anticoagulant agents, antimetabolic agents,
vasoactive agents such as nitric oxide releasing agents, anti-inflammatory,
anti proliferative, pro-endothelial, antisense and anti-migratory agents, all
of which are embodied in the present invention. The administration of
these agents, as well as antimicrobial agents to counter the possibility of
infection is therefore of major interest in the stent and stented graft art.
Among further pharmacological agents that are of interest in the
general connection discussed above is sirolimus, also known as
rapamycin, an immunosuppressive and antiproliferative compound.
Sirolimus is a macrocyclic lactone produced by Streptomyces
hygroscopicus and has the molecular weight 914.2. Although early studies
with sirolimus coated stents have been promising with regard to the
reduction of restenosis, concerns remain in the medical community
regarding drug dosing levels, the need for predictable drug deposition, and
asymmetrical stent expansion that could lead to some spots getting a
much higher concentration of drug than other spots. Furthermore, in the
long-term, there is also the potential risk for stent malopposition, or that
the
pharmaceutical agent is merely delaying the effect of restenosis, that could
eventually manifest itself. These issues will of course ultimately be
examined by the use of suitable clinical tests.
Another drug of special interest in connection with stents is
paclitaxel. Paclitaxel is a natural product that blocks vital mitotic cellular
functions, and hence cellular proliferation. Paclitaxel has a molecular
weight of 853.9. In a preliminary study, researchers at three German

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hospitals covered stents with low doses of paclitaxel designed to elute the
drug for
28 days. During a six-month test period, no patient using a paclitaxel treated
stent
exhibited restenosis, whereas 11% of control patients exhibited restenosis.
One problem that has been associated with certain drug eluting stents is the
development of an "edge effect" at the edges of the stents after placement.
The
"edge effect" comprises such phenomena as lumen reduction, neointimal
proliferation inside the stented segment, plaque proliferation, and remodeling
at
the proximal and distal edges of the stent. By the use of the drug eluting
radially
expanded tubular stented grafts of the present invention the edge effect is
drastically reduced or eliminated.
This invention generally embraces drug eluting stented grafts wherein the drug
eluting capability is provided by a composite of drug material and a
bioerodible
polymer. A feature of the invention is the discovery of a particularly useful
group
of bioerodible polymers for this purpose. These polymers are fully described
In
U.S. Pat. No. 4,131,648 by Nam S. Choi and Jorge Heller, issued Dec. 26, 1978,
assigned to Alza Corporation, and entitled "Structured Orthoester and
Orthocarbonate Drug Delivery Devices. The patent discloses a class of polymers
comprising a polymeric backbone having a repeating unit comprising
hydrocarbon radicals and a symmetrical dioxycarbon unit with a multiplicity of
organic groups bonded thereto. The polymers prepared by the invention have a
controlled degree of hydrophobicity with a corresponding controlled degree of
erosion in an aqueous or like environment to innocuous products. The polymers
can be fabricated into coatings for releasing a beneficial agent, as the
polymers
erode at a controlled rate, and thus can be used as carriers for drugs for
releasing

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drug at a controlled rate to a drug receptor, especially where bioerosion
is desired.
v. Endovascular brachytherapy stents
A further approach to reduce restenosis after percutaneous
coronary intervention is intravascular brachytherapy (VBT) which involves
irradiation of the vasculature by an endovascular source such as a stent.
Radiation sources for this purpose include palladium-103 (103Pd), a low
energy photon emitter. Other brachytherapy sources include 1921r, 32P, and
188Re. Sr/Y90 source trains have also been employed. The present
invention provides a solution to the long-standing need for a stent for VBT.
vi. Gene therapy
Recombinant Semliki Forest Virus (SFV) selectively transfers genes
into cultured vascular smooth muscle cells leaving endothelial cells
unaffected. Thus, SFV can function as a selective vector for balloon-
injured vessels and can provide a pathway to deliver genes for the
purpose of preventing restenosis. The administration of selective vectors
such as SFV through stented graft delivery is therefore a further benefit of
the present invention.
B. Elastomer Vascular Grafts
Elastomers, including fluoropolymers such as
polytetrafluoroethylene, have been heretofore used for the manufacture of
various types of prosthetic vascular grafts. These vascular grafts are
typically of tubular configuration so as to be useable to replace an excised
segment of blood vessel.
The tubular elastomer vascular grafts of the prior art have
traditionally been implanted, by open surgical techniques, whereby a

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diseased or damaged segment of blood vessel is surgically excised and
removed, and the tubular bioprosthetic graft is then anastomosed into the
host blood vessel as a replacement for the previously removed segment
thereof. Alternatively, such tubular prosthetic vascular grafts have also
been used as bypass grafts wherein opposite ends of the graft are sutured
to a host blood vessel so as to form a bypass conduit around a diseased,
injured or occluded segment of the host vessel.
In general, many tubular prosthetic vascular grafts of the prior art
have been formed of extruded, porous PTFE tubes. In some of the tubular
grafts of the prior art, a PTFE tape is wrapped about and laminated to the
outer surface of a tubular base graft to provide reinforcement and
additional burst strength. Also, some of the prior tubular prosthetic
vascular grafts have included external support member(s), such as a
PTFE beading, bonded or laminated to the outer surface of the tubular
graft to prevent the graft from becoming compressed or kinked during
implantation. These externally supported tubular vascular grafts have
proven to be particularly useful for replacing segments of blood vessel
which pass through, or over, joints or other regions of the body which
undergo frequent articulation or movement.
One commercially available, externally-supported, tubular vascular
graft is formed of a PTFE tube having a PTFE filament helically wrapped
around, and bonded to, the outer surface of the PTFE tube. (IMPRA FlexTM
Graft, IMPRA, Inc., Tempe, AZ)
One other commercially available, externally-supported, tubular
vascular graft comprises a regular walled, PTFE tube which has PTFE
reinforcement tape helically wrapped around, and bonded to, the outer
surface of the PTFE tube and individual rings of Fluorinated Ethylene
Propylene (FEP) rings disposed around, and bonded to, the outer surface

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of the reinforcement tape. (FEP ringed ePTFE vascular graft, W.L. Gore &
Associates, Inc., Flagstaff, AZ)
C. Stented Grafts
The prior art has also included a number of "stented grafts". These
stented grafts typically comprise a self-expanding or pressure-expandable
stent that is affixed to or formed within a pliable tubular graft. Because of
their radial compressibility/expandability, these stented grafts are
particularly useable in applications wherein it is desired to insert the graft
into an anatomical passageway (e.g., blood vessel) while the graft is in a
radially compact state, and to subsequently expand and anchor the graft to
the surrounding wall of the anatomical passageway. More recently,
methods have been developed for introducing and implanting tubular
prosthetic vascular grafts within the lumen of a blood vessel, by
percutaneous or minimal incision means. Such endovascular implantation
initially involves transluminal delivery of the graft, in a compacted state,
by
way of a catheter or other transluminally advancable delivery apparatus.
Thereafter, the graft is radially expanded and anchored to the surrounding
blood vessel wall, thereby holding the graft at its intended site of
implantation within the host blood vessel. An affixation apparatus such as
a stent may be utilized to anchor at least the opposite ends of the tubular
graft to the surrounding blood vessel wall. One particular application for
endovascular grafts of this type is in the treatment of vascular aneurysms
without requiring open surgical access and resection of the aneurysmic
blood vessel. Also, such stented grafts may also be useable to treat
occlusive vascular disease--especially in cases where the stented graft is
constructed in such a manner that the tubular graft material forms a
complete barrier between the stent and the blood that is flowing through
the blood vessel. In this manner the tubular graft material may serve as a

