U.S. patent application number 15/154773 was filed with the patent office on 2016-09-01 for methods of treatment with drug eluting stents with prolonged local elution profiles with high local concentrations and low systemic concentrations.
The applicant listed for this patent is ABBOTT LABORATORIES. Invention is credited to Dudley S. JAYASINGHE, Winnette S. MCINTOSH, Gregory C. ORR, John E. PAPP, Lewis B. SCHWARTZ, Kent C.B. STALKER.
Application Number | 20160250049 15/154773 |
Document ID | / |
Family ID | 39595732 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160250049 |
Kind Code |
A1 |
STALKER; Kent C.B. ; et
al. |
September 1, 2016 |
Methods of Treatment with Drug Eluting Stents with Prolonged Local
Elution Profiles with High Local Concentrations and Low Systemic
Concentrations
Abstract
A drug eluting stent can include a stent body having a polymeric
coating with a lipophilic and/or hydrophilic element. A drug that
has a bioactivity that inhibits cell proliferation can be disposed
in the polymeric coating. The drug can be present in the polymer at
an amount greater than or equal to about 150 .mu.g/cm.sup.2. The
polymeric coating and drug are configured to cooperate so as to
form a diffusion pathway with tissue when the stent is disposed in
a body lumen such that the drug preferentially diffuses into the
tissue over a body fluid passing through the body lumen such that a
maximum systemic blood concentration of the drug is less than about
40 ng/ml.
Inventors: |
STALKER; Kent C.B.; (San
Marcos, CA) ; MCINTOSH; Winnette S.; (Washington,
DC) ; JAYASINGHE; Dudley S.; (Murrieta, CA) ;
ORR; Gregory C.; (Escondido, CA) ; PAPP; John E.;
(Temecula, CA) ; SCHWARTZ; Lewis B.; (Lake Forest,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT LABORATORIES |
Abbott Park |
IL |
US |
|
|
Family ID: |
39595732 |
Appl. No.: |
15/154773 |
Filed: |
May 13, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13908854 |
Jun 3, 2013 |
9358096 |
|
|
15154773 |
|
|
|
|
12112935 |
Apr 30, 2008 |
|
|
|
13908854 |
|
|
|
|
60915355 |
May 1, 2007 |
|
|
|
Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61F 2250/0067 20130101;
A61F 2/06 20130101; A61F 2/915 20130101; A61F 2002/91583 20130101;
A61L 2300/416 20130101; A61L 31/16 20130101; A61L 31/022 20130101;
A61F 2002/91541 20130101; A61L 2420/08 20130101; A61L 31/10
20130101 |
International
Class: |
A61F 2/915 20060101
A61F002/915 |
Claims
1. A method of treating peripheral vascular disease in a subject,
the method comprising: implanting in a peripheral artery of a
subject a drug eluting stent comprising: a stent body of about 130
mm to about 170 mm in length, the stent body being a design of
annular elements and interconnectors where the annular elements are
connected adjacently by at least one interconnector; a polymeric
coating disposed on the stent body, the polymeric coating being 2
.mu.m to 50 .mu.m in thickness; and a lipophilic drug disposed in
the polymeric coating, the lipophilic drug being present at an
amount between about 4 mg to about 8 mg; wherein the maximum
systemic blood concentration of the lipophilic drug in the subject
is about 30 ng/ml or less than 30 ng/ml.
2. The method as in claim 1, wherein the lipophilic drug is present
in an amount greater than or equal to 200 .mu.g/cm.sup.2.
3. The method as in claim 1, wherein the lipophilic drug is
everolimus, zotarolimus, tacrolimus, paclitaxel, or a combination
thereof.
4. The method as in claim 3, wherein the lipophilic drug is present
at an amount between about 5 mg and about 7 mg.
5. The method as in claim 1, wherein the lipophilic drug is present
at an amount between about 5 mg and about 7 mg.
6. The method as in claim 1, wherein the polymeric coating ranges
from about 4 .mu.m to about 25 .mu.m in thickness.
7. The method as in claim 1, wherein the polymeric coating
comprises a primer layer disposed on the stent body, a drug-loaded
layer disposed on the primer layer, and a topcoat layer disposed on
the drug-loaded layer.
8. The method as in claim 7, wherein the polymeric coating is
characterized by at least one of the following: the primer layer
being from about 1% to about 20% of the total coating thickness;
the drug-loaded layer being from about 25% to about 90% of the
total coating thickness; or the topcoat being from about 5% to
about 50% of the total coating thickness.
9. The method as in claim 8, wherein the stent body is nitinol, the
lipophilic drug is everolimus, and the polymer of the polymeric
coating is an ethylenevinylalcohol copolymer.
10. The method as in claim 1, wherein the lipophilic drug is
everolimus.
11. The method as in claim 4, wherein the lipophilic drug is
everolimus.
12. The method as in claim 1, wherein the lipophilic drug is
zotarolimus.
13. The method as in claim 4, wherein the lipophilic drug is
zotarolimus.
14. The method as in claim 1, wherein the lipophilic drug is
paclitaxel.
15. The method as in claim 4, wherein the lipophilic drug is
paclitaxel.
16. The method as in claim 1, wherein the maximum systemic blood
concentration of the lipophilic drug in the subject is about 20
ng/ml or less than 20 ng/ml.
17. The method as in claim 1, wherein the maximum systemic blood
concentration of the lipophilic drug in the subject is about 10
ng/ml or less than 10 ng/ml.
18. The method as in claim 1, wherein the stent body is formed from
Nitinol.
19. The method as in claim 1, wherein the peripheral artery of the
subject into which the stent is implanted is a superficial femoral
artery.
20. The method as in claim 1, wherein the peripheral artery of the
subject into which the stent is implanted is an iliofemoral artery.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This U.S. patent application is a continuation of U.S.
patent application Ser. No. 13/908,854, filed on Jun. 3, 2013, and
published as U.S. Patent Application Publication Number US
2013-0268061 A1 on Oct. 10, 2013, which is a division of U.S.
patent application Ser. No. 12/112,935, filed on Apr. 30, 2008, and
published as U.S. Patent Application Publication Number US
2009-0093875 A1 on Apr. 9, 2009, both of which are incorporated by
specific reference herein in their entirety, including any
drawings, and both are incorporated by reference herein for all
purposes; and U.S. patent application Ser. No. 12/112,935 claims
benefit of U.S. Provisional Patent Application having Ser. No.
