U.S. patent application number 11/423418 was filed with the patent office on 2006-10-12 for drug-delivery endovascular stent and method for treating restenosis.
Invention is credited to Ronald E. Betts, Douglas R. Savage, John E. Shulze.
Application Number | 20060229706 11/423418 |
Document ID | / |
Family ID | 46150286 |
Filed Date | 2006-10-12 |
United States Patent
Application |
20060229706 |
Kind Code |
A1 |
Shulze; John E. ; et
al. |
October 12, 2006 |
Drug-Delivery Endovascular Stent and Method for Treating
Restenosis
Abstract
An intravascular stent and method for inhibiting restenosis,
following vascular injury, is disclosed. The stent has an
expandable, linked-filament body and a drug-release coating formed
on the stent-body filaments, for contacting the vessel injury site
when the stent is placed in-situ in an expanded condition. The
coating releases, for a period of at least 4 weeks, a
restenosis-inhibiting amount of the macrocyclic triene
immunosuppressive compound everolimus. The stent, when used to
treat a vascular injury, gives good protection against clinical
restenosis, even when the extent of vascular injury involves vessel
overstretching by more than 30% diameter. Also disclosed is a stent
having a drug-release coating composed of (i) 10 and 80 weight
percent of a polymer substrate and (ii) 20-90 weight percent of an
anti-restenosis compound.
Inventors: |
Shulze; John E.; (Rancho
Santa Margarita, CA) ; Betts; Ronald E.; (La Jolla,
CA) ; Savage; Douglas R.; (Del Mar, CA) |
Correspondence
Address: |
PERKINS COIE LLP
P.O. BOX 2168
MENLO PARK
CA
94026
US
|
Family ID: |
46150286 |
Appl. No.: |
11/423418 |
Filed: |
June 9, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10382426 |
Mar 5, 2003 |
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11423418 |
Jun 9, 2006 |
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10133814 |
Apr 24, 2002 |
6939376 |
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10382426 |
Mar 5, 2003 |
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Current U.S.
Class: |
623/1.16 ;
623/1.42 |
Current CPC
Class: |
A61F 2230/0054 20130101;
A61L 2300/416 20130101; A61L 2300/602 20130101; A61F 2002/072
20130101; A61F 2002/91533 20130101; A61F 2250/0067 20130101; A61K
9/0024 20130101; A61L 31/10 20130101; A61L 31/10 20130101; A61L
31/16 20130101; A61L 31/10 20130101; A61L 2300/606 20130101; A61P
9/10 20180101; C08L 67/04 20130101; C08L 29/04 20130101; A61P 35/00
20180101; A61P 29/00 20180101; A61F 2002/91575 20130101; A61F
2240/001 20130101; A61P 9/14 20180101; A61P 17/02 20180101; A61F
2/915 20130101 |
Class at
Publication: |
623/001.16 ;
623/001.42 |
International
Class: |
A61F 2/90 20060101
A61F002/90 |
Claims
1. An endovascular stent for placement at a vascular injury site,
for inhibiting restenosis at the site, comprising a body having an
open-lattice structure formed of linked filaments, and carried on
the one or more filaments, a drug-release coating having a
thickness of between 3-30 microns, and composed of (i) 20-80 weight
percent polymer substrate and (ii) 20-80 weight percent macrocyclic
triene compound having the form: ##STR5## where R is
CH.sub.2--CH.sub.2--OH, said stent being expandable from a
contracted condition in which the stent can be delivered to a
vascular injury site via catheter, and an expanded condition in
which the stent coating can be placed in contact with the vessel at
the injury site, said coating being effective to release an amount
of the compound to inhibit restenosis at the site.
2. The stent of claim 1, wherein the stent body is a metal-filament
structure and the polymer substrate in the coating is selected from
the group consisting of polymethylmethacrylate, ethylene vinyl
alcohol, poly-lactide polymers, .epsilon.-caprolactone, ethyl vinyl
acetate, polyvinyl alcohol, and polyethylene oxide.
3. The stent of claim 1, wherein the polymer substrate in the
coating is formed of poly-dl-lactide having a thickness between
3-20 microns.
4. The stent of claim 1, which further includes a parylene polymer
undercoat having a thickness of between 1-3 microns, disposed
between the filaments of the stent body and said coating.
5. The stent of claim 1, further comprising a polymer undercoat
disposed between the filaments of the stent body and said
drug-release coating.
6. The stent of claim 5, wherein said polymer undercoat is formed
of a polymer selected from the group consisting of ethylene vinyl
alcohol, parylast, silicone, a fluoropolymer, and parylene.
7. The stent of claim 1, wherein said coating further includes a
bioactive agent selected from the group consisting of antiplatelet
agents, fibrinolytic agents, and thrombolytic agents.
8. The stent of claim 1, wherein the stent body is a
polymer-filament structure, said polymer filaments formed from a
biodegradable polymer.
9. An apparatus for delivery of a stent according to claim 1,
comprising a catheter; a stent according to claim 1.
10. A method for inhibiting restenosis at a vascular injury site,
comprising delivering to the vascular injury site, an endovascular
stent having an open-lattice structure formed of linked filaments,
and carried on the one or more filaments, a drug-release coating
having a thickness of between 3-30 microns, and composed of (i)
20-80 weight percent polymer substrate and (ii) 20-80 weight
percent macrocyclic triene compound having the form: ##STR6## where
R is CH.sub.2--CH.sub.2--OH; and expanding the stent at the
vascular injury site, to bring the drug-release coating in contact
with the vessel at the injury site, said coating being effective to
release an amount of the compound to inhibit restenosis at the
site.
11. The method of claim 10, wherein the stent body is a
metal-filament structure and the polymer substrate in the coating
is selected from the group consisting of polymethylmethacrylate,
ethylene vinyl alcohol, poly-lactide polymers,
.epsilon.-caprolactone, ethyl vinyl acetate, polyvinyl alcohol, and
polyethylene oxide.
12. The method of claim 11, wherein the polymer substrate in the
coating is formed of poly-dl-lactide having a thickness between
3-20 microns.
13. The method of claim 10, wherein the stent further includes a
polymer undercoat disposed between the filaments of the stent body
and said drug-release coating.
14. The method of 13, wherein said polymer undercoat is formed of a
polymer selected from the group consisting of ethylene vinyl
alcohol, parylast, silicone, a fluoropolymer, and parylene.
15. The method of claim 12, wherein the stent further includes a
parylene polymer undercoat having a thickness of between 1-3
microns, disposed between the filaments of the stent body and said
poly-dl-lactide coating substrate.
16. The method of 10, wherein said coating further includes a
bioactive agent selected from the group consisting of an
antiplatelet agent, a fibrinolytic agent, and a thrombolytic
agent.
17. The method of claim 10, wherein the stent body is a
polymer-filament structure, said polymer-filament structure formed
of a bioerodable polymer.
18. In a method for inhibiting restenosis at a vascular injury
site, by placement at the site an intravascular stent designed to
release a macrocyclic triene compound over an extended period, an
improvement comprising employing as the macrocyclic triene
compound, a compound having the formula: ##STR7## where R is
CH.sub.2--CH.sub.2--OH, and wherein said compound is carried on
said stent in a drug-release coating having a thickness of between
3-30 microns composed of a polymer substrate and having between
20-80 weight percent of said compound.
19. The method of claim 18, for use where the vascular injury is
produced during an angiographic procedure in which a vessel region
is overstretched at least 30% in diameter.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/382,426, filed Mar. 5, 2003, now pending, which is a
continuation-in-part of U.S. application Ser. No. 10/133,814 filed
Apr. 24, 2002, now U.S. Pat. No. 6,939,376, incorporated herein by
reference.
BACKGROUND
[0002] A stent is a type of endovascular implant, usually generally
tubular in shape, typically having a lattice, connected-wire
tubular construction which is expandable to be permanently inserted
into a blood vessel to provide mechanical support to the vessel and
to maintain or re-establish a flow channel during or following
angioplasty. The support structure of the stent is designed to
prevent early collapse of a vessel that has been weakened and
damaged by angioplasty. Insertion of stents has been shown to
prevent negative remodeling and spasm of the vessel while healing
of the damaged vessel wall proceeds over a period of months.
[0003] During the healing process, inflammation caused by
angioplasty and stent implant injury often causes smooth muscle
cell proliferation and regrowth inside the stent, thus partially
closing the flow channel, and thereby reducing or eliminating the
beneficial effect of the angioplasty/stenting procedure. This
process is called restenosis. Blood clots may also form inside of
the newly implanted stent due to the thrombotic nature of the stent
surfaces, even when biocompatible materials are used to form the
stent.