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smooth, biologically compatible, inner "covering" for the stent, thereby
preventing a) turbulent blood-flow as the blood flows over the wire
members or other structural material of which the stent is formed, b)
immunologic reaction to the metal or other material of which the stent is
5 formed, and c) a barrier to separate a diseased or damaged segment of
blood vessel from the blood-flow passing therethrough. Such prevention
of turbulent blood-flow and/or immunologic reaction to the stent material is
believed to be desirable as both of these phenomena are believed to be
associated with thrombus formation and/or restenosis of the blood vessel.
10 Other uses for stented grafts may include restoring patency to, or re-
canalizing, other anatomical passageways such as ducts of the biliary
tract, digestive tract and/or genitourinary tract.
A number of specific desiderata are of special importance with
regard to the suitability of particular expandable stent designs for
incorporation into a drug eluting stented graft. Among these are high
flexibility, high hoop strength of the stent in its expanded form, minimal
foreshortening of the stent in the course of its transition from a
compressed state to an expanded state, and minimal "dog bone effect."
High flexibility is necessary in order for the drug eluting stented graft to
be
smoothly inserted into regions of convolution. High hoop strength is
necessary in order that the stent will fulfill its primary function of holding
a
lumen open. Minimal foreshortening is necessary to avoid excessive
puckering, wrinkling or invagination of the elastomer graft material during
expansion of the stent from its compressed state to its expanded state.
The "dog bone effect" is the tendency of the ends of a stent to expand
before the middle portion expands. This results in a "bone-shaped"
structure in which the ends of the stent have expanded more than the
middle portions. In addition to other undesirable characteristics of this
expansion mode, excessive foreshortening accompanies "dog-boning."

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Thus there remains a need for improved drug eluting stented grafts having high
flexibility, high hoop strength of the stent in its expanded form, minimal
foreshortening of the stent in the course of its transition from a compressed
state
to an expanded state, and minimal "dog bone effect."
Variations on the known medical use of stented grafts adapted for drug elution
have not been forthcoming, despite recent developments in the technology
related
to stent technology. Even though stented grafts are used extensively in
medical
practice, prior devices, products, or methods available to medical
practitioners
have not adequately addressed the need for advanced methods and apparatus for
minimizing the deficiencies in drug elution as set forth above.
The present invention embraces and finally addresses the clear need for
advanced
methods and apparatus for solving the long-standing needs in drug eluting
stents
as set forth above. Thus, as pioneers and innovators attempt to make methods
and
apparatus for stented grafts cheaper, more universally used, and of higher
quality,
none has approached the desiderata outlined above in combination with
simplicity
and reliability of operation, until the teachings of the present invention. It
is
respectfully submitted that other references merely define the state of the
art or
show the type of systems that have been used to alternately address those
issues
ameliorated by the teachings of the present invention. Accordingly, further
discussions of these references has been omitted at this time due to the fact
that
they are readily distinguishable from the instant teachings to one of skill in
the art.

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OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide a drug eluting
stented graft of high flexibility. It is another object of the present
invention to provide a drug eluting stented graft of high hoop strength of
the stent in its expanded form. It is still another object of the present
invention to provide a drug eluting stented graft having minimal
foreshortening of the stent in the course of its transition from a
compressed state to an expanded state. It is yet still another object of
the present invention to provide a drug eluting stented graft having
minimal "dog bone effect" in the course of its transition from a
compressed state to an expanded state. It is even yet still another object
of the present invention to provide a drug eluting stented graft having
minimal puckering, wrinkling or invagination of the elastomer graft
material during expansion of the stent from its compressed state to its
expanded state. It is a further object of the present invention to provide a
drug eluting stented graft that can be smoothly inserted into regions of
convolution. It is yet a further object of the present invention to provide a
means to administer drugs locally by means of drug eluting stented grafts.
It is yet still a further object of the present invention to administer
antiplatelet agents, anticoagulant agents, antimetabolic agents, vasoactive
agents such as nitric oxide releasing agents, anti-inflammatory,
antiproliferative, pro-endothelial, anti-migratory agents, and antimicrobial
agents by means of drug eluting stented grafts. It is even still a further
object of the present invention to provide a drug eluting stented graft that
can provide sirolimus or paclitaxil to a local area. It is even yet still a
further object of the present invention to provide a drug eluting stented
graft whereby drug delivery is regulated both by a drug delivery coating on
a stent and the porosity of the polymer comprising the stented graft.

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These and other objects are accomplished by the parts,
constructions, arrangements, combinations and subcombinations
comprising the present invention, the nature of which is set forth in the
following general statement, and preferred embodiments of which -
illustrative of the best modes in which applicant has contemplated
applying the principles - are set forth in the following description and
illustrated in the accompanying drawings, and are particularly and
distinctly pointed out and set forth in the appended claims forming a part
hereof.
The present invention is directed to improved tubular drug eluting
stented grafts and their methods of manufacture. The present invention
may exist in numerous embodiments, including those wherein the stent
component of the graft is formed integrally within the tubular graft or
wherein it is situated on the inner surface of the tubular graft.
Embodiments of the invention may be self-expanding, incorporating a self-
expanding stent, or pressure-expandable, incorporating a pressure-
expandable stent.
In accordance with one embodiment of the invention, there is
provided an improved integrally drug eluting stented elastomer graft which
comprises a tubular base graft, a radially expandable stent surrounding the
outer surface of the tubular base graft, and an outer elastomer layer. The
tubular outer layer is fused to the tubular base graft through lateral
openings or perforations formed in the stent. A drug delivery coating is
disposed on the stent.
In accordance with another embodiment of the invention, there is
provided an improved internally drug eluting stented, tubular elastomer
graft which comprises a radially compressible/expandable stent having a
elastomer tube coaxially disposed outside of the stent, with the inner

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surface of the tubular elastomer graft being fused or attached to the stent.
A drug delivery coating is applied to or formed on the stent.
The invention may be manufactured by a method which comprises
the steps of: a) initially positioning a generally cylindrical stent of either
the
self-expanding or pressure-expandable variety in contacting coaxial
relation with the tubular base graft and/or the tubular outer layer, upon a
cylindrical mandrel or other suitable support surface, and b) subsequently
fusing (i.e., heating to a lamination temperature) the assembled
components (i.e., the stent in combination with the inner base graft and/or
outer tubular layer) of the drug eluting stented graft into a unitary drug
eluting stented graft structure. Heating is accomplished using a "waffle-
iron" heater wherein heat is applied only to areas that correspond to the
spaces not occupied by the stent. The purpose of the "waffle-iron" heater
is to avoid heating the drug covering the stent to its decomposition
temperature. Such heating will cause the outer layer to heat fuse to the
inner base graft through the openings that exist in the stent. An alternative
to the "waffle-iron" heater is to use a laser beam controlled by a computer
to "hit" only the areas corresponding to the openings that exist in the stent.
Computer controlled laser beams to accomplish such a purpose are
known in the art. In integrally drug eluting stented embodiments where
both the tubular base graft and the tubular outer layer are present, such
heating will additionally cause the tubular outer layer to fuse to the inner
tubular base graft, through lateral openings or perforations which exist in
the stent.
By the above-described materials and methods of construction, the
drug eluting stented elastomer grafts of the present invention are capable
of radially expanding and contracting without excessive puckering,
wrinkling or invagination of the graft material. Furthermore, in
embodiments wherein the stent is constructed of individual members