60/915,355, filed on May 1, 2007, which Provisional patent
application is incorporated herein by specific reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. The Field of the Invention
[0003] The present invention generally relates to a
polymer/drug-coated stent. More particularly, the
polymer/drug-coated stent is configured have the drug disposed
within the polymer coating in a manner that controls the elution of
the drug so as to preferentially deliver the drug into vascular
tissue adjacent to the stent while maintaining a sufficiently low
systemic concentration range of the drug below a specified
value.
[0004] 2. the Relevant Technology
[0005] Endovascular techniques have become important adjuncts in
the management of atherosclerotic occlusive disease. Once amendable
only to open surgical revascularization, a wide range of lesions
can now be approached percutaneously without the need for incision
and dissection. Endovascular interventions within coronary arteries
are particularly effective, and have become the preferred method of
treatment for the majority of patients with occlusive syndromes of
the coronary circulation.
[0006] Endovascular intervention in the peripheral circulation has
proven more problematic. Although generally effective in the
relatively large inflow arteries of the extracranial
cerebrovascular, renal and iliac circulations, endovascular
manipulation of the infrainguinal arteries is technically more
challenging, and the outcome less durable.
[0007] A variety of approaches have been suggested to enhance
patency during peripheral endovascular intervention including
pharmacotherapy, stenting, cryoplasty, cutting balloon angioplasty,
radiation brachytherapy and atherectomy. The most popular to date
is stenting, as results from a recent randomized clinical trial
suggest that routine nitinol stenting enhances both angiographic
and clinical results following balloon angioplasty, especially in
patients with long, complex occlusive lesions of the superficial
femoral artery (SFA).
[0008] However, the long-term results of stenting in the peripheral
vasculature continue to be plagued by restenosis. Restenosis,
mediated by the pathological process of neointimal hyperplasia,
complicates roughly 40% of all peripheral vascular interventions
after one year, leading a recent international consensus panel of
cardiologists, vascular surgeons, and interventional radiologists
to suggest that the current state-of-the-art of SFA stenting
results in only 62% patency after one year.
[0009] As significant enhancements in stented arterial patency have
been achieved in the coronary circulation through the use of
drug-eluting stents (DES), it was natural that this technology
would be eventually applied to the peripheral circulation. Several
small series have been published that suggest that drug-eluting
stents designed for the coronary arteries might also be efficacious
in limiting restenosis and improving patency in the infrapopliteal
arteries. Similarly, the hypothesis that drug-eluting stents might
also be efficacious in the larger and more complex SFA was
previously addressed. Also, self-expanding drug-eluting stents
utilized a nitinol platform, was loaded with 90 .mu.g
sirolimus/cm.sup.2 stent area using a 5-10 .mu.m co-polymer matrix
for total drug load .about.1 mg per 80 mm stent (i.e., stent 1),
and delivered its drug load over a period of about seven days. A
total of 93 patients were enrolled in combined clinical trials for
the stent. Unfortunately, neither trial achieved its primary
endpoint of a reduction in restenosis and, even after four years,
there was no difference in any metric comparing patients treated
with the bare nitinol stent vs. the sirolimus-eluting nitinol
stent. The development of this drug-eluting stent was terminated,
and no drug-eluting stent is yet available for clinical use
anywhere in the world.
[0010] In retrospect, some have hypothesized that the failure of
the drug-eluting stent design (e.g., stent 1) was in its inadequate
drug delivery. As stated, Stent 1 was loaded with 90 .mu.g
sirolimus/cm.sup.2 stent area which was lower that one successful
sirolimus-eluting coronary stent (e.g., stent 2), which had 140
.mu.g sirolimus/cm.sup.2 stent area. Moreover, stent 1 released
sirolimus over about seven days, which is considerably shorter than
the 30 day release of stent 2, both being insufficient in duration
for intended therapeutic purposes. As coronary stents with short
elution profiles are generally less efficacious than their
longer-eluting counterparts, it was perhaps not surprising that
stent I failed to demonstrate efficacy in reducing restenosis.
[0011] A second observation made from the aforementioned studies
was that large peripheral drug-eluting stents with relatively high
drug loads and fast elution can subsequently generate significant
levels of drug in the systemic circulation. These systemic levels
of drug can be considered unsafe and may have adverse side effects.
In any event, high systemic levels of drug is not advantageous and
may counteract the intended therapy. Some coronary drug-eluting
stents, with their minimal drug loads (.about.100 .mu.g), generate
little in the way of systemic drug concentration; whole blood
levels exceeding 2 ng/ml are rarely observed. In contrast, large
peripheral drug-eluting stents carry drug loads in the milligram
(mg) range, and thereby have extremely fast drug elution that
increases systemic concentration of the drug and may result in
adverse systemic drug exposure. Such was the case in the
aforementioned trial in which treated patients exhibited a mean
systemic sirolimus concentration of 20.4.+-.10.0 ng/ml one hour
after stenting, including one patient with a peak concentration of
35.5 ng/ml sirolimus after receiving three 80 mm stents configured
as stent 1. These concentrations are measurably higher than the 9
ng/ml trough concentration observed in kidney transplant recipients
receiving the usual oral dose of sirolimus of 2 mg per day. These
high systemic drug concentrations have been deemed excessive in
terms of adverse effects that may occur by long-term exposure to
high systemic drug concentrations.
[0012] Lastly, a final unexpected consequence of the aforementioned
trial, and a possible reason for its failure, was the observation
that the stent platform was prone to fracture. Of the 93 patients
enrolled, stent fracture was found in 18% at six months, including
single strut fractures in eight patients, multiple strut fractures
in four patients, complete transverse linear stent separations in
two patients, and transverse linear fractures with stent
displacement in two patients. It has been suggested that stent
fracture may create a nidus for restenosis, given the documented
association between strut fracture, restenosis and therapeutic
failure. Indeed, the reported frequency of strut fracture following
peripheral stenting is surprisingly high, including one
retrospective clinical study demonstrating a fracture rate of
65%.
BRIEF SUMMARY OF THE INVENTION
[0013] Generally, the present invention includes a
polymer/drug-coated stent. The polymer/drug-coated stent is
configured have the drug disposed within the polymer coating in a
manner that controls the elution of the drug so as to
preferentially deliver the drug into vascular tissue adjacent to
the stent while maintaining a sufficiently low systemic
concentration of the drug.
[0014] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and a
lipophilic drug. The polymeric coating can have a lipophilic
element and be disposed on the stent body. The lipophilic drug can
have a bioactivity that inhibits cell proliferation, and can be
disposed in the polymeric coating. However, any lipophilic drug
with any activity can be used for the treatment of an appropriate
condition.