[0004] While large blood clots may not form during the angioplasty
procedure itself or immediately post-procedure due to the current
practice of injecting powerful anti-platelet drugs into the blood
circulation, some thrombosis is always present, at least on a
microscopic level on stent surfaces, and it is thought to play a
significant role in the early stages of restenosis by establishing
a biocompatible matrix on the surfaces of the stent whereupon
smooth muscle cells may subsequently attach and multiply.
[0005] Stent coatings are known which contain bioactive agents that
are designed to reduce or eliminate thrombosis or restenosis. Such
bioactive agents may be dispersed or dissolved in either a
bio-durable or bio-erodable polymer matrix that is attached to the
surface of the stent wires prior to implant. After implantation,
the bioactive agent diffuses out of the polymer matrix and
preferably into the surrounding tissue over a period lasting at
least four weeks, and in some cases up to one year or longer,
ideally matching the time course of restenosis, smooth muscle cell
proliferation, thrombosis or a combination thereof.
[0006] If the polymer is bioerodable, in addition to release of the
drug through the process of diffusion, the bioactive agent may also
be released as the polymer degrades or dissolves, making the agent
more readily available to the surrounding tissue environment.
Bioerodable stents and biodurable stents are known where the outer
surfaces or even the entire bulk of polymer material is porous. For
example, PCT Publication No. WO 99/07308, which is commonly owned
with the present application, discloses such stents, and is
expressly incorporated by reference herein. When bioerodable
polymers are used as drug delivery coatings, porosity is variously
claimed to aid tissue ingrowth, make the erosion of the polymer
more predictable, or to regulate or enhance the rate of drug
release, as, for example, disclosed in U.S. Pat. Nos. 6,099,562,
5,873,904, 5,342,348, 5,873,904, 5,707,385, 5,824,048, 5,527,337,
5,306,286, and 6,013,853.
[0007] Heparin, as well as other anti-platelet or anti-thrombolytic
surface coatings, is known which is chemically bound to the surface
of the stent to reduce thrombosis. A heparinized surface is known
to interfere with the blood-clotting cascade in humans, preventing
attachment of platelets (a precursor to thrombin) on the stent
surface. Stents have been described which include both a heparin
surface and an active agent stored inside of a coating (see U.S.
Pat. Nos. 6,231,600 and 5,288,711, for example).
[0008] A variety of agents specifically claimed to inhibit smooth
muscle-cell proliferation, and thus inhibit restenosis, have been
proposed for release from endovascular stents. As examples, U.S.
Pat. No. 6,159,488 describes the use of a quinazolinone derivative;
U.S. Pat. No. 6,171,609, the use of taxol, and U.S. Pat. No.
5,716,981, the use of paclitaxel, a cytotoxic agent thought to be
the active ingredient in the agent taxol. The metal silver is cited
in U.S. Pat. No. 5,873,904. Tranilast, a membrane stabilizing agent
thought to have anti-inflammatory properties is disclosed in U.S.
Pat. No. 5,733,327.
[0009] More recently, rapamycin, an immunosuppressant reported to
suppress both smooth muscle cell and endothelial cell growth, has
been shown to have improved effectiveness against restenosis, when
delivered from a polymer coating on a stent. See, for example, U.S.
Pat. Nos. 5,288,711 and 6,153,252. Also, in PCT Publication No. WO
97/35575, the macrocyclic triene immunosuppressive compound
everolimus and related compounds have been proposed for treating
restenosis, via systemic delivery.
[0010] Ideally, a compound selected for inhibiting restenosis, by
drug release from a stent, should have three properties. First,
because the stent should have a low profile, meaning a thin polymer
matrix, the compound should be sufficiently active to produce a
continuous therapeutic dose for a minimum period of 4-8 weeks when
released from a thin polymer coating. Secondly, the compound should
be effective, at a low dose, in inhibiting smooth muscle cell
proliferation. Finally, endothelial cells which line the inside
surface of the vessel lumen are normally damaged by the process of
angioplasty and/or stenting. The compound should allow for regrowth
of endothelial cells inside the vessel lumen, to provide a return
to vessel homeostasis and to promote normal and critical
interactions between the vessel walls and blood flowing through the
vessel.
SUMMARY
[0011] The invention includes, in one aspect, an endovascular stent
for placement at a vascular injury site, for inhibiting restenosis
at the site. The stent is comprised of a body having an
open-lattice structure formed of linked filaments, and carried on
the one or more filaments, a drug-release coating having a
thickness of between 3-30 microns, and composed of (i) 20-80 weight
percent polymer substrate and (ii) 20-80 weight percent macrocyclic
triene compound having the form: ##STR1## where R is
CH.sub.2--CH.sub.2--OH. The stent is expandable from a contracted
condition in which the stent can be delivered to a vascular injury
site via catheter, and an expanded condition in which the stent
coating can be placed in contact with the vessel at the injury
site, where the coating is effective to release an amount of the
compound to inhibit restenosis at the site.
[0012] In one embodiment of this aspect, the stent body is a
metal-filament structure, and the polymer substrate in the coating
is selected from the group consisting of polymethylmethacrylate,
ethylene vinyl alcohol, poly-lactide polymers,
.epsilon.-caprolactone, ethyl vinyl acetate, polyvinyl alcohol, and
polyethylene oxide. In one exemplary embodiment, the polymer
substrate in the coating is formed of poly-dl-lactide having a
thickness between 3-20 microns.
[0013] The stent, in another embodiment, includes a parylene
polymer undercoat having a thickness of between 1-3 microns,
disposed between the filaments of the stent body and a
poly-dl-lactide coating substrate.
[0014] More generally, the stent can comprise a polymer undercoat
disposed between the filaments of the stent body and said
drug-release coating. Exemplary materials for the polymer undercoat
include ethylene vinyl alcohol, parylast, silicone, a
fluoropolymer, and parylene.
[0015] In another embodiment, the stent coating further includes a
second bioactive agent selected from the group consisting of
antiplatelet agents, fibrinolytic agents, and thrombolytic
agents.
[0016] In another embodiment, the stent body filaments are
comprised of a biodegradable polymer.
[0017] The invention also contemplates an apparatus for delivery of
a stent as described above, the apparatus comprised of a catheter
suitable for delivery of the stent and the stent.
[0018] In yet another aspect, the invention includes a method for
inhibiting restenosis at a vascular injury site. The method
comprises delivering to the vascular injury site an endovascular
stent having an open-lattice structure formed of linked filaments,
and carried on the one or more filaments, a drug-release coating.
The drug release coating has a thickness of between 3-30 microns
and is composed of (i) 20-80 weight percent polymer substrate and
(ii) 20-80 weight percent macrocyclic triene compound having the
form: ##STR2## where R is CH.sub.2--CH.sub.2--OH. The stent is
expanded at the vascular injury site to bring the drug-release
coating in contact with the vessel at the injury site, where the
coating is effective to release an amount of the compound to
inhibit restenosis at the site.
[0019] In one embodiment, the stent body is a metal-filament
structure, and the polymer substrate in the coating is selected
from the group consisting of polymethylmethacrylate, ethylene vinyl
alcohol, poly-lactide polymers, .epsilon.-caprolactone, ethyl vinyl
acetate, polyvinyl alcohol, and polyethylene oxide. In one
preferred embodiment, the polymer substrate in the coating is
formed of poly-dl-lactide having a thickness between 3-20
microns.
[0020] In another embodiment, the stent for use in the method
further includes a polymer undercoat disposed between the filaments
of the stent body and the drug-release coating. Exemplary polymers
for the undercoat include ethylene vinyl alcohol, parylast,
silicone, a fluoropolymer, and parylene. In an exemplary stent, a
parylene polymer undercoat having a thickness of between 1-3
microns is deposited, the underlayer disposed between the filaments
of the stent body and a poly-dl-lactide coating substrate.
[0021] The compound can be present in the coating in an amount
between 20% to 90% by weight. In a preferred embodiment, the drug
release coating has a drug-to-polymer ratio of 54% drug and 46%
polymer by weight.
[0022] The polymer coating on the stent can further include a
bioactive agent selected from the group consisting of an
antiplatelet agent, a fibrinolytic agent, and a thrombolytic
agent.
[0023] In another aspect, the invention includes an improvement in
a method for inhibiting restenosis at a vascular injury site, by
placement at the site an intravascular stent designed to release a
macrocyclic triene compound over an extended period. The
improvement comprises employing as the macrocyclic triene compound,
a compound having the formula: ##STR3## where R is
CH.sub.2--CH.sub.2--OH.