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which move or reposition relative to one another during respective
5 expansion and contraction of the drug eluting stented graft, the
manufacturing methods and materials of the present invention render the
elastomer sufficiently strong and sufficiently firmly laminated or fused so as
to permit such relative movement of the individual members of the stent
without tearing or rupturing of the tubular graft.
10 In particular, the present invention relates to a stented graft that is
able
to change configuration between a compact configuration having a first
diameter and an expanded configuration having a greater diameter, said
stented graft comprising,
at least one stent formed in a generally cylindrical shape having an
15 outer surface and a hollow bore extending longitudinally therethrough, said
stent being able to change configuration between a compact configuration
wherein said stent has a first diameter, and an expanded configuration
wherein said stent has a greater diameter and a plurality of lateral openings;
and,
a flexible, porous, biocompatible tubular elastomer covering having a
first end, a second end, an outer surface and a hollow bore that extends
longitudinally there through to define an inner surface;
wherein said stent is deployed coaxially within said hollow bore of said
covering such that said inner surface of said tubular covering is in contact
with said outer surface of said stent;
said stented graft being further characterized in that said tubular elastomer
covering is a tubular PTFE covering formed of expanded, sintered PTFE
tape, said tape having been helically wound about the outer surface of said
stent to create said covering thereon and in that
said stent further comprises a coating comprising a composite of at least one
polymer and at least one therapeutic substance so as to form a drug eluting
stented graft.
The present invention further relates to a tubular stented graft which is

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15a
alternately deployable in a radially compact configuration having a first
diameter and a radially expanded configuration having a second diameter,
said stented graft comprising:
a stent comprising:
at least one member formed in a generally cylindrical shape having an outer
surface and a hollow bore which extends longitudinally therethrough to define
an inner surface;
said stent being initially radially collapsible to a diameter which is
substantially equal to said first diameter of the stented graft, and
subsequently radially expandable to a diameter which is substantially equal
to said second diameter of the stented graft; and,
a plurality of lateral openings existing in said stent when said stent is at
its
radially expanded second diameter;
a continuous, tubular PTFE covering formed on said stent, said PTFE
covering comprising:
a tubular inner base graft formed of expanded, sintered PTFE, said tubular
base graft having an outer surface and an inner surface, said tubular base
graft being deployed coaxially within the hollow bore of said stent such that
the outer surface of the tubular base graft is in contact with the inner
surface
of the stent, and the inner surface of said tubular base graft thereby
defining
a luminal passageway through the stented graft; and,
a tubular outer layer formed of expanded, sintered PTFE tape which has a
width of less than about 1 inch, said tape having been helically wound about
the outer surface of said stent to create said tubular outer layer thereon,
such
that said stent is captured between said outer layer and said tubular base
graft;
said tubular outer layer being attached to said tubular base graft, through
said lateral openings in said stent, to thereby form an integrally stented,
continuous PTFE tube which is alternately disposable in said radially
compact configuration of said first diameter and said radially expanded
configuration of said second diameter; said stented graft being further
characterized in that said stent comprising a composite of at least one

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15b
polymer and at least one therapeutic substance so as to form a drug eluting
stented graft.
Further objects and advantages of the invention will become
apparent to those skilled in the art upon reading and understanding the
following detailed description and the accompanying drawings.
BRIEF EXPLANATION OF THE DRAWINGS
Figure 1 is a perspective view of a drug eluting radially expandable tubular
stented graft of the present invention, wherein a portion of the graft has
been
inserted into a tubular catheter.
Figure la is an enlarged perspective view of a segment of Figure 1.
Figure 2 is an enlarged, cut-away, elevational view of a drug eluting
radially expandable tubular stented graft of the present invention.
Figure 3a is an enlarged perspective view of a portion of the drug eluting
radially expandable stent of the present invention incorporated in the graft
of
Figure 2.
Figure 3b is an enlarged cross-sectional view through line 3b-3d of Figure
3a.
Figures 4a-4f are a step-by-step illustration of a preferred method for
manufacturing a drug eluting radially expandable tubular stented graft of the
present invention.
Figure 5 is a schematic illustration of an alternative electron beam
deposition method which is usable for depositing a coat comprising a
composite of at least one polymer and at least one therapeutic

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substance on the drug eluting radially expandable stent of the present
invention.
Figure 6 is a schematic diagram of a "waffle iron" heating
apparatus which is useable in the manufacture of a drug eluting radially
expandable stent of the present invention.
Figure 7 is a perspective view of a section of a drug eluting radially
expandable stent of the present invention that illustrates portions of three
elements each comprising an undulating zigzag shape.
Figure 7a is an enlarged longitudinal sectional view of a drug
eluting radially expandable stent of the invention shown in Fig. 7 taken
along section line 7a therein.
Figure 8 is a perspective view of a section of a drug eluting radially
expandable stent of the invention that illustrates portions of two elements
each comprising an undulating sinusoidal shape.
Figure 8a is an enlarged longitudinal sectional view of a drug
eluting radially expandable stent of the invention shown in Fig. 8 taken
along section line 8a therein.
Figure 9 is an enlarged, cut-away, elevational view of a drug eluting
radially expandable tubular stented graft of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following detailed description is provided for the purpose of
describing and illustrating presently preferred embodiments of the
invention only, and is not intended to exhaustively describe all possible
embodiments in which the invention may be practiced.
The drug delivery polymers in the drug delivery stents of the
invention can be used as a single film or in a number of layers made of
the same or of different polymers. They have a controlled degree of
hydrophobicity in the environment of use and they erode into innocuous

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products at a continuous rate which exhibits no known deleterious
effects on the environment or towards an animal body.
The term "hydrophobicity" as used above and in the remainder of
the specification broadly refers to the property of the polymers not to
absorb appreciable amounts of water. The terms "erodible" and
"bioerodible" as used herein define the property of the polymers to break
down as a unit structure or entity in a non-biological or in a biological
environment over a period of time to innocuous products. The terms
"erosion", "bioerode" and "bioerosion" generally define the method and
environment where breakdown or degradation of the polymer occurs.
The phrase "prolonged period of time" as used herein, generally means
the period between the start of erosion or the breakdown of the polymers
when the polymers are placed in a moisture laden environment and that
period in time when the polymer is gone. Depending upon the structure
and dimensions of the stented graft, such as number of layers and
thickness, the period may continue over days, several months such as
ninety days, one hundred and eighty days, a year or longer. The
environment includes aqueous and aqueous-like biological
environments.
The term "therapeutic agent" as used in the specification and
accompanying claims includes any compound, mixture of compounds, or
composition of matter consisting of a compound and a carrier, which
when released from a stented graft produces a beneficial and useful
result. The drugs that may be administered include inorganic and
organic drugs without limitation. The agents or drugs also can be in
various forms, such as uncharged molecules, components of molecular
complexes, pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate,
acetate, maleate, tartrate, oleate, and salicylate. For acidic drugs, salts