[0015] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and a
hydrophilic drug. The polymeric coating can have a hydrophilic
element and be disposed on the stent body. For example, the
hydrophilic drug can have a bioactivity that inhibits cell
proliferation, and can be disposed in the polymeric coating.
However, any hydrophilic drug with any activity can be used for the
treatment of an appropriate condition.
[0016] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and an
amphipathic drug having both hydrophilic and lipophilic components.
The polymeric coating can have a hydrophilic and/or hydrophilic
element and be disposed on the stent body. For example, the
amphipathic drug can have a bioactivity that inhibits cell
proliferation, and can be disposed in the polymeric coating.
However, any amphipathic drug with any activity can be used for the
treatment of an appropriate condition.
[0017] In one embodiment, the drug can be present in the polymer at
an amount from about 10 .mu.g/cm.sup.2 (micrograms drug/area of
stent) to about 2000 .mu.g/cm.sup.2, more preferably from about 100
.mu.g/cm.sup.2 to about 1000 .mu.g/cm.sup.2, and most preferably
from about 200 .mu.g/cm.sup.2 to about 500 .mu.g/cm.sup.2.
[0018] In one embodiment, the drug per area can be greater or equal
to about 150 .mu.g/cm.sup.2, more preferably greater or equal to
about 175 .mu.g/cm.sup.2, even more preferably greater or equal to
about 200 .mu.g/cm.sup.2, and most preferably greater or equal to
about 225 .mu.g/cm.sup.2.
[0019] In one embodiment, the amount of drug on the stent can be
described as the total amount of drug per stent. Accordingly, the
amount of drug per stent can be from about 0.5 mg to about 12 mg,
more preferably from about 0.75 mg to about 10 mg, and most
preferably from about 1 mg to about 5 mg.
[0020] The polymeric coating and drug are configured to cooperate
so as to form a lipophilic diffusion pathway with tissue when the
stent is disposed in a body lumen such that the lipophilic drug
preferentially diffuses into the tissue over a body fluid passing
through the body lumen such that a maximum systemic blood
concentration of the drug is less than or about 30 ng/ml, more
preferably less than or about 20 ng/ml, and most preferably less
than or about 10 ng/ml.
[0021] In one embodiment, the stent body is comprised of a
superelastic alloy, such as nitinol. The nitinol can have an
ethylenevinylalcohol copolymer coating disposed thereon. A
therapeutically effective amount of everolimus can be disposed in
the polymeric coating so as to be present at an amount greater than
or equal to about 150 .mu.g/cm.sup.2. The polymer coating and
everolimus are configured so as to cooperate to form a lipophilic
diffusion pathway with tissue when the stent is disposed in a body
lumen such that the everolimus preferentially diffuses into the
tissue over a body fluid passing through the body lumen and such
that a maximum systemic blood concentration of everolimus is less
than about 40 ng/ml.
[0022] In one embodiment, the present invention includes a method
of inhibiting occlusion, stenosis, restenosis, or cell
over-proliferation in a body lumen in a subject. Such a method
includes providing a stent as described herein and deploying the
drug eluting stent into the body lumen.
[0023] In one embodiment, the present invention includes a method
of manufacturing a stent in accordance with the present invention.
Such a method includes preparing a stent body, preparing a
polymer/drug solution, and applying the polymer/drug solution to
the stent body. Alternatively, the polymer and drug can be applied
to the stent separately. Additionally, a polymeric topcoat can be
applied over the polymeric coating that has the drug.
[0024] In one embodiment, the drug eluting stent produces a
systemic blood concentration of the drug that in turn produces at
least one of the following: a maximum kidney concentration of less
than or about 50 ng/g, more preferably less than or about 40 ng/g,
and most preferably less than or about 30 ng/g; a maximum lung
concentration of less than or about 45 ng/g, more preferably less
than or about 35 ng/g, and most preferably less than or about 25
ng/g; a maximum muscle concentration of less than or about 35 ng/g,
less than or about 30 ng/g, and most preferably less than or about
25 ng/g; a maximum liver concentration of less than or about 30
ng/g, more preferably less than or about 25 ng/g, and most
preferably less than or about 17 ng/g; or a maximum spleen
concentration of less than or about 35 ng/g, more preferably less
than or about 30 ng/g, and most preferably less than or about 25
ng/g.
[0025] In one embodiment, the maximum systemic blood concentration
of the drug is less than about 4 ng/ml per milligram of total drug
on the stent.
[0026] In one embodiment, the maximum systemic blood concentration
of the drug is less than about 15 pg/ml per millimeter of stent
length.
[0027] In one embodiment, the stent is characterized by at least
one of the following: the drug is present at greater than or about
3.8 mg; the maximum systemic blood concentration is from about 0.6
ng/ml to about 15 ng/ml; the drug is present at greater than or
about 7.5 mg; the maximum systemic blood concentration is from
about 1.5 ng/ml to about 30 ng/ml; the drug is present at greater
than or about 10 mg; or the maximum systemic blood concentration is
from about 2 ng/ml to about 40 ng/ml.
[0028] In one embodiment, the polymeric coating ranges from about 2
um to about 50 um. Optionally, the polymeric coating includes a
primer layer disposed on the stent body, a drug-loaded layer
disposed on the primer layer, and a topcoat layer disposed on the
drug-loaded layer so as to control elution of the drug.
Accordingly, the polymeric coating is characterized by at least one
of the following: the primer layer being from about 1% to about 20%
of the total coating thickness; the drug-loaded layer being from
about 25% to about 90% of the total coating thickness; or the
topcoat being from about 5% to about 50% of the total coating
thickness.
[0029] In one embodiment, the stent body is a superelastic alloy
such as nitinol. This can be linear superelastic and non-linear
superelastic nitinol.
[0030] In one embodiment, the drug is a rapamycin analog such as
everolimus or zotarolimus.
[0031] In one embodiment, the polymer coating and/or polymeric
topcoat is an ethylenevinylalcohol copolymer.
[0032] These and other embodiments and features of the present
invention will become more fully apparent from the following
description and appended claims, or may be learned by the practice
of the invention as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] To further clarify the above and other advantages and
features of the present invention, a more particular description of
the invention will be rendered by reference to specific embodiments
thereof which are illustrated in the appended drawings. It is
appreciated that these drawings depict only typical embodiments of
the invention and are therefore not to be considered limiting of
its scope. The invention will be described and explained with
additional specificity and detail through the use of the
accompanying drawings in which:
[0034] FIG. 1 is a planar side view of a portion of an embodiment
of an exemplary endoprosthesis in accordance with the present
invention.