[0024] In one embodiment, the improvement is for use where the
vascular injury is produced during an angiographic procedure in
which a vessel region is overstretched at least 30% in
diameter.
[0025] In another embodiment, the compound is carried on the stent
in a drug-release coating composed of a polymer substrate and
having between 20-80 weight percent of the compound.
[0026] These and other objects and features of the invention will
become more fully apparent when the following detailed description
of the invention is read in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIGS. 1 and 2 illustrate an endovascular stent having a
metal-filament body, and formed in accordance with one embodiment
of the present invention, showing the stent in its contracted (FIG.
1) and expanded (FIG. 2) conditions;
[0028] FIG. 3 is an enlarged cross-sectional view of a coated metal
filament in the stent of FIG. 1;
[0029] FIG. 4 is an enlarged cross-sectional view of coated polymer
stent;
[0030] FIGS. 5A and 5B are schematic illustrations of a polymer
coating method suitable for use in producing the coated stent of
the invention;
[0031] FIGS. 6A and 6B are plots showing release of everolimus from
stents constructed in accordance with the invention;
[0032] FIG. 7 is a cross-sectional view of a stent in the invention
deployed at a vascular site;
[0033] FIGS. 8A-8C are histological sections of a vessel 28 days
after implantation of a bare-metal stent;
[0034] FIGS. 9A-9C are histological sections of a vessel 28 days
after implantation of a metal-filament stent with a polymer
coating;
[0035] FIGS. 10A-10C and 11A-11C are histological sections of a
vessel 28 days after implantation of a metal-filament stent with a
polymer coating containing everolimus;
[0036] FIG. 12 is an enlarged histological section of a vessel seen
with a filament of the stent employed in FIGS. 10A-10C, which been
overgrown by new tissue forming a healed vessel wall;
[0037] FIG. 13 is a plot of area of stenosis at 28 days
post-implant, as a function of injury score, with a variety of
different stents, including those constructed in accordance with
the invention; and
[0038] FIG. 14 shows a correlation plot between injury score (Y
axis) and B/A (balloon/artery) ratio at time of stent
implantation.
DETAILED DESCRIPTION
I. Endovascular Stent
[0039] FIGS. 1 and 2 show a stent 20 constructed in accordance with
the invention, in the stent's contracted and expanded states,
respectively. The stent includes a structural member or body 22 and
an outer coating for holding and releasing an anti-restenosis
compound, as will be described further below with reference to
FIGS. 3 and 4.
[0040] A. Stent Body
[0041] In the embodiment shown, the stent body is formed of a
plurality of linked tubular members by filaments, such as members
24, 26. Each member has an expandable zig-zag, sawtooth, or
sinusoidal wave structure. The members are linked by axial links,
such as links 28, 30 joining the peaks and troughs of adjacent
members. As can be appreciated, this construction allows the stent
to be expanded from a contracted condition, shown in FIG. 1, to an
expanded condition, shown in FIG. 2, with little or no change in
the length of the stent. At the same time, the relatively
infrequent links between peaks and troughs of adjacent tubular
members allows the stent to accommodate bending. This feature may
be particularly important when the stent is being delivered to a
vascular site in its contracted state, in or on a catheter. The
stent has a typical contracted-state diameter (FIG. 1) of between
0.5-2 mm, more preferably 0.71 to 1.65 mm, and a length of between
5-100 mm. In its expanded state, shown in FIG. 2, the stent
diameter is at least twice and up to 8-9 times that of the stent in
its contracted state. Thus, a stent with a contracted diameter of
between 0.7 to 1.5 mm may expand radially to a selected expanded
state of between 2-8 mm or more.
[0042] Stents having this general stent-body architecture of
linked, expandable tubular members are known, for example, as
described in PCT Publication No. WO 99/07308, which is commonly
owned with the present application, and which is expressly
incorporated by reference herein. Further examples are described in
U.S. Pat. Nos. 6,190,406, 6,042,606, 5,860,999, 6,129,755, or
5,902,317, which patents are incorporated by reference herein.
Alternatively, the structural member in the stent may have a
continuous helical ribbon construction, that is, where the stent
body is formed of a single continuous ribbon-like coil. The basic
requirement of the stent body is that it be expandable, upon
deployment at a vascular injury site, and that it is suitable for
receiving a drug-containing coating on its outer surface, for
delivering drug contained in the coating into the vessel wall (i.e.
medial, adventitial, and endothelial layers of tissue) lining the
vascular target site. Preferably, the body also has a lattice or
open structure, allowing endothelial cell wall ingrowth "through"
the stent from outside to inside.
[0043] B. Stent Coatings
[0044] According to an important feature of the invention, the
stent filaments are coated with a drug-release coating composed of
a polymer matrix and an anti-restenosis compound (active compound)
distributed within the matrix for release from the stent over an at
least a several week period, typically 4-8 weeks, and optionally
over a 2-3-month period or more.
[0045] FIG. 3 shows, in enlarged sectional view, a stent filament
24 having a coating 32 that covers the filament completely on all
sides, that is, on top (the filament side forming the outer surface
of the stent body) bottom (the filament side forming the interior
surface of the stent) and the opposing filament sides. As will be
discussed further below, the coating has a thickness typically
between 3 and 30 microns, depending on the nature of the polymer
matrix material forming the coating and the relative amounts of
polymer matrix and active compound. Ideally, the coating is made as
thin as possible, e.g., 15 microns or less, to minimize the stent
profile in the vessel at the injury site.
[0046] The coating should also be relatively uniform in thickness
across the upper (outer) surfaces, to promote even distribution of
released drug at the target site. Methods for producing a
relatively even coating thickness on stent filaments are discussed
below in Section II.
[0047] Also shown in FIG. 3 is a polymer underlayer 34 disposed
between the stent filament and the coating. The purpose of the
underlayer is to help bond the coating to the stent-body filaments,
that is, to help stabilize the coating on the filaments. As will be
seen below, this function is particularly valuable where the
coating is formed of a polymer substrate containing a high
percentage of anti-restenosis compound, e.g. between 35-80 weight
percent compound. One exemplary underlayer polymer is parylene, and
in one embodiment parylene is used in conjunction with a polymer
substrate formed of bioerodable (poly-dl-lactide). Other suitable
polymer underlayers are ethylene vinyl alcohol (EVOH),
paryLAST.TM., silicone, TEFLON.TM. and other fluoropolymers that
may be deposited on the metal stent surfaces by plasma-coating or
other coating or deposition processes. The underlayer has a typical
thickness between 1-5 microns.
[0048] The polymer forming the substrate may be any biocompatible
polymer material from which entrapped compound can be released by
diffusion and/or released by erosion of the polymer matrix. Two
well-known non-erodable polymers for the coating substrate are
polymethylmethacrylate and ethylene vinyl alcohol. Methods for
preparing these polymers in a form suitable for application to a
stent body are described for example, in US 2001/0027340A1 and WO
01/45763 A1, incorporated herein by reference. In general, the
limit of drug addition to the polymers is about in the range of
20-40 weight percent.
[0049] Bioerodable polymers, particularly poly-dl-lactide polymer,
are also suitable for coating substrate material. In one general
embodiment, of the invention, the coating is a bioerodable
poly-dl-lactide polymer substrate, i.e., poly-dl-lactic acid
polymer, that may contain up to 80% by dry weight of the active
compound distributed within the polymer substrate. More generally,
the coating contains 35-80% dry weight active compound and 20-65%
percent by dry weight of the polymer. Exemplary coatings include
25-50% dry weight polymer matrix and 50-75 weight percent active
compound. The polymer is formulated with the active compound for
deposition on the stent filaments as detailed in Section II
below.
[0050] A variety of anti-restenosis compounds may be employed in
the embodiment, including anti-proliferative agents, such as taxol,
antisense compounds, doxorubicin, and most particularly,
macrocyclic triene immunosuppressive compounds having the general
structure indicated below. The latter class of compounds, and their
synthesis, are described, for example in U.S. Pat. Nos. 4,650,803,
5,288,711, 5,516,781, 5,665,772, 6,273,913, and 6,153,252, in PCT
Publication No. WO 97/35575, and in published U.S. patent
applications Nos. 60/176,086, 2000/0212/17, and 2001/0029351 A1,
all of which are incorporated herein by reference. An exemplary
macrocyclic triene immunosuppressive compound has the form:
##STR4## where (i) R is H or CH.sub.2--X--OH, and X is CH.sub.2.
This compound is known as everolimus. Where R.dbd.H, the compound
is known as rapamycin.