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of metals, amines, or organic cations, for example quaternary
ammonium can be employed. Furthermore, simple derivatives of drugs
such as esters, ethers, and amides that have solubility characteristics
that are suitable for the purpose of the invention can be employed.
Also, an agent or drug that is water insoluble can be used in a form that
is a water soluble derivative thereof to effectively serve as a solute, and
on its release from the device, is converted by enzymes,
hydrolyzed by body pH, or metabolic processes to the original form or to
a biologically active form. Additionally, agents or drug formulations
within the devices can have various art known forms such as solutions,
dispersions, pastes, particles, granules, emulsions, suspensions and
powders.
The drug eluting stented grafts of the present invention utilize
bioerodible, agent-release, rate controlling materials that bioerode at
a controlled and continuous rate concurrently with the release of agent
at a corresponding controlled and continuous rate. Devices made with
the present bioerodible polymers are reliable and easy to use for
releasing an agent as they normally require intervention or handling only
at the time when the device is positioned in the patient. Additionally, the
devices can be made to release an agent at a zero rate or at a variable
rate by controlling the molecular weight and composition of the polymer,
by controlling the concentration of the agent in the polymer and the
surface area exposed, and by making the devices with different drug
delivery polymers that undergo bioerosion and agent release at different
rates, or by fabricating the polymer coated stents integrally into stented
grafts wherein the graft polymer controls drug release.
The polymers comprising a carbon-oxygen backbone having a
dioxycarbon moiety with a plurality of organic groups pendant from the

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dioxycarbon. The bioerodible polymers are represented by the following
general formula:
1 RI-O-C-O
R2 R3
WHEREIN R, is a di, tri or tetravalent alkylene, alkenylene, alkyleneoxy,
cycloalkylene, cycloalkylene substituted with an alkyl, alkoxy or alkenyl,
cycloalkenylene, cycloalkenylene substituted with an alkyl, alkoxy or
alkenyl, arylene, or a arylene substituted with an alkyl, alkoxy or alkenyl,
R2 and R3 are alkyl, alkenyl, alkoxy, alkenyloxy, alkylene, alkenylene,
alkyleneoxy, alkenyleneoxy, alkylenedioxy, alkenylenedioxy, aryloxy,
aralkyleneoxy, aralkenyleneoxy, aralkylenedioxy, aralkenylenedioxy,
oxa, or OR1O with R1 defined as above; and wherein, (a) R1 is divalent
when R2 and R3 are alkyl,
alkenyl, alkoxy, or alkenyloxy, with at least one of R2 and R3 an alkoxy or
alkenyloxy; (b) R1 is divalent when R2 and R3 are intramolecularly
covalently bonded to each other and to the same dioxycarbon atom to
form a heterocyclic ring or a heterocyclic ring substituted with an alkyl,
alkoxy or alkenyl when R2 is an alkyleneoxy or alkenyleneoxy and R3 is
an alkyleneoxy, alkenyleneoxy
or alkylene; (c) R1 is divalent when R2 and R3 are intramolecularly
covalently bonded to each other and to the same dioxy carbon atom to

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form a fused polycyclic ring or a fused polycyclic ring substituted with an
alkyl, alkoxy or alkenyl when R2 is an oxa, alkyleneoxy or alkenyleneoxy
and R3 is aryloxy, aralkyleneoxy, aralkenyleneoxy or aralkylene; (d) Ri is
divalent when R2 or R3 is an OR1O bridge between polymer backbones
5 bonded through their dioxycarbon moieties, and the other R2 or R3 is an
alkyl, alkenyl, alkyloxy, or alkenyloxy; (e) R1 is tri or tetravalent when R2
and R3 are covalently bonded to each other and to the same
dioxycarbon atom to form a heterocyclic ring or a heterocyclic ring
substituted with an alkyl, alkoxy or alkenyl when R2 is an alkyleneoxy or
10 alkenyleneoxy and R3 is an alkyleneoxy, alkenyleneoxy or alkylene; (f)
R, is tri or tetravalent when R2 and R3 are covalently bonded to each
other and to the same dioxy carbon atom to form a fused polycyclic ring
or fused polycyclic ring substituted with an alkyl, alkoxy or alkenyl when
R2 is an oxa, alkyleneoxy or
15 alkenyleneoxy and R3 is aryloxy, aralkyleneoxy, aralkenyleneoxy or
aralkylene.
The polymers include homopolymers, copolymers of the random
and block types formed by reacting monomers or mixtures of preformed
homopolymers and/or copolymers, branched polymers and
20 cross-linked polymers. Thermoplastic linear polymers are afforded when
R, is divalent, R2 and R3 are substituted with a noncross-linking group or
are bonded
intramolecularly; thermosetting cross-linked polymers are produced
when R, is
divalent and R2 and R3 is intermolecularly bonded between different
polymeric backbones; and, thermosetting cross-linked polymers result
when R1 is tri or tetravalent and R2 and R3 are substituted with noncross-
linking groups, or bonded intramolecularly.

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21
A typical drug eluting radially expandable tubular stented graft
having a stent coated with a polymer having an erosion rate of about 2 p
per hour in a biological aqueous environment with a physiological pH of
6 to 8 and a drug concentration of 5% can be prepared as follows: To
2.375 g of poly(2,2-dioxo-trans-l,4-cyclohexane dimethylene
tetrahydrofuran) was added 0.125 g of hydrocortisone and the
ingredients heated to 1500 C. to give a melt. The drug was dispersed
throughout the melt by mixing the ingredients for 5 minutes to give a
good dispersion. The mixing was performed in a dry, inert environment,
at atmospheric pressure, and with dry equipment. A stent was dipped
into the molten polymer and withdrawn in order to coat the stent. After
cooling, the stent was fabricated into a stented graft. The graft, was
placed in a biological aqueous environment where the coat bioeroded
and released steroid for the potential management of inflammation.
A. The Structure of an Integrally Drug eluting stented PTFE Graft
With reference to Figures 1-3b, there is shown a drug eluting
radially expandable tubular stented graft 10 of the present invention.
Graft 10 comprises a tubular base graft 12, a stent 14 coated with a coat
comprising a composite of at least one polymer and at least one
therapeutic substance, and an outer layer of elastomer 16. Stent 14 is
formed of metal, such as an alloy of cobalt, chromium, nickel or
molybdenum, wherein the alloying residue is iron. One specific example
of a commercially available alloy which may is usable to form the wires
18 of the stent 14 is Elgiloy (The Elgiloy Company, 1565 Fleetwood
Drive, Elgin, IL 60120. Stent 14 may be radially compressed to a
smaller diameter D, and radial constraint, as may be applied by the
surrounding wall of the tubular delivery catheter 22 shown in Figure 1,
may be applied to hold the stent 14 in such radially compressed state

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(diameter Di). Thereafter, when the radial constraint is removed from the
stent 14, the stent 14 will resiliently spring back to its radially expanded
diameter D2. Stent 14 may be a shape memory alloy that can alternately
exist in a first and a second crystalline state, or it may be a pressure-
expandable stent. Stent 14 may be formed of a metal alloy comprising
at least two elements selected from the group consisting of iron, cobalt,
chromium, nickel, titanium, niobium, and molybdenum. For example, the
alloy may comprise at least about 51 % to about 59% nickel and the
remainder comprising titanium. Alternatively, it may comprise about
0.25% chromium, at least about 51 % to about 59% nickel, and the
remainder comprising titanium.
B. Preparation of the PTFE Tubular Base Graft
i.) Preparation of Paste
The manufacture of tubular base graft 12 begins with the step of
preparing a PTFE paste dispersion for subsequent extrusion. This PTFE
paste dispersion may be prepared by known methodology whereby a fine,
virgin PTFE powder (e.g., F-104 or F-103 Virgin PTFE Fine Powder, Dakin
America, 20 Olympic Drive, Orangebury, NY 10962) is blended with a
liquid lubricant, such as odorless mineral spirits (e.g., Isopar , Exxon
Chemical Company, Houston, TX 77253-3272), to form a PTFE paste of
the desired consistency.
ii.) Extrusion of Tube
The PTFE-lubricant blend dispersion is subsequently passed
through a tubular extrusion dye to form a tubular extrudate.
iii.) Drying
The wet tubular extrudate is then subjected to a drying step
whereby the liquid lubricant is removed. This drying step may be
accomplished at room temperature or by placing the wet tubular extrudate