[0035] FIG. 2A is a graph illustrating the percent of drug eluted
from a drug eluting stent.
[0036] FIG. 2B is a graph illustrating the arterial tissue drug
concentration obtained from a drug eluting stent.
[0037] FIG. 3 includes a graph illustrating everolimus blood
concentration after drug eluting stent implantation.
[0038] FIGS. 4A-4C include photographs of vessels (FIGS. 4A and 4C)
and cross-sections (FIGS. 4B and 4D) of vessels at 90 days after
drug eluting stent (DES) (FIGS. 4A and 4B) and bare metal stent
(BMS) (FIGS. 4C and 4D) implantation.
[0039] FIGS. 5A-5C include schematic representations of a stent
delivery system (FIG. 5A) and a method of delivering the stent into
a body lumen (FIG. 5B) with the stent delivery system of FIG.
5A.
[0040] FIGS. 6A-6C include schematic representations of a lumen
filter (FIG. 6A) that is deployed into a body lumen with a lumen
filter delivery system (FIG. 6B) and a method of delivering the
stent into a body lumen (FIG. 6C) with the lumen filter delivery
system of FIG. 6B.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0041] Generally, the present invention includes drug eluting
implantable medical devices such as endoprostheses, vena cava
filters, embolic protection filters, and the like that are
configured with controlled drug delivery profiles that allow for
enhanced drug delivery into the lumen tissue adjacent to the
implantable medical device and that inhibits drug delivery into the
systemic blood circulation. The preferential drug delivery into the
lumen tissue can be facilitated by a hydrophobic component being
included in a coating on the medical device (e.g., stent or vena
cava filter) that is in contact with the lumen tissue. The
hydrophobic components of the tissue cooperate with the hydrophobic
component of the coating so as to facilitate preferential diffusion
of a hydrophilic drug into the tissue over into systemic blood.
Similarly, the drug can be hydrophilic or amphipathic by having
both lipophilic and hydrophilic portions. The polymer can include a
hydrophilic component for the hydrophilic drug, and hydrophilic
and/or hydrophobic components for the lipophilic, hydrophilic, or
amphipathic drugs.
[0042] As used herein, the term "micro" has been abbreviated with
the standard symbol ".mu." or "u" for simplicity.
I. Drug Eluting Endoprosthesis
[0043] In accordance with the present invention, a drug eluting
endoprosthesis can be provided for improved drug delivery within a
body lumen of a human or other animal. Examples of drug eluting
endoprostheses can include stents, filters, grafts, valves,
occlusive devices, trocars, aneurysm treatment devices, or the
like. Additionally, the drug eluting endoprosthesis can be
configured for a variety of intraluminal applications, including
vascular, coronary, biliary, esophageal, urological,
gastrointestinal, or the like.
[0044] Additional medical device embodiments, i.e. vena cava filter
that can be implanted in the vena cava to elute drug over time. The
device becomes a systemic drug release device instead of a device
to treat an area of stenosis. The drug release device could replace
daily pills for individuals in need of the therapy provided by the
drug, such as transplant patients.
[0045] Generally, an endoprosthesis of the present invention can
include at least a first set of interconnected strut elements that
cooperatively define an annular element. A strut element can be
more generally described as an endoprosthetic element, wherein all
well-known endoprosthetic elements can be referred to here as a
"strut element" for simplicity. Usually, each strut element can be
defined by a cross-sectional profile as having a width and a
thickness, and including a first end and a second end bounding a
length. The stent element can be substantially linear, arced,
rounded, squared, combinations thereof, or other configurations.
The strut element can include a bumper, crossbar, connector,
interconnector, intersection, elbow, foot, ankle, toe, heel, medial
segment, lateral segment, coupling, sleeve, combinations thereof,
or the like, as described in more detail below. The strut element
can have improved structural integrity by including
crack-inhibiting features, which are described in detail in the
incorporated references.
[0046] Usually, the annular elements can include a plurality of
circumferentially-adjacent crossbars that are interconnected
end-to-end by an elbow connection, intersection, or a foot
extension. As such, at least one annular element or endoprosthesis
can include an elbow, intersection, or a foot extension (foot)
extending between at least one pair of circumferentially-adjacent
crossbars. The elbow or foot can thus define an apex between the
pair of circumferentially-adjacent crossbars of the annular element
or endoprosthesis. Also, an intersection can have a shape similar
to a crossbar or interlinked crossbars so as to provide a junction
between two coupled pairs of circumferentially-adjacent
crossbars.
[0047] The elbow can be configured in any shape that connects
adjacent ends of circumferentially-adjacent crossbars, and can be
described as having a U-shape, V-shape, L-shape, X-shape, Y-shape,
H-shape, K-shape, or the like. The elbow and/or intersection can be
configured in any shape that connects longitudinal and
circumferentially adjacent crossbars, and can be described as
having a cross shape, X-shape, Y-shape, H-shape, K-shape, or the
like. The foot can have a foot shape having a first foot portion
extending circumferentially from an end of one of the adjacent
strut members and a second foot portion extending circumferentially
from a corresponding end of the other of the
circumferentially-adjacent strut members. In combination, the first
and second foot portions generally define an ankle portion
connected to a toe portion through a medial segment and the toe
portion connected to a heel portion through a lateral segment.
[0048] As described herein, an endoprosthesis, in one
configuration, can include two or more interconnected annular
elements. Each annular element can generally define a ring-like
structure extending circumferentially about a longitudinal or
central axis. The cross-sectional profile of each annular element
can be at least arcuate, circular, helical, or spiral, although
alternative cross-sectional profiles, such as oval, oblong,
rectilinear or the like, can be used. The different annular
elements can be defined as having the same characterization or
different characterizations.
[0049] The first and second annular elements generally define a
tubular structure. For example, each annular element can define a
continuous closed ring such that the longitudinally-aligned annular
elements form a closed tubular structure having a central
longitudinal axis. Alternatively, each annular element can define
an open ring shape such that a rolled sheet, open tubular, or
"C-shape" type structure is defined by the annular elements. That
is, the annular element is not required to be closed. Furthermore,
each annular element can define substantially a 360-degree turn of
a helical pattern or spiral, such that the end of one annular
element or endoprosthesis can be joined with the corresponding end
of a longitudinally-adjacent annular element or endoprosthesis to
define a continuous helical pattern along the length of the
endoprosthesis.
[0050] FIG. 1 is a side view of a flattened portion of an
embodiment of an endoprosthesis 1a. The illustrated endoprosthesis
is a stent, but it will be understood that the benefits and
features of the present invention are also applicable to other
types of endoprosthesis or other medical devices known to those
skilled in the art.