[0051] One preferred coating is formed of 25-50 weight percent
poly-dl-lactide polymer substrate, and 50-75 weight percent
macrocyclic triene immunosuppressant compound, having a coating
thickness of between 3-15 microns. The underlayer is formed of
parylene, and has a thickness between 1-5 microns. This embodiment
typically contains an amount of compound equal to about 15
micrograms drug/mm of stent length.
[0052] In another exemplary embodiment, the coating is formed of
15-35 weight percent of an erodable or non-erodable polymer
substrate, and 65-85 weight percent of the macrocyclic triene
compound. The coating thickness is preferably 10-30 microns, and
the stent may include a 1-5 micron polymer underlayer, e.g.,
parylene underlayer. This embodiment typically contains an amount
of compound equal to about 15 micrograms drug/mm of stent
length.
[0053] The coating may additionally include a second bioactive
agent effective to minimize blood-related events, such as clotting,
that may be stimulated by the original vascular injury, the
presence of the stent; or to improve vascular healing at the injury
site. Exemplary second agents include anti-platelet, fibrinolytic,
or thrombolytic agents in soluble crystalline form. Exemplary
anti-platelet, fibrinolytic, or thrombolytic agents are heparin,
aspirin, hirudin, ticlopidine, eptifibatide, urokinase,
streptokinase, tissue plasminogen activator (TPA), or mixtures
thereof. The amount of second-agent included in the stent coating
will be determined by the period over which the agent will need to
provide therapeutic benefit. Typically, the agent will be
beneficial over the first few days after vascular injury and stent
implantation, although for some agents, longer period of release of
the agent will be required.
[0054] The second agent may be included in the coating formulation
that is applied to the stent-body filaments, according to known
methods.
[0055] C. Bioerodable Stent
[0056] In another general embodiment, both the stent body and
polymer coating are formed of a bioerodable polymer, allowing
complete resorption of the stent over time. The stent preferably is
an expandable coiled stent having a helical-ribbon filament forming
the stent body (not shown). Self-expandable coil stents are
described in U.S. Pat. No. 4,990,155 for implantation into blood
vessels and are incorporated herein by reference.
[0057] A coiled stent, may be formed using a preform with the final
expanded diameter of the preform specified to be slightly larger
than the internal lumen size of the blood vessel to be treated with
the coil (3.5 mm OD.+-.1 mm would be common for a coronary artery).
More generally, the stent may be formed by molding, in its expanded
shape, and placed in its contracted state by twisting around the
stent's long axis or forcing the stent radially into a contracted
condition for delivery to the blood vessel when mounted on the tip
of a catheter. The stent has a total thickness preferably between
about 100 and 1000 microns, and a total length of between 0.4 and
10 cm. In fact, an important advantage of a bioerodable stent of
this type is that relatively long stents, e.g., over 3 cm in
length, can be readily delivered and deployed at a vascular injury
site.
[0058] Methods for forming balloon-expandable stents formed of a
knitted, bioerodable polymer filament such as poly-l-lactide have
been reported (U.S. Pat. No. 6,080,177). A version of the device
has also been adapted to release drugs (U.S. Pat. No.
5,733,327).
[0059] A preferred polymer material for forming the stent is
poly-l-or poly-dl-lactide (U.S. Pat. No. 6,080,177). As indicated
above, the stent body and coating may be formed integrally as a
single expandable filament stent having anti-restenosis compound
contained throughout. Alternatively, a bioerodable coating may be
applied to a preformed bioerodable body, as detailed in Section II
below. In the latter case, the stent body may be formed of one
bioerodable polymer, such as poly-l-lactide polymer, and the
coating from a second polymer, such as poly-dl-lactide polymer. The
coating, if applied to a preformed stent, may have substantially
the same compositional and thickness characteristics described
above.
[0060] FIG. 4 shows a cross section of a filament, e.g., helical
ribbon, in a bioerodable stent of the type just described, having
separately formed polymer body and coating. The figure shows an
internal polymer stent filament 36 coated on all sides with a
bioerodable coating 38. An exemplary coating is formed of
poly-dl-lactide and contains between 20-40 weight percent
anti-restenosis drug, such as the macrocyclic triene
immunosuppressant compound everolimus, and 60-80 weight percent
polymer substrate. In another general embodiment, the coating
contains 45-75 weight percent compound, and 25-55 weight percent
polymer matrix. Other types of anti-restenosis compounds, such as
listed above, may be employed in either embodiment.
[0061] The bioerodable stent has the unique advantage of treating
the entire vessel with one device, either in conjunction with
pre-dilatation of the vessel with balloon angioplasty if large
obstructions are present, or as a prophylactic implant in patients
of high risk of developing significant future blockages. Since the
stent is fully biodegradable, it does not affect the patient's
chances for later uncomplicated surgery on the vessel, as does a
"full metal jacket," i.e., a string of drug eluting stents
containing metal substrates.
[0062] A secondary agent, such as indicated above, may be
incorporated into the coating for release from the coating over a
desired time period after implantation. Alternatively, if a
secondary agent is used, it may be incorporated into the stent-body
filament if the coating applied to the stent body does not cover
the interior surfaces of the stent body. The coating methods
described below in Section II with respect to a metal-filament
stent body are also suitable for use in coating a polymer-filament
stent body.
II. Stent Coating Methods
[0063] Referring now to FIGS. 5A and 5B, schematic illustrations of
a stent coating process according to the invention are shown. A
polymer solution 40 is made by dissolving a polymer in a compatible
solvent. At least one anti-restenosis compound, and if desired, a
secondary agent, is added to the solution, either as a suspension
or in solution using the same solvent or a different solvent. The
completed mixture is placed in a pressurizable reservoir 42.
Connected to the reservoir is a fluid pressurization pump 44.
[0064] The pressurization pump may be any source of pressure
capable of urging the solvent mixture to move at a programmed rate
through a solution delivery tube 46. The pressure pump 44 is under
the control of a microcontroller (not shown), as is well known in
the field of precision dispensing systems. For example, such a
microcontroller may comprise 4-Axis Dispensing Robot Model numbers
I&J500-R and I&J750-R available from I&J Fisnar Inc, of
Fair Lawn, N.J., which are controllable through an RS-232C
communications interface by a personal computer, or precision
dispensing systems such as Automove A-400, from Asymtek, of
Carlsbad, Calif. A suitable software program for controlling an
RS232C interface may comprise the Fluidmove system, also available
from Asymtek Inc, Carlsbad, Calif.
[0065] Attached to reservoir 42, for example, at the bottom of the
reservoir, is a solution delivery tube 48 for delivery of the
solvent mixture to the surface of the stent. The pressurizable
reservoir 42 and delivery tube 48 are mounted to a moveable support
(not shown) which is capable of moving the solvent delivery tube in
small steps such as 0.2 mm per step, or continuously, along the
longitudinal axis of the stent as is illustrated by arrow X1. The
moveable support for pressurizable reservoir 42 and delivery tube
46 is also capable of moving the tip (distal end) of the delivery
tube closer to the microfilament surface or up away from the
microfilament surface in small steps as shown by arrow Y1.
[0066] The uncoated stent is gripped by a rotating chuck contacting
the inner surface of the stent at least one end. Axial rotation of
the stent can be accomplished in small degree steps, such as 0.5
degree per step, to reposition the uppermost surface of the stent
structure for coating by the delivery tube by attachment of a
stepper motor to the chuck as is well known in the art. If
desirable, the stent can be rotated continuously. The method of
precisely positioning a low volume fluid delivery device is well
known in the field of X-Y-Z solvent dispensing systems and can be
incorporated into the present invention.
[0067] The action of the fluid pressurizing pump, X1 and Y1
positioning of the fluid delivery tube, and R1 positioning of the
stent are typically coordinated by a digital controller and
computer software program, such that the precisely required amount
of solution is deposited wherever desired on the surfaces of the
stent, whereupon the solvent is allowed to escape, leaving a
hardened coating of polymer and agent on the stent surfaces.
Typically, the viscosity of the solvent mixture is prepared by
varying the amount of solvent, and it ranges from 2 centipoise to
2000 centipoise, and typically can be 300 to 700 centipoise.
Alternatively, the delivery tube can be held at a fixed position
and, in addition to the rotation movement, the stent is moved along
its longitudinal direction to accomplish the coating process.