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in an oven maintained at an elevated temperature at or near the lubricant's
dry point for a sufficient period of time to result in evaporation of
substantially all of the liquid lubricant.
iv.) Expansion
Thereafter, the dried tubular extrudate is longitudinally expanded or
longitudinally drawn at a temperature less than 327 C and typically in the
range of 250-326 C. This longitudinal expansion of the extrudate may be
accomplished through the use of known methodology, and may be
implemented by the use of a batch expander. Typically, the tubular
extrudate is longitudinally expanded by an expansion ratio of more than
two to one (2:1) (i.e., at least two (2) times its original length).
v.) Sintering
After the longitudinal expansion step has been completed, the
expanded PTFE tube is subjected to a sintering step whereby it is heated
to a temperature above the sintering temperature of PTFE (i.e., 350-
370 C) to effect amorphous-locking of the PTFE polymer. The
methodology used to effect the sintering step, and the devices used to
implement such methodology, are known in the art. The PTFE tape 16
may be manufactured by any suitable method, including the general
method for manufacturing expanded PTFE tape.
C. Coating of Stent 14
Prior to assembly of the components of graft 10, stent 14 is coated
with a coating 20 comprising a composite of at least one polymer and at
least one therapeutic substance. For example, it may be coated with a
polymer having an erosion rate of about 2 p per hour in a biological
aqueous environment with a physiological pH of 6 to 8 and a drug
concentration of 5% prepared as follows: To 2.375 g of poly(2,2-dioxo-

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24
trans-1,4-cyclohexane dimethylene tetrahydrofuran) was added 0.125 g
of hydrocortisone and the ingredients heated to 150 C. to give a melt.
The drug was dispersed throughout the melt by mixing the ingredients
for 5 minutes to give a good dispersion. The mixing was performed in a
dry, inert environment, at atmospheric pressure, and with dry equipment.
The manner in which such coating of stent 14 may be carried out is
illustrated in Figure 4a. As shown in Figure 4a, stent 14 may be immersed
in a vessel 30 into the molten polymer 32 and withdrawn in order to coat
the stent. The time in which stent 14 must remain immersed in liquid 32
varies depending on the construction of stent 14 and the chemical
composition of liquid 32. However, in most cases, an immersion time of
10-15 seconds will be sufficient to obtain uniform deposition of the coating
on the wire members 18 of stent 14 (Fig. 3b). After stent 14 has been
removed from liquid 32, it will be permitted to air dry such that a dry
15 coating 20 remains deposited upon the outer surface of each wire 18 of
stent 14.
Optionally, after the air drying has been completed, coated stent 14
may be subjected to electron beam deposition, as illustrated in Figure 5, to
enhance the bonding of coating 20 to wire members 18 of stent 14. In
20 accordance with this alternative deposition method, stent 14 is positioned
within a closed vacuum chamber 36 wherein a mass comprising a
composite of at least one polymer and at least one therapeutic
substance 38 is located. An electron beam apparatus 40 is then utilized to
project electron beam radiation onto mass 38 within the chamber 36 so as
to cause sublimation of mass 38 and resultant deposition of layer 20 on
the outer surface of stent 14. The apparatus and specific methodology
useable to perform this electron beam deposition of coating 20 are well
known to those of skill in the relevant art.

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D. Assembly and Construction of the Integrally Drug eluting
stented PTFE Graft
Figures 4b-4f show, in step-wise fashion, the preferred method for
assembling and constructing graft 10.
5 As shown in Figure 4b, tubular base graft 12 is initially disposed on
a rod or mandrel 50. Mandrel 50 may comprise a stainless steel rod
having an outer diameter that is only slightly smaller than the inner
diameter of graft 12. In this manner, graft 12 may be slidably advanced
onto the outer surface of mandrel 50 without undue effort or damage.
10 Thereafter, coated stent 14 is axially advanced onto the outer surface of
graft 12, as shown in Figure 4c.
Thereafter, as shown in Figure 4d, PTFE tape 17 is helically
wrapped in a first direction in overlapping fashion on the outer surface of
stent 14. In the preferred embodiment, tape of %2 inch width is used. The
15 tape is helically wrapped about the stent at a pitch angle whereby 6 to 8
revolutions of the tape are applied per linear inch of stent 14. Thereafter,
as shown in Figure 4e, a second tape wrap in the opposite direction is
accomplished, preferably using the same width of tape at the same pitch
angle, thereby applying another 6-8 revolutions of tape 17 per linear inch
20 of stent 14. In this manner, both wrappings of tape 17 (Figs. 4d and 4e)
combine to form a tubular, outer PTFE layer 16 which preferably has a
thickness of less than 0.1 inches, and which may be formed of 1 to 10
consecutive (e.g., laminated) layers of the tape 17. for example, when
using ePTFE tape of less than 1.6g/cc density and %2 inch width, the first
25 helical wrap (Fig. 4d) may deposit four consecutive layers of tape 17 and
the second helical wrap (Fig. 4e) may deposit an additional 4 layers of
tape 17, thereby resulting in an outer tubular layer 16 which is made up of
a total of 8 layers of tape 17.

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Optionally, to further promote bonding of the outer tubular layer 16
to stent 14 and/or inner base graft 12, liquid PTFE dispersion may be
sprayed, painted or otherwise applied to and dried upon tape 17 prior to
wrapping, or such liquid PTFE dispersion may be deposited by any
suitable means (spraying, painting, etc.) between the outer tubular layer 16
formed by helically wrapped tape 17 and inner base graft 12. Or such
liquid PTFE dispersion may be sprayed onto or otherwise applied to the
outer surface of helically wrapped tape 17 such the small particles of PTFE
contained within the liquid dispersion will migrate inwardly through pores in
the layers of tape 17, and will thereby become deposited between outer
tubular layer 16 and inner base graft 12 prior to subsequent heating of the
assembly, as described below.
Thereafter, as shown in Figure 4f, ligatures 52 of stainless steel
wire are tied about the opposite ends of graft 10 so as to securely hold
base graft 12, coated stent 14 and outer layer 16 on the mandrel 50. The
mandrel having graft 10 disposed thereon is then heated using a "waffle-
iron" heater, schematically shown in Fig. 4f, wherein heat is applied only to
areas that correspond to the spaces not occupied by stent 14. The
purpose of the "waffle-iron" heater is to avoid heating the drug covering the
stent to its decomposition temperature. Heating causes outer PTFE layer
16 to heat fuse to inner base graft 12 through the openings 19 which exist
in stent 14. In this manner, the desired integrally-drug eluting stented
PTFE tubular graft 10 is formed. An alternative to the "waffle-iron" heater
is to use a laser beam controlled by a computer to "hit" only the areas
corresponding to the openings 19 which exist in stent 14. Computer
controlled laser beams to accomplish such a purpose are known in the art.