[0051] For purposes of clarity and not limitation, the
endoprosthesis 1a is illustrated in a planar format. As shown, the
endoprosthesis 1a can include a plurality of annular elements 10
aligned longitudinally adjacent to each other along a longitudinal
axis 15 extending from a first end 16 to a second end 18. Although
only two interconnected annular elements need to be provided for
the endoprosthesis, it is possible that an endoprosthesis include
one or a plurality of annular elements 10. As depicted in FIG. 1,
at least a first annular element 10a and a second annular element
10b are identified.
[0052] Each annular element 10 can include a set of interconnected
strut elements, shown as strut crossbars 20, which are disposed
circumferentially about the longitudinal axis 15; the
circumferential direction is represented by arrow 17. Each crossbar
20 can have a first end 22a and a second end 22b, referenced
generally as end 22. The first end 22a of selected
circumferentially-adjacent crossbars 20a-b can be interconnected at
elbows 30 that are proximate to a first longitudinal side 12 of
each annular element 10, and the second end 22b of selected
circumferentially-adjacent crossbars 20b-c can be interconnected to
define elbows 30 that are proximate to a second longitudinal side
14 of the annular element.
[0053] Each annular element 10 can be expanded to a deployed
configuration as shown in FIG. 1 by altering or opening the angle
of the elbows 30 interconnecting the circumferentially-adjacent
crossbars 20, or can be collapsed into a deployable configuration
by closing the angle of the elbows 30. Also,
circumferentially-adjacent elbows 30 on each side 12, 14 of the
annular element 10 can be spaced apart by a circumferential
distance D, such that each annular element 10 is expanded by
increasing the distance D and collapsed by decreasing the distance
D. At any given condition between the delivery configuration and
the deployed configuration, the distance D can be balanced or
constant from one set of circumferentially-adjacent elbows to the
next, or it can be varied if desired.
[0054] Selected elbows 30 on each side 12, 14 of the annular
element 10 can be defined by interconnecting corresponding ends 22
of circumferentially-adjacent crossbars 20a-b directly together to
form a zigzag pattern of alternating U-shapes, V-shapes, L-shapes,
combinations thereof, or the like when deployed. Alternatively, an
elbow 30 can be provided between the corresponding ends of adjacent
crossbars to form another contoured shape, such as by using a
straight elbow member to form a flat connection configuration.
[0055] FIG. 1 also depicts an embodiment of a foot extension 40
that can extend between a pair 24 of circumferentially-adjacent
crossbars 20d-e of each annular element 10. As depicted, the foot
extension 40 can include an ankle 41 that circumferentially couples
an end 22 of one of the adjacent crossbars 20d to a medial segment
44. The medial segment 44 extends from the ankle 41 to a toe 48
that circumferentially couples the medial segment to a lateral
segment 46. The lateral segment 46 can extend from the toe 48 to a
heel 42 that circumferentially couples the lateral segment to the
next circumferentially-adjacent crossbar 20e. Accordingly, the
juncture of the crossbar 20d and the medial segment 44 can define a
circumferentially-extending toe portion 48 of the foot extension
40; the juncture of the medial segment 44 and the lateral segment
46 defines a circumferentially-extending toe portion 48 of the foot
extension 40; and the juncture of the lateral segment 46 and
crossbar 20e defines a circumferentially-extending toe portion 48
of the foot extension 40. Each portion of the foot extension 40, as
well as each of the circumferentially-adjacent crossbars 20, can
have a substantially uniform cross-sectional profile illustrated by
a substantially uniform width W and thickness (not shown).
[0056] For purposes of discussion and not limitation, FIG. 1 shows
that a toe portion 48 can extend in a first circumferential
direction a distance greater than the distance the heel portion 42
of the foot extension 40 extends in an opposite circumferential
direction. As such, the entirety of the foot extension 40 can
extend in the circumferential direction of the toe portion 48.
Furthermore, at least one of the medial segment 44 or lateral
segment 46 can open foot region 49.
[0057] The adjacent annular elements 10a-10b or 10c-10d can be
interconnected with an interconnector 50 as described herein. For
example, the interconnector 50 can have a form of a means for
reducing force transmission between adjacent annular elements.
Stated another way, the interconnector 50, optionally referred to
as a force absorber or force absorbing connector, can include one
or more force absorbing members that allow limited movement of
adjacent annular elements, while reducing the possibility of
cracking and fatigue failure due to the movement of adjacent
annular elements. As such, the endoprosthesis 1a can include a
plurality of interconnectors 50 to connect adjacent annular
elements 10a-10b or 10c-10d. Each interconnector 50 can include a
first bending member or shock 52 and a second bending member or
shock 54, which can bend toward each other to separate the adjacent
annular elements 10a-10b or 10c-10d or bend away from each other to
being adjacent annular elements closer together. Accordingly, the
interconnector 50 can include a first bending point 60 opposite of
a second bending point 64. The first bending member or shock 52 can
have at least a first arm 66 and a second arm 67. The second
bending member or shock 54 can have at least a first arm 68 and a
second arm 69. The interconnector 50 can couple with a first
crossbar 20 of a first annular element 10c at a first coupling 62a,
and couple with a second crossbar of a second annular element 10d
at a second coupling 62b.
[0058] The endoprosthesis 1a can be easily deployed because of the
improved flexibility provided within each annular element 10 or
between adjacent annular elements 10a-10b. As such, the
resiliently-flexible bending members or shocks 52, 54 can cooperate
so as to enable the endoprosthesis 1a to bend around a tight corner
by the bending members or force-absorbing members on one side of
the annular element contracting while bending members or
force-absorbing members on an opposite side expanding. Also, the
combination of elbows 30, foot extensions 40, and/or resiliently
flexible interconnectors 50 can allow for radial, longitudinal,
torsional, or bending loading to be absorbed without cracking,
fracturing or damage occurring to the endoprosthesis 1a. Moreover,
the resiliently-flexible interconnectors 50 can allow adjacent
annular elements to move independently with respect to each other
in radial, longitudinal, and cross directions.
[0059] While FIG. 1 illustrates one type of endoprosthesis, the
general teachings thereof can be applied to other types of
endoprostheses. This includes other types of stents that have
different strut elements in different shapes and configurations. As
such, FIG. 1 is provided as an example of one type of
endoprosthesis that can be coated with the polymer/drug of the
present invention in order to achieve preferential drug delivery
into lumen tissue adjacent to the endoprosthesis.