[0068] The X-Y-Z positioning table and moveable support may be
purchased from I&J Fisnar. The solution delivery tube preferred
dimensions are preferably between 18-28 gauge stainless steel
hypotubes mounted to a suitable locking connector. Such delivery
tubes may be obtained from EFD Inc of East Providence, R.I. See
EFD's selection guide for Special Purpose Tips. The preferred tips
are reorder #'s 5118-1/4-B through 5121-1/4-B "Burr-free passivated
stainless steel tips with 1/4'' length for fast point-to-point
dispensing of particle-filled or thick materials", reorder #'s
51150VAL-B "Oval stainless steel tips apply thick pastes, sealants,
and epoxies in flat ribbon deposits", and reorder #'s 5121-TLC-B
through 5125-TLC-B "Resists clogging of cyanoacrylates and provides
additional deposit control for low viscosity fluids. Crimped and
TEFLON.TM. lined". A disposable pressurizable solution reservoir is
also available from EFD, stock number 1000Y5148 through 1000Y5152F.
An alternate tip for use with the invention is a glass
micro-capillary with an I.D. of about 0.0005 to 0.002 inch, such as
about 0.001 inch, which is available from VWR Catalog No. 15401-560
"Microhematocrit Tubes", 60 mm length, I.D. 0.5-0.6 mm.
[0069] The tubes are further drawn under a Bunsen burner to achieve
the desired I.D. for precise application of the
polymer/drug/solvent mixture. The programmable microcontroller to
operate the stepper motor, and XYZ table is available from Asymtek,
Inc. It is within the scope of the invention to use more than one
of the fluid dispensing tube types working in concert to form the
coating, or alternately to use more than one moveable solution
reservoir equipped with different tips, or containing different
viscosity solutions or different chemical makeup of the multiple
solutions in the same process to form the coating. The chuck and
stepper motor system may be purchased from Edmund Scientific of
Barrington, N.J.
[0070] Typically, as described above, the coating is applied
directly onto the outside support surface(s) of the stent, and may
or may not cover the entire or a portion(s) of the inside
surface(s) of the stent depending on how control is applied to the
above described coating system of the present invention, as
illustrated in FIGS. 5A and 5B. The latter figure shows application
of a coating material 52 to top and side regions of a filament 50.
Alternatively, the coating or coating mixture can also be applied
directly onto the inside surface of the stent. A thin delivery tip
may penetrate through one or more of the cut out areas (i.e.
windows) in the wall of the stent structure, and thereby apply the
coating mixture directly onto the inside surfaces at desired areas.
In this method, it is possible to apply different coating materials
having different drug components to outer and inner sides of the
filaments. For example, the coating on the outer filament surfaces
could contain an anti-restenosis compound, and the coating of the
inner filament surfaces, one of the above secondary agents, such an
anti-thrombotic or anti-clotting compound. If the stent has a large
enough diameter, a thin "L-shaped" delivery tip can be inserted
into the stent open ends along the longitudinal axis of the stent
for the purpose of applying coating to the inside surfaces.
[0071] The polymer for use in the invention includes, but is not
limited to, poly(d,l-lactic acid), poly(l-lactic acid),
poly(d-lactic acid), ethylene vinyl alcohol (EVOH), e-caprolactone,
ethylvinyl hydroxylated acetate (EVA), polyvinyl alcohol (PVA),
polyethylene oxides (PEO), and co-polymers thereof and mixtures
thereof, dissolved in a suitable solvent or solvent mixture
Exemplary solvents include chloroform, ethyl acetate, acetone, and
the like, and mixtures of these solvents. These polymers all have a
history of safe and low inflammatory use in the systemic
circulation.
[0072] A non-polymer coating such as everolimus which has been
ionically bound to the metal stent surface can also be used in the
present invention.
[0073] Using the coating system as described, it has been
discovered that it is feasible to coat all of the top, side, and
inside surfaces of the stent. By the careful selection of a
suitable ratio of solvent to polymer, the viscosity of the solution
can be adjusted such that some of the solution will migrate down
the sides of the strut and actually inhabit the bottom surface
before solidifying, as shown in FIG. 5B. By controlling the dwell
time of the delivery tube close to the edge of the stent, the
amount of polymer coating the edges or bottom of the stent can be
increased or reduced. In the embodiment illustrated in FIG. 3, an
underlayer 34 of pure polymer and solvent is applied to the stent
surfaces 24 first using the coating system of the invention and the
solvent is allowed to evaporate. Then a second layer of polymer 32
is applied containing the bioactive agent.
[0074] As noted above, a secondary agent may be incorporated into
the polymer mixture. As an example, heparin in crystalline form may
be incorporated into the coating. The heparin crystals are
micronized to a particle size of approximately 1-5 microns and
added in suspension to the polymer solution. Suitable forms of
heparin are those of crystalline form that exhibit bioactivity in
mammalian hosts when applied according to the process of the
invention, including heparin salts (i.e. sodium heparin and low
molecular weight forms of heparin and their salts). Upon deployment
of the drug delivering stent 62 into vessel wall 60, as seen in
FIG. 7, the heparin crystals near the surface of the coating of
cured polymer 66 begin to dissolve, increasing the porosity of the
polymer. As the polymer slowly dissolves, more heparin and
bioactive agent are released in a controlled manner, as indicated
by arrows 68.
[0075] It should be appreciated however, with reference to FIG. 7,
that it is not always desirable to coat the inside surfaces of the
stent (indicated at 64 in FIG. 7). For example, coating the inside
surface of the stent increases the crimped delivery profile of the
device, making it less maneuverable in small vessels. And, after
implantation, the inside surfaces are directly washed by the flow
of blood through the stent, causing any drug released on the inside
surface to be lost to the systemic circulation. Therefore, in the
embodiments shown in FIGS. 3 and 4, the bulk of the cured polymer
and agent is deployed on the outside circumference of the stent
supports, and secondarily on the sides. In a preferred embodiment,
only a minimum amount of polymer and agent is applied on the inside
surfaces of the stent. If desired, it is also possible to have at
least a portion of the inside surfaces of the stent uncoated or
exposed.
[0076] Further, the coating of FIGS. 3 and 4, may be placed onto
the stent filament surfaces in a selective manner. The depth of the
coated section may correspond to the volume of bioactive coating to
be available for presentation to the tissue. It may be advantageous
to restrict the coating from certain areas, such as those which
could incur high strain levels during stent deployment.
[0077] A uniform underlayer may be first placed on the stent
surface to promote adhesion of the coating that contains the
bioactive agent, and/or to help stabilize the polymer coating on
the stent. The primer coat may be applied by using any of the
methods as already known in the art, or by the precision dispensing
system of the invention. It is also within the scope of the
invention to apply a primer coat using a different polymer
material, such as parylene (poly(dichloro-para-xylylene)) or a
parylene derivative or analog, or any other material which exhibits
good adhesion to both the base metal substrate and the coating
which contains the bioactive agent. Parylene
(poly(dichloro-para-xylylene)) may be deposited via plasma
deposition or vapor deposition techniques, as is well known in the
art and described, for example, in U.S. Pat. No. 6,299,604, the
portions of which relating to plasma and vapor deposition of
parylene are incorporated by reference herein. In one embodiment of
the present invention, islands or a layer of a coating containing
heparin are formed on inside surface(s) of a stent and an
anti-proliferation coating containing the drugs of the present
invention as described above is formed on outside surface(s) of the
stent.
[0078] Where it is desired to form a coating with a high
drug/polymer substrate ratio, e.g., where the drug constitutes
40-80 weight percent of the coating on a metal stent substrate, it
is advantageous to form an underlayer on the stent filaments to
stabilize and firmly attach the coating to the substrate. The
underlayer may be further processed, prior to deposition of the
coating material, by swelling in a suitable solvent, e.g., acetone,
chloroform, ethyl acetate, xylene, or mixtures thereof. This
approach is described in Example 5 for preparing a stent having a
high ratio of everolimus to poly-dl-lactide.
[0079] Here a parylene underlayer is formed on the stent filaments
by plasma deposition, and the underlayer then allowed to swell in
xylene prior to final deposition of the coating material. The
method was effective in producing coating containing 50% drug in
one case and 75% drug in another case in a poly-dl-lactide polymer
substrate, in a coating having a thickness of only 5-10
microns.
III. Methods of Use and Performance Characteristics
[0080] This section describes vascular treatment methods in
accordance with the invention, and the performance characteristics
of stents constructed in accordance with the invention.
[0081] A. Methods
[0082] The methods of the invention are designed to minimize the
risk and/or extent of restenosis in a patient who has received
localized vascular injury, or who is at risk of vascular occlusion.
Typically the vascular injury is produced during an angiographic
procedure to open a partially occluded vessel, such as a coronary
or peripheral vascular artery. In the angiographic procedure, a
balloon catheter is placed at the occlusion site, and a distal-end
balloon is inflated and deflated one or more times to force the
occluded vessel open. This vessel expansion, particularly involving
surface trauma at the vessel wall where plaque may be dislodged,
often produces enough localized injury that the vessel responds
over time by cell proliferation and reocclusion. Not surprisingly,
the occurrence or severity of restenosis is often related to the
extent of vessel stretching involved in the angiographic procedure.