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E. Assembly and Construction of Internally Drug eluting stented
Tube Graft
In one embodiment of the invention, inner base graft 12 is
eliminated, thereby providing a drug eluting stented graft 10 comprising
only stent 14 and outer tubular layer 16. This embodiment is of particular
utility in connection with reducing the tendency of tissue ingrowth into the
stent in certain applications. Thus, therapeutic agents including, sirolimus,
paclitaxel, brachytherapeutic agents, and the like may be incorporated into
the stent as taught by the invention to avoid such ingrowth. These stents
are of particular importance as trans-hepatic stents, where such ingrowth
is an important problem.
Here, the above-described manufacturing method is performed as
described without tubular base graft 12, thereby forming a modified version
of drug eluting stented graft 10 wherein outer tubular layer 16 is fused only
to stent 14.
In these embodiments stent 14 is coated with a lubricious polymer coating
to provide lubricity and biocompatibility, which renders the graft suitable
for
use in applications wherein the exposed stent 14 will come in direct
contact with biological fluid or blood. Thus, this embodiment of the present
invention includes all possible arrangements wherein only outer tubular
layer 16 is utilized in conjunction with stent 14, to provide an internally
drug
eluting stented graft 10 which is devoid of any internal tubular base graft
12.
Referring now to Fig. 7 and Fig. 8, there are shown portions of two
embodiments of the stent of the invention. They comprise a plurality of
elements, wherein each element comprises an undulating shape formed
into a generally cylindrical configuration having a cylinder axis, wherein
each element is connected to an adjacent neighbor element by at least

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28
one linear connector. In FIG. 7, a portion of one embodiment of the stent is
shown
generally at 100. Stent portion 100 consists of three elements 101, 102 and
103,
each of which comprises a zigzag pattern comprising a plurality of zigs having
tips and a plurality of zags having tips. A tip 104 on a zig of element 101
and a
nearest tip 105 of a zag of an adjacent neighbor element 105 generally lie in
a
plane passing through the cylinder axis, and are connected by a linear
connector
105. Likewise, a tip 106 on a zig of element 102 and a nearest tip 107 on a
zag of
an adjacent neighbor element 103 generally lie in a plane passing through the
cylinder axis, and are connected by a linear connector 111. Connector 111 is
substantially circumferentially offset from adjacent neighbor connector 105.
Stent
100 is constructed of material that has a width dimension 140 and a depth
dimension 150 each of which is smaller than the length dimension of linear
connectors 110 and 111. In FIG. 8, a portion of another embodiment of the
stent is
shown generally at 200. Stent portion 200 consists of two elements 201 and
202,
each of which comprises an undulating pattern comprising a plurality of peaks
and
valleys. A valley 220 on element 201 and a nearest peak 230 of adjacent
neighbor
element 202 generally lie in a plane passing through the cylinder axis, and
are
connected by a linear connector 210. Stent 200 is constructed of material that
has
a width dimension 240 and a depth dimension 250 each of which is smaller than
the length dimension of connector 210.
Uncoated stent designs comprising individual elements or wires and gaps or
lateral openings are described in detail. in U.S. Pat. Nos. 4,655,771
Wallsten); U.S.
Pat. No. 4,954,126 (Wallsten); and U.S. Pat. No. 5,061,275 (Wallsten et al.).
An
improved design combining these older features with the features shown in
FIGS.
7 and 8, described above, is shown in the drug

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eluting radially expandable tubular stented graft shown generally at 290 in
Fig. 9. Here, in the stent generally shown at 280, the wire and gap
features of the older stent art, shown at 330 and 340 are combined
elements having zigzag features, shown at 310, and sinusoidal features,
shown at 300. All elements of the 310 and 300 type are connected
using connectors as shown at 320. The resulting stent may be
fabricated into any of the embodiments of the present invention.
In general, the invention comprises an improved stented graft that
can alternately include a compact configuration having a first diameter
and an expanded configuration having a greater diameter, comprising, in
combination
at least one stent formed in a generally cylindrical shape having an outer
surface and a hollow bore extending longitudinally therethrough, wherein
the stent can alternately exist in a compact configuration having a first
diameter, and an expanded configuration having a greater diameter and
a plurality of lateral openings; and, a flexible, porous, biocompatible
tubular elastomer covering having a first end, a second end, an outer
surface and a hollow bore that extends longitudinally therethrough to
define an inner surface. The stent is deployed coaxially within the
hollow bore of the covering such that the inner surface of the tubular
covering is in contact with the outer surface of the stent.
Another embodiment is a tubular stented graft that is alternately
deployable in a radially compact configuration having a first diameter
and a radially expanded configuration having a second diameter. This
stented graft includes a stent comprising at least one member formed in
a generally cylindrical shape having an outer surface and a hollow bore
which extends longitudinally therethrough to define an inner surface.
The stent is initially radially collapsible to a diameter that is
substantially
equal to the first diameter of the stented graft, and subsequently radially

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expandable to a diameter which is substantially equal to the second
diameter of the stented graft. A plurality of lateral openings exists in the
stent when the stent is at its radially expanded second diameter. A
continuous, tubular PTFE covering is formed on the stent, the PTFE
5 covering comprising a tubular inner base graft formed of expanded,
sintered PTFE. The
tubular base graft has an outer surface and an inner surface, the tubular
base graft being deployed coaxially within the hollow bore of the stent
such that the outer surface of the tubular base graft is in contact with the
10 inner surface of the stent, and the inner surface of the tubular base graft
thereby defining a luminal passageway through the stented graft. A
tubular outer layer is formed of expanded, sintered PTFE tape which has
a width of less than about 1 inch, the tape having been wound about the
outer surface of the stent to create the tubular outer layer thereon, such
15 that the stent is captured between the outer layer and the tubular base
graft. The tubular outer layer is attached to the tubular base graft
through the lateral openings in the stent to form an integrally stented,
continuous PTFE tube which is alternately disposable in the radially
compact configuration of the first diameter and the radially expanded
20 configuration of the second diameter.
The improvement comprises the device wherein the stent is
coated with a coat comprising a composite of at least one biocompatible,
pharmaceutically acceptable, bioerodible polymer and at least one
therapeutic substance to form a drug eluting stented graft. The polymer
25 may be a polyester. The therapeutic agent may be selected from the
group consisting of antiplatelet agents, anticoagulant agents,
antimetabolic agents, vasoactive agents, nitric oxide releasing agents,
anti-inflammatory agents, antiproliferative agents, antisense agents, pro-
endothelial agents, anti-migratory agents, antimicrobial agents, selective

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31
gene delivery vectors, sirolimus, actinomycin-D and paclitaxel. The
selective gene delivery vectors may include Semliki Forest Virus (SMV)
adapted to deliver restenosis preventing genes.
The polymer may be a hydrophobic, bioerodible, copolymer
comprising mers I and II according to the following formula wherein:
pa F(ICH
CH21b 15 o R1 is a member selected from the group consisting of alkylene
of 1 to 10 carbons; alkenylene of 2 to 10 carbons; alkyleneoxy of
2 to 6 carbons; cycloalkylene of 3 to 7 carbons; cycloalkylene of
3 to 7 carbons substituted with a member selected from the
group consisting of alkyl of 1 to 7 carbons, an alkoxy of 1 to 7
carbons, an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7
carbons; cycloalkenylene of 4 to 7 carbons; cycloalkenylene of 4
to 7 carbons substituted with an alkyl of 1 to 7 carbons, an
alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and an
alkenyl of 2 to 7 carbons; arylene; and arylene substituted with
an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an
alkylene of 1 to 10 carbons, an alkenyl of 2 to 7 carbons; and
wherein a is 0 to 1; b is 2 to 6; m is greater than 10; n is greater
than 10; and at least one of R1, a, and b in mer I is different than
Ri, a, and b in mer II; and wherein:

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^ a composite of at least one polymer and at least one therapeutic
substance when in operation bioerodes and releases the at least
one therapeutic substance at a rate selected from (1) a zero
order rate,(2) a continuous rate, and (3) a variable rate, which
rate is produced by preselecting the composite of at least one
polymer and at least one therapeutic substance, and the
elastomer to give the desired result.
Alternatively, the at least one polymer may be a hydrophobic,
bioerodible, terpolymer comprising mers I, II, and III according to the
following formula, wherein:
o)a .
0 a N
CH2]b CH2]b 20
R1 is a member selected from the group consisting of alkylene of 1 to 10
carbons; alkenylene of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons;
cycloalkylene of 3 to 7 carbons; cycloalkylene of 3 to 7 carbons
substituted with a member selected from the group consisting of alkyl of
1 to 7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons,
and an alkenyl of 2 to 7 carbons; cycloalkenylene of 4 to 7 carbons;

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cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7
carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and
an alkenyl of 2 to 7 carbons; arylene; and arylene substituted with an
alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to
10 carbons, an alkenyl of 2 to 7 carbons; and wherein a is 0 to 1; b is 2
to 6; m is greater than 10; n is greater than 10; p is greater than 10; and
at least one of R1, a, and b in mers I, II and III is different than R1, a,
and
b in mers I, 11 and III. The composite of at least one polymer and at least
one therapeutic substance when in operation bioerodes and releases
the at least one therapeutic substance at a rate selected from (1) a zero
order rate,(2) a continuous rate, and (3) a variable rate, which rate is
produced by preselecting the composite of the at least one polymer and
the at least one therapeutic substance, and the elastomer to give the
desired result. The drug eluting stented graft may include a multiplicity
of microcapsules dispersed within the at least one polymer. The
microcapsules have a wall formed of a drug release rate controlling
material and therapeutic substance is contained within the multiplicity of
microcapsules. The at least one polymer may have the formula:
1
RI-p_C_O
R2 R3
L-- .J a
wherein R1 is a member selected from the group of divalent, trivalent
and tetravalent radicals consisting of alkylene of 1 to 10 carbons;

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alkenylene of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons;
cycloalkylene of 3 to 7 carbons; cycloalkylene of 3 to 7 carbons
substituted with an alkyl of 1 to 7 carbons, alkoxy of 1 to 7 carbons, an
alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons;
cycloalkenylene of 4 to 7 carbons cycloalkenylene of 4 to 7 carbons
substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons,
an alkylene of 1 to 10 carbons, and an alkenyl of 2 to 7 carbons; arylene;
and arylene substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to
7 carbons, and an alkenyl of 2 to 7 carbons; R2 and R3 are selected from
the group consisting of alkyl of I to 7 carbons; alkenyl of 2 to 7 carbons;
alkoxy of 1 to 7 carbons; alkenyloxy of 2 to 7 carbons; alkylene of 2 to 6
carbons; alkenylene of 3 to 6 carbons; alkyleneoxy of 2 to 6 carbons;
alkenyleneoxy of 3 to 6 carbons; aryloxy; aralkyleneoxy of 8 to 12
carbons; aralkenyleneoxy of 8 to 12 carbons; oxa; OR10 with R, as
defined above; a heterocyclic ring of 5 to 8 carbon and oxygen atoms
formed when R2 and R3 are taken together; a heterocyclic ring of 5 to 8
carbon and oxygen atoms substituted with an alkyl of 1 to 7 carbons, an
alkoxy of 1 to 7 carbons and alkenyl of 2 to 7 carbons formed when R2
and R3 are taken together; a fused polycyclic ring of 8 to 12 carbon and
oxygen atoms formed when R2 and R3 are taken together; a fused
polycyclic ring of 8 to 12 carbon and oxygen atoms substituted with an
alkyl of 1 to 7 carbons; an alkoxy of 1 to 7 carbons and an alkenyl of 2 to
7 carbons; and wherein at least one of the R2 and R3 is a member
selected from the group consisting of alkoxy, alkenyloxy and OR1O; R2
and R3 when taken together are a member selected from the group of
heterocyclic and fused polycyclic rings having at least one oxygen atom
in the ring; and wherein n is greater than 10.
In operation, the polymer and the microcapsules bioerode at a
controlled and continuous rate over a prolonged period of time, thereby

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releasing the at least one therapeutic substance at a controlled and
continuous rate over a prolonged period of time.
The coat of the stent of the drug eluting stented graft may further
comprise at least a first layer and a second layer, wherein the first layer
5 comprises the at least one therapeutic substance and at least a first
polymer, and the second layer comprises the at least one therapeutic
substance and at least a second polymer. At least one of the first
polymer and the second polymer are selected from the group consisting
of polymers of the formula:
1RI-0%C-0
R2 R3
wherein R, is a member selected from the group of divalent, trivalent and
tetravalent radicals consisting of alkylene of 1 to 10 carbons; alkenylene
of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons; cycloalkylene of 3 to 7
carbons;
cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to 7
carbons, alkoxy of 1 to 7 carbons, alkylene of 1 to 10 carbons, and an
alkenyl of 2 to 7 carbons; cycloalkenylene of 4 to 7 carbons;
cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7
carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and
an alkenyl of 2 to 7 carbons; arylene; and arylene substituted with an
alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2

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to 7 carbons; R2 and R3 are selected from the group consisting
of alkyl of 1 to 7 carbons; alkenyl of 2 to 7 carbons; alkoxy of 1 to 7
carbons; alkenyloxy of 2 to 7 carbons; alkylene of 2 to 6 carbons;
alkenylene of 3 to 6 carbons; alkyleneoxy of 2 to 6 carbons;
alkenyleneoxy
of 3 to 6 carbons; aryloxy; aralkyleneoxy of 8 to 12 carbons;
aralkenyleneoxy of 8 to 12 carbons; oxa; 0 R,O with R, as
defined above; a heterocyclic ring of 5 to 8 carbon and oxygen atoms
formed when R2 and R3 are taken together; a heterocyclic ring of
5 to 8 carbon and oxygen atoms substituted with an alkyl of 1 to 7
carbons; an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons
formed when R2 and R3 are taken together; a fused polycyclic
ring of 8 to 12 carbon and oxygen atoms formed when R2 and R3
are taken together; a fused polycyclic ring of 8 to 12 carbon and oxygen
atoms substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7
carbons and an alkenyl of 2 to 7 carbons; and wherein at least one of
the R2 and R3 is a member selected from the group consisting of alkoxy,
alkenyloxy and OR,0; R, and R3 when taken together are a member
selected from the group of heterocyclic and fused polycyclic rings having
at least one oxygen atom in the ring; and wherein is greater than 10 In
operation, the layers bioerode at a controlled and continuous rate over a
prolonged period of time, thereby releasing the at least one therapeutic
substance at a controlled and continuous rate over a prolonged period of
time. In this case, the first polymer may be a pharmaceutically
acceptable biocompatible non-bioerodible polymer that sequesters an
agent, such as palladium-103 (103Pd), 1921r, 32P, 188Re, and Sr/Y90 source
trains, for brachytherapy.
The drug eluting stented graft may have a multiplicity of discrete,
closed cells within the at least one polymer, the cells having a wall