[0060] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and a
lipophilic drug. The polymeric coating can have a lipophilic
element and be disposed on the stent body. The lipophilic drug can
have a bioactivity that inhibits cell proliferation, and can be
disposed in the polymeric coating. However, any lipophilic drug
with any activity can be used for the treatment of an appropriate
condition.
[0061] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and a
hydrophilic drug. The polymeric coating can have a hydrophilic
element and be disposed on the stent body. For example, the
hydrophilic drug can have a bioactivity that inhibits cell
proliferation, and can be disposed in the polymeric coating.
However, any hydrophilic drug with any activity can be used for the
treatment of an appropriate condition.
[0062] In one embodiment, the present invention can include a drug
eluting stent that has a stent body, a polymeric coating, and a
amphipathic drug having both hydrophilic and lipophilic components.
The polymeric coating can have a hydrophilic and/or hydrophilic
element and be disposed on the stent body. For example, the
amphipathic drug can have a bioactivity that inhibits cell
proliferation, and can be disposed in the polymeric coating.
However, any amphipathic drug with any activity can be used for the
treatment of an appropriate condition.
[0063] The drug can be present in the polymer at an amount from
about 10 .mu.g/cm.sup.2 (micrograms drug/area of stent) to about
2000 .mu.g/cm.sup.2, more preferably from about 100 .mu.g/cm.sup.2
to about 1000 .mu.g/cm.sup.2, and most preferably from about 200
.mu.g/cm.sup.2 to about 500 .mu.g/cm.sup.2. In exemplary stents,
the drug per area can include 150 .mu.g/cm.sup.2 to about 500
.mu.g/cm.sup.2, more preferably from about 175 .mu.g/cm.sup.2 to
about 400 .mu.g/cm.sup.2, and most preferably from about 200
.mu.g/cm.sup.2 to about 300 .mu.g/cm.sup.2. Within this narrower
range, the drug per area can include 210 .mu.g/cm.sup.2 to about
275 .mu.g/cm.sup.2, more preferably from about 215 .mu.g/cm.sup.2,
to about 250 .mu.g/cm.sup.2, and most preferably 225
.mu.g/cm.sup.2.+-.10 .mu.g/cm.sup.2.
[0064] In one embodiment, the amount of drug on the stent can be
described as the total amount of drug per stent. Accordingly, the
amount of drug per stent can be from about 0.5 mg to about 12 mg,
more preferably from about 0.75 mg to about 10 mg, and most
preferably from about 1 mg to about 5 mg.
[0065] In one embodiment, the amount of drug on the stent can be
described as the total amount of drug for a stent of a specific
length. The amount of drug per stent can be from about 0.5 mg to
about 12 mg for stents ranging from about 10 mm to about 300 mm,
and more preferably from about 20 mm to about 150 mm stent lengths.
This includes about 0.5 mg to about 5 mg, more preferably from
about 0.75 mg to about 2.5 mg, and most preferably about 1 mg for a
stent having a length from about 10 mm to about 30 mm, more
preferably from about 15 mm to about 25 mm, and most preferably
about 20 mm. This also includes about 2 mg to about 6 mg, more
preferably about 3 mg to about 5 mg, and most preferably from about
3.5 mg to about 4 mg or about 3.8 mg for a stent having a length
from about 60 mm to about 100 mm, more preferably from about 70 mm
to about 90 mm, and most preferably about 80 mm. Additionally, this
can include about 4 mg to about 8 mg, more preferably from about 5
mg to about 7 mg, and most preferably about 6 mg for a stent having
a length from about 130 mm to about 170 mm, more preferably from
about 140 mm to about 160 mm, and most preferably about 150 mm.
[0066] The polymeric coating and drug are configured to cooperate
so as to form a diffusion pathway (e.g., lipophilic, hydrophilic
and/or amphipathic) with tissue when the stent is disposed in a
body lumen such that the drug preferentially diffuses into the
tissue over a body fluid passing through the body lumen such that a
maximum systemic blood concentration of the drug is less than or
about 30 ng/ml, more preferably less than or about 20 ng/ml, and
most preferably less than or about 10 ng/ml.
[0067] In one embodiment, the polymeric coating can control the
systemic delivery of the drug so as to retain a sufficiently low
concentration in order to inhibit negative systemic side effects.
This can include a 100 mm stent having about 3.8 mg drug eluting
the drug so as to obtain a blood maximum concentration (i.e., Cmax)
from about 0.6 ng/ml to about 15 ng/ml, more preferably from about
1 ng/ml to about 10 ng/ml, even more preferably from about 2 ng/ml
to about 5 ng/ml, and most preferably about 3 ng/ml. This can also
include a 200 mm stent having about 7.5 mg drug eluting the drug so
as to obtain a blood Cmax from about 1.5 ng/ml to about 30 ng/ml,
more preferably from about 3 ng/ml to about 15 ng/ml, even more
preferably from about 5 ng/ml to about 10 ng/ml, and most
preferably about 6 ng/ml. Additionally, this can include a 300 mm
stent having about 12 mg drug eluting the drug so as to obtain a
blood Cmax from about 2 ng/ml to about 40 ng/ml, more preferably
from about 4 ng/ml to about 30 ng/ml, even more preferably from
about 6 ng/ml to about 20 ng/ml, and most preferably about 9
ng/ml.
[0068] In one embodiment, the systemic delivery of the drug can be
characterized as concentration of drug per length of stent. As
such, the systemic delivery of the drug can provide a blood maximum
concentration that can be from about 0.6 pg/ml per millimeter (mm)
of stent (e.g., 0.6 pg drug per ml of blood per mm of stent) to
about 15 pg/ml per mm of stent, more preferably from about 1 pg/ml
per mm of stent to about 10 pg/ml per mm of stent, even more
preferably about 2 pg/ml per mm of stent to about 5 pg/ml per mm of
stent, and most preferably about 3 pg/ml per mm of stent.
[0069] In one embodiment, the systemic delivery of the drug can be
characterized as concentration of drug per amount of total amount
of drug on the stent. As such, the systemic delivery of the drug
provide a blood maximum concentration can be from about 0.16 ng/ml
per milligram (mg) of drug on the stent to about 4 ng/ml per mg
total drug, more preferably from about 0.2 ng/ml per mg total drug
to about 3.3 ng/ml per mg total drug, even more preferably about
0.5 ng/ml per mg total drug to about 2.5 ng/ml per mg total drug,
and most preferably about 0.75 ng/ml per mg total drug to about 0.8
ng/ml per mg total drug.