Particularly where overstretching is 35% or more, restenosis occurs
with high frequency and often with substantial severity, i.e.,
vascular occlusion.
[0083] In practicing the present invention, the stent is placed in
its contracted state typically at the distal end of a catheter,
either within the catheter lumen, or in a contracted state on a
distal end balloon. The distal catheter end is then guided to the
injury site, or the site of potential occlusion, and released from
the catheter, e.g., by using a trip wire to release the stent into
the site, if the stent is self-expanding, or by expanding the stent
on a balloon by balloon inflation, until the stent contacts the
vessel walls, in effect, implanting the stent into the tissue wall
at the site.
[0084] Once deployed at the site, the stent begins to release
active compound into the cells lining the vascular site, to inhibit
cellular proliferation. FIG. 6A shows everolimus release kinetics
from two stents constructed in accordance with the invention, each
having an approximately 10 micron thick coating (closed squares).
Drug-release kinetics were obtained by submerging the stent in a
25% ethanol solution, which greatly accelerates rate of drug
release from the stent coating. The graphs indicate the type of
drug release kinetics that can be expected in vivo, but over a much
longer time scale.
[0085] FIG. 6B shows drug release of everolimus from coatings of
the present invention on metal stent substrates. The upper set of
curves shows drug release where the coating has been applied
directly to the metal surface. The lower set of curves (showing
slower release) were obtained by applying an underlayer or primer
coat of parylene to the metal stent surface, followed by coating of
the surface with the coating system of the invention. As seen, the
primer increases the mechanical adhesion of the coating to the sent
surface, resulting in slower breakdown of the bioerodable coating
and slower release of drug. Such a configuration is useful where it
desired to have a strongly attached stent coating which can
withstand repeated abrasions during tortuous maneuvering of the
drug eluting stent inside the guide catheter and/or vessel, and/or
where it is desired to slow down the drug release for extended
treatment of the atherosclerosis disease process at the implant
site following implantation of the device.
[0086] FIG. 7 shows in cross-section, a vascular region 60 having
an implanted stent 62 whose coated filaments, such as filament 64
with coating 66, are seen in cross section. The figure illustrates
the release of anti-restenosis compound from each filament region
into the surrounding vascular wall region. Over time, the smooth
muscle cells forming the vascular wall begin to grow into and
through the lattice or helical openings in the stent, ultimately
forming a continuous inner cell layer that engulfs the stent on
both sides. If the stent implantation has been successful, the
extent of late vascular occlusion at the site will be less than
50%, that is, the cross-sectional diameter of flow channel
remaining inside the vessel will be at least 50% of expanded stent
diameter at time of implant.
[0087] Trials in a swine restenosis animal model as generally
described by Schwartz et al. ("Restenosis After Balloon
Angioplasty-A Practical Proliferative Model in Porcine Coronary
Arteries", Circulation 82:(6) 2190-2200, December 1990.)
demonstrate the ability of the stent of this invention to limit the
extent of restenosis, and the advantages of the stent over
currently proposed and tested stents, particularly in cases of
severe vascular injury, i.e., greater than 35% vessel stretching.
The studies are summarized in Example 4.
[0088] Briefly, the studies compare the extent of restenosis at 28
days following stent implantation, in bare metal stents,
polymer-coated stents, and polymer-coated stents containing high or
low concentrations of sirolimus (rapamycin) and everolimus.
[0089] Table 1 in Example 4 shows that both rapamycin (Rapa-high or
Rapa-low) and everolimus stents (C-high or C-low) greatly reduced
levels of restenosis, with the smallest amount of restenosis being
observed in the high-dose everolimus stent. Similar results were
obtained in studies on animals with low injury (Table 2).
[0090] FIGS. 8A-8C are examples of stent cross-sections of
neointimal formation at 28 days in a bare metal S-Stent (available
from Biosensors International Inc, Newport Beach, Calif.). FIGS.
9A-9C are examples of neointimal formation in a polymer-coated (no
drug) S-Stent; and FIGS. 10A-10C and 11A-11C of neointimal
formation in everolimus/polymer coated stents. In general, the
vessels with everolimus-coated stent treatment appeared to be
well-healed with a well established endothelial layer, evidence of
complete healing and vessel homeostasis at 28 days. FIG. 12 is an
example of vessel cross-section at 91.times. magnification showing
healing and establishment of an endothelial layer on the inside of
the vessel lumen at 28 days post implant.
[0091] The photographs indicate that the most favorable combination
for elimination of restenosis at 28 days is the C-high, or C-Ulight
formulation (see Example 4), which contained 325 microgram and 275
microgram dosages of everolimus, respectively, on a 18.7 mm length
stent. The data predicts a 50% reduction in restenosis compared to
a currently marketed bare metal stent (the S-Stent) at 28 days
follow-up in outbred juvenile swine. The data also shows that the
drug everolimus is better than, or at least equivalent to the 180
microgram dosage of sirolimus on the same stent/polymer delivery
platform. These results are supported by morphometric analysis
(Example 4).
[0092] FIG. 13 is a plot showing "best fit" linear regression
curves of the chosen dosings of agents in polymers, coated on the
S-Stent, relating injury score to area stenosis at follow-up. Area
stenosis is an accurate indicator of neointimal formation which is
determined by morphometric analysis. As can be seen from this
chart, the high everolimus stent was the only coating in the group
of samples tested that exhibited a negative slope vs. increasing
injury score. This analysis suggests that the C-high coating may be
capable of controlling restenosis in an injured coronary artery
which is virtually independent of injury score. None of the other
coating formulations tried exhibited this unique
characteristic.
[0093] FIG. 14 shows the relationship between balloon overstretch
of the vessel, as measured by balloon/artery ration (B/A Ratio),
and vessel injury, in the animal experiment. This data shows that
use of an over-expanded angioplasty balloon to create a high
controlled vessel injury is a reasonably accurate method of
creating a predictable and known vascular injury in the porcine
model.
[0094] From the foregoing, it can be seen how various objects and
features of the invention are met. In one aspect, the invention
provides a bioerodable stent coating with high drug/polymer ratios,
e.g., 40-80% drug by weight. This feature allows continuous
delivery of an anti-restenosis compound over an extended period
from a low-profile stent. At the same time, the total amount of
polymer breakdown components such as lactide and lactic acid
released during bioerosion is relatively small, minimizing possible
side effects, such as irritation, that may result from bioerosion
of the stent coating.
[0095] In another aspect, the invention provides an improved method
for treating or inhibiting restenosis. The method, which involves a
novel combination of macrocyclic triene immunosuppressant compound
in a stent polymer coating, provides at least the effectiveness
against restenosis as the best stent in the prior art, but with the
added advantage over the prior art that the efficacy of the method
appears to be independent of the extent of injury, and the method
may offer a greater degree of endothelialization of the stented
vessel.
[0096] Finally, the method provides a completely bioerodable stent
that has the advantageous features just mentioned and the more
design flexibility than a metal-body stent, particularly in total
stent length and future operability on the treated vessel.
[0097] The following examples illustrate various aspects of the
making and using the stent invention herein. They are not intended
to limit the scope of the invention.
EXAMPLE 1
Preparation of Everolimus
STEP A. Synthesis of 2-(t-butyidimethylsilyl)oxyethanol(TBS
glycol)
[0098] 154 mL of dry THF and 1.88 g NaH are stirred under in a
nitrogen atmosphere in a 500 mL round bottom flask condenser. 4.4
mL dry ethylene glycol is added into the flask, resulting in a
large precipitate after 45 minutes of stirring. 11.8 g
tert-butyldimethylsilyl chloride is added to the flask and vigorous
stirring is continued for 45 minutes. The resulting mixture is
poured into 950 mL ethylether. The ether is washed with 420 mL
brine and solution is dried with sodium sulfate. The product is
concentrated by evaporation of the ether in vacuo and purified by
flash chromatography using a 27.times.5.75 cm column charged with
silica gel using a hexanes/Et.sub.2O (75:25v/v) solvent system. The
product is stored at 0.degree. C.