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formed and defined by the at least one polymer. The polymer has the
formula:
RI-0-C-0--
I
I R2 R3
wherein R1 is a member selected from the group of divalent, trivalent and
tetravalent radicals consisting of alkylene of 1 to 10 carbons; alkenylene
of 2 to 10 carbons; alkyleneoxy of 2 to 6 carbons; cycloalkylene of 3 to 7
carbons; cycloalkylene of 3 to 7 carbons substituted with an alkyl of 1 to
7 carbons, alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and
an alkenyl of 2 to 7 carbons; cycloalkenylene of 4 to 7 carbons;
cycloalkenylene of 4 to 7 carbons substituted with an alkyl of 1 to 7
carbons, an alkoxy of 1 to 7 carbons, an alkylene of 1 to 10 carbons, and
an alkenyl of 2 to 7 carbons; arylene; and arylene substituted with an
alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons, and an alkenyl of 2
to 7 carbons; R2 and R3 are selected from the group consisting of alkyl of
1 to 7 carbons; alkenyl of 2 to 7 carbons; alkoxy of 1 to 7 carbons;
alkenyloxy of 2 to 7 carbons; alkylene of 2 to 6 carbons; alkenylene of 3
to 6 carbons; alkyleneoxy of 2 to 6 carbons; alkenyleneoxy of 3 to 6
carbons; aryloxy; aralkyleneoxy of 8 to 12 carbons; aralkenyleneoxy of 8
to 12 carbons; oxa; OR10 with R, as defined above; a heterocyclic ring
of 5 to 8 carbon and oxygen atoms formed when R2 and R3 are taken
together; a heterocyclic ring of 5 to 8 carbon and oxygen atoms

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substituted with an alkyl of 1 to 7 carbons, an alkoxy of 1 to 7 carbons
and an alkenyl of 2 to 7 carbons formed when R2 and R3 are taken
together; a fused polycyclic ring of 8 to 12 carbon and oxygen atoms
formed when R2 and R3 are taken together; a fused polycyclic ring of 8
to 12 carbon and oxygen atoms substituted with an alkyl of 1 to 7
carbons, an alkoxy of 1 to 7 carbons and an alkenyl of 2 to 7 carbons;
and wherein at least one of the R2 and R3 is a member selected from the
group consisting of alkoxy, alkenyloxy and OR10; R2 and R3 when taken
together are a member selected from the group of heterocyclic and
fused polycyclic rings having at least one oxygen atom in the ring; and
wherein n is greater than 10.
The at least one therapeutic substance is dissolved in a
pharmaceutically acceptable carrier that is a solvent for the at least one
therapeutic substance and a nonsolvent for the at least one polymer is
contained within the multiplicity of discrete, closed cells. When in
operation, the at least one polymer is capable of bioeroding at a
controlled and continuous rate over a prolonged period of time, thereby
releasing the at least one therapeutic substance at a controlled and
continuous rate over a prolonged period of time.
The stent comprises a plurality of elements. Each element comprises
an undulating linear shape formed into a generally cylindrical
configuration having a cylinder axis generally aligned on the axis of the
hollow bore, and each element is connected to an adjacent neighbor
element by at least one linear connector. The elements may comprise a
spiral. One connector may be substantially circumferentially offset from
an adjacent neighbor connector, and may form a helical array.
Alternatively, a connector may not be substantially circumferentially
offset from an adjacent neighbor connector.

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The undulating linear shape may be a generally zigzag shape
comprising a plurality of zigs having tips and a plurality of zags having
tips, wherein the tip of each zig of each element and the nearest the tip
of each zig of an adjacent neighbor element generally lie in a plane
passing through the axis of the hollow bore, and wherein the tip of at
least one zig of each element and at least one nearest tip of a zig of an
adjacent neighbor are connected by one linear connector.
Alternatively, the undulating linear shape may be a sinusoidal shape
having a plurality of peaks and a plurality of valleys. Each peak of each
element and each valley of an adjacent neighbor may lie generally in a
common plane passing through the axis of the hollow bore, and at least
one peak of each element and the valley of an adjacent neighbor lying
generally in the common plane may be connected by one linear
connector. The length of each linear connector is greater than its width
or depth, and may be 3-10 times greater than the width or depth.
The stent and elastomer may be anchored to each other by means
for anchoring, such as protrusions of the covering that fixedly protrude
into the lateral openings in the stent. The elastomer may be
polytetrafluoroethylene, fluorinated ethylene propylene,
polytetrafluoroethylene-perfluoroalkyl vinyl ether copolymer, polyvinyl
chloride, polypropylene, polyethylene terephthalate, broad fluoride, other
biocompatible plastics, and expanded, sintered PTFE (which may be
tape) having fibrils measuring about 300 p-5 p in length. The tape may
have a width of less than about 0.5 inches to about 1 inch, a thickness of
less than 0.015 inch (0.038 cm.), and a density of less than 1.6 g/cc.
The tape may be wound about the stent in overlapping fashion, for
example, helically. The tape may be wound in a first direction and then
in the opposite direction, and comprise 1 to 10 layers. The tape may be
helically wrapped such that 6-8 revolutions of tape are applied per

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longitudinal inch (2.54 cm.) of the drug eluting stented graft. The
thickness of the covering may be less than 0.1 inch (0.25 cm.)
The drug eluting stented graft may include a self-expanding stent
comprising a shape memory alloy that can alternately exist in a first and
5 a second crystalline state, or it may include a pressure-expandable
stent. The stent may be formed of a metal alloy comprising at least two
elements selected from the group consisting of iron, cobalt, chromium,
nickel, titanium, niobium, and molybdenum. For example, the alloy may
comprise at least about 51 % to about 59% nickel and the remainder
10 comprising titanium. Alternatively, it may comprise about 0.25%
chromium, at least about 51 % to about 59% nickel, and the remainder
comprising titanium.
The composite coating of the drug eluting stented graft may be
applied to the stent by the steps of immersing the stent in a liquid
15 dispersion of the composite, removing the stent from the liquid
dispersion of the composite, and drying the liquid dispersion of the
composite that has remained on the stent. The composite coating may
be formed by electron beam deposition, and
the tubular covering may be adherent to the coat.
20 A method for the treatment of cardiovascular disease, comprises
implanting the drug eluting stented graft in a patient in need of such
treatment wherein the implantation is effective to ameliorate one or more
of the symptoms of the cardiovascular disease. An article of
manufacture, comprises packaging material and the drug eluting stented
25 graft contained within the packaging material, wherein the drug eluting
stented graft is effective for implantation in a patient afflicted with
cardiovascular disease, and the packaging material includes a label that
indicates that the device is effective for said implantation.

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It will be appreciated that the invention has been described with
reference to certain presently preferred embodiments of the invention.
Various additions, deletions, alterations and modifications may be made to
the above-described embodiments without departing from the intended
spirit and scope of the invention. For example, the linear connectors may
collectively form arrays that may be helical, linear, or neither helical nor
linear. Likewise, linear connectors may connect peaks to peaks, valleys to
valleys, or peaks to valleys. Again, linear connectors may connect zigs to
zigs, zags to zags, or zigs to zags. Accordingly, it is intended that all such
reasonable additions, deletions, modifications and alterations to the above
described embodiments be included within the scope of the following
claims.
On this basis, the instant invention should be recognized as
constituting progress in science and the useful arts, as solving the
problems in cardiology enumerated above. In the foregoing description,
certain terms have been used for brevity, clearness and understanding,
but no unnecessary limitation are to be implied therefrom beyond the
requirements of the prior art, because such words are used for
descriptive purposes herein and are intended to be broadly construed.
Having described preferred embodiments of the invention with
reference to the accompanying drawings, it is to be understood that the
invention is not limited to those precise embodiments, and that the
various changes and modifications may be effected therein by one
skilled in the art without departing from the scope or spirit of the
invention s defined in the appended claims. For example, the product
can have other shapes, or could make use of other metals and plastics.
Thus, the scope of the invention should be determined by the appended
claims and their legal equivalents, rather than by the examples given.

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All changes that come within the meaning and range of equivalency of the
claims
are to be embraced within their scope.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have
the
same meaning as is commonly understood by one of skill in the art to which
this
invention belongs.

Dessin représentatif