[0070] In one embodiment, the stent body is comprised of a
superelastic alloy, such as nitinol. The nitinol can have an
ethylenevinylalcohol copolymer coating disposed thereon. A
therapeutically effective amount of everolimus can be disposed in
the polymeric coating so as to be present at an amount greater than
or equal to about 150 .mu.g/cm.sup.2. The polymer coating and
everolimus are configured so as to cooperate to form a lipophilic
diffusion pathway with tissue when the stent is disposed in a body
lumen such that the everolimus preferentially diffuses into the
tissue over a body fluid passing through the body lumen and such
that a maximum systemic blood concentration of everolimus is less
than about 10 ng/ml. In one aspect, the drug can present in an
amount greater than or equal to about 200 .mu.g/cm.sup.2 and the
maximum systemic blood concentration of the drug can be less than
about 5 ng/ml. This can also be similar for hydrophilic and
amphipathic drugs.
[0071] In one embodiment, the drug eluting stent produces a
systemic blood concentration of the drug that in turn produces at
least one of the following: a maximum kidney concentration of less
than or about 50 ng/g, more preferably less than or about 40 ng/g,
and most preferably less than or about 30 ng/g; a maximum lung
concentration of less than or about 45 ng/g, more preferably less
than or about 35 ng/g, and most preferably less than or about 25
ng/g; a maximum muscle concentration of less than or about 35 ng/g,
less than or about 30 ng/g, and most preferably less than or about
25 ng/g; a maximum liver concentration of less than or about 30
ng/g, more preferably less than or about 25 ng/g, and most
preferably less than or about 17 ng/g; or a maximum spleen
concentration of less than or about 35 ng/g, more preferably less
than or about 30 ng/g, and most preferably less than or about 25
ng/g.
[0072] In one embodiment, the stent can be characterized by one of
the following: the drug is present at greater than or about 1070
.mu.g on the stent body that is about 10.times.28 mm so as to
produce a maximum blood concentration of less than or about 3 ng/ml
and a maximum lumen tissue concentration of greater than or about
5000 ng/g; the drug is present at greater than or about 1070 .mu.g
on the stent body that is about 8.times.28 mm so as to produce a
maximum blood concentration of less than or about 3 ng/ml and a
maximum lumen tissue concentration of greater than or about 8000
ng/g; the drug is present at greater than or about 3209 .mu.g on
the stent body that is about 8.times.28 mm so as to produce a
maximum blood concentration of less than or about 5 ng/ml and a
maximum lumen tissue concentration of greater than or about 20000
ng/g; or the drug is present at greater than or about 3777 .mu.g on
the stent body that is about 7.times.100 mm so as to produce a
maximum blood concentration of less than or about 10 ng/ml and a
maximum lumen tissue concentration of greater than or about 15000
ng/g.
II. Endoprosthesis Compositions
[0073] The drug eluting endoprostheses of the present invention can
be made of a variety of materials, such as, but not limited to,
those materials which are well known in the art of endoprosthesis
(e.g., stent) manufacturing. This can include, but is not limited
to, an endoprosthesis body having a primary material.
Alternatively, at least two of the annular elements or different
portions can be made of different materials. Generally, the
materials for the endoprosthesis can be selected according to the
structural performance and biological characteristics that are
desired.
[0074] In one configuration, the endoprosthesis body has multiple
layers, with at least one layer being applied to a primary material
forming the annular elements. As such, at least one annular element
can have multiple layers that are different from at least one other
annular element. The multiple layers can be resiliently flexible
materials or rigid and inflexible materials, and selected
combinations thereof. For example, materials such as Ti3Al2.5V,
Ti6Al4V, 3-2.5Ti, 6-4Ti and platinum may be particularly good
choices for adhering to a flexible material, such as, but not
limited to, nitinol and providing good crack arresting properties.
The use of resiliently flexible materials can provide
force-absorbing characteristics to the structures, interconnectors,
and/or other endoprosthesis components, which can also be
beneficial for absorbing stress and strains, which may inhibit
crack formation at high stress zones. Also, the multiple layers can
be useful for applying radiopaque materials to selected annular
elements, such as end annular elements to provide different
characteristics. For example, types of materials that are used to
make an endoprosthesis can be selected so that the endoprosthesis
is capable of being collapsed during placement and expanded when
deployed. Usually, the endoprosthesis can be self-expanding,
balloon-expandable, or can use some other well-known configuration
for deployment. For purposes of illustration and not limitation,
reference is made generally to self-expanding embodiments and
balloon-expandable embodiments of the endoprosthesis of the present
invention; however, other types of endoprostheses can be configured
in accordance with the present invention.
[0075] Embodiments of the endoprosthesis body can include a
material made from any of a variety of known suitable materials,
such as a shaped memory material (SMM). For example, the SMM can be
shaped in a manner that allows for restriction to induce a
substantially tubular, linear orientation while within a delivery
shaft, but can automatically retain the memory shape of the
endoprosthesis once extended from the delivery shaft. SMMs have a
shape memory effect in which they can be made to remember a
particular shape. Once a shape has been remembered, the SMM may be
bent out of shape or deformed and then returned to its original
shape by unloading from strain or heating. Typically, SMMs can be
shape memory alloys (SMA) comprised of metal alloys, or shape
memory plastics (SMP) comprised of polymers. The materials can also
be referred to as being superelastic.
[0076] Usually, an SMA can have any non-characteristic initial
shape that can then be configured into a memory shape by heating
the SMA and conforming the SMA into the desired memory shape. After
the SMA is cooled, the desired memory shape can be retained. This
allows for the SMA to be bent, straightened, compacted, and placed
into various contortions by the application of requisite forces;
however, after the forces are released, the SMA can be capable of
returning to the memory shape. The main types of SMAs are as
follows: copper-zinc-aluminium; copper-aluminium-nickel; nickel
titanium (NiTi) alloys known as nitinol; nickel-titanium platinum;
nickel-titanium palladium; and cobalt-chromium-nickel alloys or
cobalt-chromium-nickel-molybdenum alloys known as elgiloy alloys.
The temperatures at which the SMA changes its crystallographic
structure are characteristic of the alloy, and can be tuned by
varying the elemental ratios or by the conditions of
manufacture.
[0077] For example, the primary material of an endoprosthesis can
be of a NiTi alloy that forms superelastic nitinol. In the present
case, nitinol materials can be trained to remember a certain shape,
straightened in a shaft, catheter, or other tube, and then released
from the catheter or tube to return to its trained shape. Also,
additional materials can be added to the nitinol depending on the
desired characteristic. The alloy may be utilized having linear
elastic properties or non-linear elastic properties.