STEP B. Synthesis of 2-(t-butyidimethylsilyl)oxyethyl triflate (TBS
glycol Trif)
[0099] 4.22 g TBS glycol and 5.2 g 2,6-lutidine are combined in a
double-necked 100 mL flask with condenser under nitrogen with
vigorous stirring. 10.74 g of trifluoromethane sulfonic anhydride
is added slowly to the flask over a period of 35-45 minutes to
yield a yellowish-brown solution. The reaction is then quenched by
adding 1 mL of brine, and the solution washed 5 times in 100 mL
brine to a final pH value of between 6-7. The solution is dried
using sodium sulfate, and concentrated by evaporation of the
methylene chloride in vacuo. The product is purified using a flash
chromatography column of approximately 24.times.3 cm packed with
silica gel using hexane/Et.sub.2O (85:15v/v) solvent system, then
stored at 0.degree. C.
STEP C. Synthesis of
40-O-[2-(t-butyidimethylsilyl)oxy]ethyl-rapamycin (TBS Rap)
[0100] 400 mg rapamycin, 10 mL of toluene, and 1.9 mL 2,6-lutidine
are combined and stirred in a 50 mL flask maintained at
55-57.degree. C. In a separate 3 mL septum vial, 940 .mu.L
2,6-lutidine is added to 1 mL toluene, followed by addition of 2.47
g TBS glycol Trif. The contents of the vial are added to the 50 mL
flask and the reaction allowed to proceed for 1.5 hours with
stirring. 480 .mu.L 2,6-lutidine plus an additional 1.236 g TBS
glycol Trif is added to the reaction flask. Stirring is continued
for an additional hour. Finally, a second portion of 480 .mu.L
2,6-lutidine and 1.236 g TBS glycol Trif is added to the mixture,
and the mixture is allowed to stir for an additional 1-1.5 hours.
The resulting brown solution is poured through a porous glass
filter-using vacuum. The crystal like precipitate is washed with
toluene until all color has been removed. The filtrate is then
washed with 60 mL saturated NaHCO.sub.3 solution twice and then
washed again with brine. The resulting solution is dried with
sodium sulfate and concentrated in vacuo. A small quantity of a
hexanes/EtOAc (40:60 v/v) solvent is used to dissolve the product,
and purification is achieved using a 33.times.2 cm flash
chromatography column packed with silica gel, and developed with
the same solvent. The solvent is removed in vacuo and the product
stored at 5C.
STEP D. Synthesis process of 40-O-(2-hydroxyl)ethyl-rapamycin
(everolimus)
[0101] A PYREX.TM. glass dish (150.times.75 mm) is filled with ice
and placed on a stirring plate. A small amount of water is added to
provide an ice slurry. 60-65 mg of TBS-Rap is first dissolved in a
glass vial by adding 8 mL methanol. 0.8 mL 1 N HCl is added to the
vial, the solution is stirred for 45 minutes and then neutralized
by adding 3 mL aqueous saturated NaHCO.sub.3. 5 mL brine is added
to the solution, followed with 20 mL EtoAc, resulting in the
formation of two phases. After mixing of the phases, a separatory
funnel is used to draw off the aqueous layer. The remaining solvent
is washed with brine to a final pH of 6-7, and dried with sodium
sulfate. The sodium sulfate is removed using a porous glass filter,
and the solvent removed in vacuo. The resulting concentrate is
dissolved in EtoAc/methanol (97:3) and then purified using in a
23.times.2 cm flash chromatography column packed with silica gel,
and developed using the same solvent system. The solvent is removed
in vacuo and the product stored at 5.degree. C.
EXAMPLE 2
Preparation of Stent Containing Everolimus in a poly-dl-lactide
Coating
[0102] 100 mg poly (dl-lactide) was dissolved into 2 mL acetone at
room temperature. 5 mg everolimus was placed in a vial and 400
.mu.L lactide solution added. A microprocessor-controlled syringe
pump was used to precision dispense 10 .mu.L of the drug containing
lactide solution to the stent strut top surfaces. Evaporation of
the solvent resulted in a uniform, drug containing single polymer
layer on the stent.
[0103] A 15 .mu.L volume was used in a similar manner to coat the
stent top and side strut surfaces, resulting in a single layer
coating on the stent strut top and sides.
EXAMPLE 3
In Vitro Drug Release from Stent Containing Everolimus in a
poly-dl-lactide Coating
[0104] In vitro drug release was conducted by placing the coated
stents into 2 mL pH 7.4 phosphate buffered saline solution
containing 25% ETOH, and preserved with 0.05% (w/v) sodium azide
and maintained at 37.degree. C. Sampling was periodically conducted
by withdrawing the total buffer volume for drug measurement while
replacing solution with a similar volume of fresh buffer (infinite
sink). FIG. 6 illustrates drug release from two similar stents
coated with a single polymer layer microdispensed in this
manner.
EXAMPLE 4
Animal Implant Tests
[0105] A. QCA Results of Safety and Dose-Finding Studies in
Swine
Rationale:
[0106] It was reasoned that the most challenging treatment
condition for the drug eluting stent is a severely injured vessel,
as it is known that the degree of restenosis (neointimal formation)
increases directly with extent of vessel injury. Experiments were
conducted in pigs, and a substantial number of the vessels which
were the target of drug-coated stent implants were seriously
injured (averaging approximately 36% overstretch injury of the
vessel) using an angioplasty balloon. This caused severe tearing
and stretching of the vessel's intimal and medial layers, resulting
in exuberant restenosis at 28 days post implant. In this way, it
was possible to assess the relative effectiveness of various
dosings of drug, and drug to polymer weight ratios on the same
metal stent/polymer platform for reduction of restenosis at 28 days
post-implant.
Definitions:
[0107] 1. Bare stent: An 18.7 mm bare metal stent of a corrugated
ring design (i.e. a currently marketed "S-Stent" as manufactured by
Biosensors Intl., Inc).
[0108] 2. C-high: An 18.7 mm long stent carrying 325 micrograms of
everolimus in a PDLA (poly-dl-lactate) polymer coating.
[0109] 3. C-low: An 18.7 mm long stent carrying 180 micrograms of
everolimus in a PDLA polymer coating.
[0110] 4. Rap-high: An 18.7 mm long stent carrying 325 micrograms
of sirolimus in a PLA polymer coating.
[0111] 5. Rap-low: An 18.7 mm long stent carrying 180 micrograms of
sirolimus in a PDLA polymer coating.
[0112] 6. C-Ulight: An 18.7 mm long stent carrying 275 micrograms
of Everolimus in an ultrathin coating of PDLA polymer (37% drug to
polymer weight ratio).
[0113] 7. C-Ulow: An 18.7 mm long stent carrying 180 micrograms of
Everolimus or equivalent in an ultrathin coating of PDLA polymer
(37% drug to polymer weight ratio).
[0114] 8. Polymer stent: An 18.7 mm S-Stent stent covered by PDLA
polymer coating only.
[0115] 9. B/A is the final inflated balloon-to-artery ratio, an
indication of the extent of overstretching of the vessel.
[0116] 10. Mean Lumen Loss (MLL)-Average of 3 measurements taken
inside the stent internal lumen at time of implant minus average of
3 measurements at follow-up angiography indicates the amount of
neointima that has formed inside the stent.
Methods:
[0117] Drug-eluting stents using a metal wire-mesh scaffold of a
corrugated ring design (i.e. S-Stent) and polymer coating were
implanted in out-bred juvenile swine (alternately Yucatan Minipigs
for implant studies lasting longer than 28 days), using different
dosings of either the drug everolimus or the drug sirolimus. At
time of implant, Quantitative Coronary Angiography (QCA) was
performed to measure the diameter of the vessels both before and
after stent implantation. At 28 days, or longer when specified in
the table below, the animals were again subjected to QCA in the
area of the stent, prior to euthanization.
[0118] Following euthanasia of animals according to approved
protocols, the hearts were removed from the animals and pressurized
formaldehyde solution was infused into the coronary arteries. The
coronary segments containing the stents were then surgically
removed from the surface of the heart and subsequently fixed in
acrylic plastic blocks for transverse sectioning with a diamond
saw. Sections of the acrylic material, 50 .mu.m in thickness,
containing cross-sections of the vessels located proximally,
center, and distally were then optically polished and mounted to
microscope slides.
[0119] A microscope containing a digital camera was used to
generate high resolution images of the vessel cross-sections which
had been mounted to slides. The images were subjected to
histomorphometric analysis by the procedure as follows:
[0120] A computerized imaging system Image Pro Plus 4.0 through an
A. G. Heinze slide microscope for a PC-based system was used for
histomorphometric measurements of:
[0121] 1. The mean cross sectional area and lumen thickness (area
circumscribed by the intima/neointimal-luminal border); neointimal
(area between the lumen and the internal elastic lamina, IEL, and
when the IEL was missing, the area between the lumen and the
remnants of media or the external elastic lamina, EEL); media (area
between the IEL and EEL); vessel size (area circumscribed by the
EEL but excluding the adventitial area); and adventitia area (area
between the periadventitial tissues, adipose tissue and myocardium,
and EEL).
[0122] 2. The injury score. To quantify the degree of vascular
injury, a score based on the amount and length of tear of the
different wall structures was used. The degree of injury was
calculated as follows:
[0123] 0=intact IEL
[0124] 1=ruptured IEL with exposure to superficial medial layers
(minor injury)
[0125] 2=ruptured IEL with exposure to deeper medial layers (medial
dissection)
[0126] 3=ruptured EEL with exposure to the adventitia.
[0127] The following table shows the results of the QCA analysis
(measurements of mean late loss due to restenosis) at follow-up
QCA. The data in the tables below under column heading "Neo-intimal
area" report the results of morphometric analysis of stents and
vessels removed from the pigs at follow-up (f/u): TABLE-US-00001
TABLE 1 Results of "high injury" experiment Neo- B/A Mean Lumen
Intima Device Ratio Days Loss, mm Area Stent Description (avg) f/u
(avg) (mm.sup.2) numbers Bare Metal 1.33 28 1.69 5.89 31, 39, 40,
Stent 45, 47, 50 Polymer 1.36 28 2.10 5.82 32, 41, 43, Coated 48,
51, 60 Rapa-high 1.39 28 1.07 3.75 42, 44, 49, 65, 69, 73 Rapa-low
1.42 28 0.99 2.80 52, 56, 61, 64, 68, 72 C-high 1.37 28 0.84 3.54
54, 55, 59, 63 C-low 1.36 28 1.54 3.41 53, 57, 58, 62, 66, 70, 74
C-Uhigh 1.36 28 0.85 2.97 67, 75, 92, 103
[0128] B. Low-Injury Studies
[0129] To further determine which dosage of everolimus would be
best in a lightly injured vessel, more typical of the patient with
uncomplicated coronary disease and a single denovo lesion, the
everolimus-eluting stents were implanted to create moderate to low
overstretch injury (approximately 15%). Farm swine were used for a
30 day experiment, and adult Yucatan minipigs were implanted for a
3 month safety study. The angiographic results were as follows:
TABLE-US-00002 TABLE 2 QCA Results of "low injury" experiments Neo-
Days Mean Intima Device B/A post Lumen Area Stent Description ratio
implant Loss (mm.sup.2) numbers Bare Metal 1.14 28 0.95 2.89 20,
22, 26, Stent 29 Bare Metal 1.13 90 76, 80, 84, Stent 87, 91
C-Uhigh 1.15 28 0.60 2.14 94, 96, 98, 102 C-Ulow 1.09 28 0.49 2.26
93, 95, 97, 100, 101 C-Uhigh 1.15 90 77, 81, 85, 86, 90
[0130] The above data predict that with either the C-Ulow or
C-Uhigh doses of everolimus will produce a 45-48% reduction in
neointimal formation in a low to moderately injured vessel.
[0131] C. Morphometric Analysis
[0132] The total cross-sectional area inside each stent, and
cross-sectional area of new tissue (neo-intima) that had formed
inside the stent were measured by computer, and the percent area
stenosis computed. The average vessel injury score, neo-intimal
area, and % area stenosis for each formulation of drug and polymer,
averaging three slices per stent, is shown in the table below.
TABLE-US-00003 TABLE 3 Results of "high injury" experiment Neo-
Intimal Device Injury Days Area % Area Stent Description Score f/u
(mm.sup.2) Stenosis numbers Bare Metal 1.9 28 5.89 0.72 31, 39, 40,
Stent 45, 47, 50 Polymer 2.11 28 5.82 0.70 32, 41, 43, Coated 48,
51, 60 Rapa-high 2.10 28 3.75 0.55 42, 44, 49, 65, 69, 73 Rapa-low
1.90 28 2.80 0.43 52, 56, 61, 64, 68, 72 C-high 1.89 28 3.54 0.38
54, 55, 59, 63 C-low 2.1 28 3.41 0.53 53, 57, 58, 62, 66, 70, 74
C-Uhigh 2.13 28 2.97 0.45 67, 75, 92, 103
[0133] Morphometric analysis is considered a highly accurate method
of measuring in-stent restenosis in the pig coronary model. In the
high injury model, the C-High formulation produced the lowest
amounts of neointima formation in the `High Injury` experiment at
28 days; however, the C-Uhigh had the highest injury score of the
group, and still managed a very low % Area Stenosis of 0.45.
Therefore, the data independently confirm the findings of the QCA
analysis, and supports the choice of C-Uhigh as the preferred
formulation for human trials.
[0134] D. Histological Analysis
[0135] The slides for the C-Uhigh and Sirolimus Low were submitted
to an experienced cardiac pathologist, who reviewed the vessel
cross-sections for evidence of inflammation, fibrin, and
endothelialization of the newly healed vessel lumen. No difference
was found between the histological changes caused by the sirolimus
and everolimus eluting stents. In general, the vessels appeared to
be well-healed with a well established endothelial layer, evidence
of complete healing and vessel homeostasis at 28 days. FIG. 12 is
an example of vessel cross-section at 91.times. magnification
showing healing and establishment of an endothelial layer on the
inside of the vessel lumen at 28 days post-implant.
[0136] E. Comparison to Published Results
[0137] Carter et al. have published results of sirolimus-coated
stents using the Palmaz Schatz metal stent in swine. A table
comparing the published results of Carter to Biosensors'
experimental results is shown below: TABLE-US-00004 TABLE 4 Mean
Neointima Late Std Cross- Vessel Loss Deviation Sectional DEVICE
Overstretch (mm) (mm) Area (mm.sup.2) DESCRIPTION % mm mm Mm.sup.2
S-Stent BARE 33.5% .+-. 9.2% 1.80 .+-.0.5 7.6 METAL control S-Stent
Polymer- 34.9% .+-. 4.8% 2.02 .+-.0.8 8.5 Only Coated S-Stent
Polymer/ 32.9% .+-. 10.1% 0.66 .+-.0.2 3.27 Rapamycin (-57% vs 325
micrograms control) S-Stent Polymer/ 36.8% .+-. 8.5% 0.74 .+-.0.3
3.61 Everolimus (-50% vs 325 micrograms control) PS Stent BARE*
10-20% 1.19 -- 4.5 control PS Stent Polymer- 10-20% 1.38 -- 5.0
only PS Rapamycin- 10-20% 0.70 -- 2.9 eluting Stent* (-35.5% vs 166
micrograms control) PS Rapamycin- 10-20% 0.67 -- 2.8 eluting Stent*
(-37.7% vs 166 micrograms control) (Slow Release) PS Rapamycin-
10-20% 0.75 -- 3.1 eluting Stent* (-31.1% vs 450 micrograms
control)
EXAMPLE 5
Preparation of Stent with High Drug Loading
[0138] As-marketed metal corrugated-ring stents ("S-stent,
corrugated ring design, Biosensors Intl.), 14.6 mm in length, were
coated with an approximately 2 micron thick layer of parylene `C`
primer coating using a plasma deposition process. Parylene coated
stents were placed in xylene overnight at ambient temperature. A
stock poly(dl)-lactic acid solution containing 50 .mu.g/.mu.L
polylactic acid (PDLA) was prepared by dissolving 100 mg PDLA in 2
mL acetone.
[0139] To prepare stents containing a drug to polymer ratio of 50%,
5 mg everolimus was dissolved in 100 .mu.L of the PDLA stock
solution. An additional 20 .mu.L acetone was added to aid in
dispensing the solution. The stents were removed from the xylene
and carefully blotted to remove solvent. A total of 5.1 .mu.L
coating solution was dispensed onto the outer surface of each
stent. The stents were dried at ambient temperature and placed into
overnight desiccation. This resulted in a total of 212 .mu.g
everolimus contained in 212 .mu.g PDLA per stent.
[0140] To prepare stents containing a drug to polymer ratio of 75%,
5 mg everolimus and 33.3 .mu.L stock PDLA solution were mixed. An
additional 33.3 .mu.L acetone was added and the mixture was
dissolved. Stents were removed from the xylene and blotted similar
to above. A total of 2.8 .mu.L coating solution was dispensed onto
the outer surface of each stent. The stents were dried at ambient
temperature and placed into overnight desiccation. This resulted in
a total of 212 .mu.g everolimus contained in 70 .mu.g PDLA per
stent.
[0141] The finished stents exhibited an approximately 5
microns-thick coating of everolimus/PDLA, or slightly milky
appearance, which was smoothly distributed on the top and side
surfaces, and firmly attached to the metal strut surfaces.
* * * * *