[0078] An SMP is a shape-shifting plastic that can be fashioned
into an endoprosthesis in accordance with the present invention.
Also, it can be beneficial to include at least one layer of an SMA
and at least one layer of an SMP to form a multilayered body;
however, any appropriate combination of materials can be used to
form a multilayered endoprosthesis. When an SMP encounters a
temperature above the lowest melting point of the individual
polymers, the blend makes a transition to a rubbery state. The
elastic modulus can change more than two orders of magnitude across
the transition temperature (Ttr). As such, an SMP can formed into a
desired shape of an endoprosthesis by heating it above the Ttr,
fixing the SMP into the new shape, and cooling the material below
Ttr. The SMP can then be arranged into a temporary shape by force,
and then resume the memory shape once the force has been applied.
Examples of SMPs include, but are not limited to, biodegradable
polymers, such as oligo(.epsilon.-caprolactone)diol,
oligo(.rho.-dioxanone)diol, and non-biodegradable polymers such as,
polynorborene, polyisoprene, styrene butadiene, polyurethane-based
materials, vinyl acetate-polyester-based compounds, and others yet
to be determined. As such, any SMP can be used in accordance with
the present invention.
[0079] An endoprosthesis body having at least one layer made of an
SMM or suitable superelastic material and other suitable layers can
be compressed or restrained in its delivery configuration within a
delivery device using a sheath or similar restraint, and then
deployed to its desired configuration at a deployment site by
removal of the restraint as is known in the art. An endoprosthesis
body made of a thermally-sensitive material can be deployed by
exposure of the endoprosthesis to a sufficient temperature to
facilitate expansion as is known in the art.
[0080] Also, the endoprosthesis body can be comprised of a variety
of known suitable deformable materials, including stainless steel,
silver, platinum, tantalum, palladium, nickel, titanium, nitinol,
nitinol having tertiary materials (U.S. 2005/0038500, which is
incorporated herein by specific reference), niobium-tantalum alloy
optionally doped with a tertiary material (U.S. 2004/0158309,
2007/0276488, and U.S. Ser. No. 12/070,646, which are each
incorporated herein by specific reference) cobalt-chromium alloys,
or other known biocompatible materials. Such biocompatible
materials can include a suitable biocompatible polymer in addition
to or in place of a suitable metal. The polymeric endoprosthesis
can include biodegradable or bioabsorbable materials, which can be
either plastically deformable or capable of being set in the
deployed configuration. If plastically deformable, the material can
be selected to allow the endoprosthesis to be expanded in a similar
manner using an expandable member so as to have sufficient radial
strength and scaffolding and also to minimize recoil once expanded.
If the polymer is to be set in the deployed configuration, the
expandable member can be provided with a heat source or infusion
ports to provide the required catalyst to set or cure the
polymer.
[0081] In one embodiment, the stent or other medical device is made
from a superelastic alloy such as nickel-titanium or nitinol, and
includes a ternary element selected from the group of chemical
elements consisting of iridium, platinum, gold, rhenium, tungsten,
palladium, rhodium, tantalum, silver, ruthenium, or hafnium. The
added ternary element improves the radiopacity of the nitinol stent
comparable to that of a stainless steel stent of the same size and
strut pattern coated with a thin layer of gold. The nitinol stent
has improved radiopacity yet retains its superelastic and shape
memory behavior and further maintains a thin strut/wall thickness
for high flexibility. For example, the stent according to the
present invention has 42.8 atomic percent nickel, 49.7 atomic
percent titanium, and 7.5 atomic percent platinum.
[0082] In one embodiment, the implant can be made at least in part
of a high strength, low modulus metal alloy comprising Niobium,
Tantalum, and at least one element selected from the group
consisting of Zirconium, Tungsten, and Molybdenum. The medical
devices according to the present invention provide superior
characteristics with regard to bio-compatibility, radio-opacity and
MRI compatibility.
[0083] Furthermore, the endoprosthesis body can be formed from a
ceramic material. In one aspect, the ceramic can be a biocompatible
ceramic which optionally can be porous. Examples of suitable
ceramic materials include hydroxylapatite, mullite, crystalline
oxides, non-crystalline oxides, carbides, nitrides, silicides,
borides, phosphides, sulfides, tellurides, selenides, aluminum
oxide, silicon oxide, titanium oxide, zirconium oxide,
alumina-zirconia, silicon carbide, titanium carbide, titanium
boride, aluminum nitride, silicon nitride, ferrites, iron sulfide,
and the like. Optionally, the ceramic can be provided as sinterable
particles that are sintered into the shape of an endoprosthesis or
layer thereof.
[0084] Moreover, the endoprosthesis body can include a radiopaque
material to increase visibility during placement. Optionally, the
radiopaque material can be a layer or coating any portion of the
endoprosthesis. The radiopaque materials can be platinum, tungsten,
silver, stainless steel, gold, tantalum, bismuth, barium sulfate,
or a similar material.
[0085] It is further contemplated that the external surface and/or
internal surface of the endoprosthesis body (e.g., exterior and
luminal surfaces) as well as the entire body can be coated with
another material having a composition different from the primary
endoprosthetic material. The use of a different material to coat
the surfaces can be beneficial for imparting additional properties
to the endoprosthesis, such as providing radiopaque
characteristics, drug-reservoirs, and improved
biocompatibility.
[0086] In one embodiment, at least one biocompatible polymeric
layer can be a coating that is applied over the entire
endoprosthesis body, or to select portions. Examples of such
biocompatible polymeric materials can include a suitable hydrogel,
hydrophilic polymer, hydrophobic polymer biodegradable polymers,
bioabsorbable polymers, and monomers thereof. Examples of such
polymers can include nylons, poly(alpha-hydroxy esters), polylactic
acids, polylactides, poly-L-lactide, poly-DL-lactide,
poly-L-lactide-co-DL-lactide, polyglycolic acids, polyglycolide,
polylactic-co-glycolic acids, polyglycolide-co-lactide,
polyglycolide-co-DL-lactide, polyglycolide-co-L-lactide,
polyanhydrides, polyanhydride-co-imides, polyesters,
polyorthoesters, polycaprolactones, polyesters, polyanydrides,
polyphosphazenes, polyester amides, polyester urethanes,
polycarbonates, polytrimethylene carbonates,
polyglycolide-co-trimethylene carbonates, poly(PBA-carbonates),
polyfumarates, polypropylene fumarate, poly(p-dioxanone),
polyhydroxyalkanoates, polyamino acids, poly-L-tyrosines,
poly(beta-hydroxybutyrate), polyhydroxybutyrate-hydroxyvaleric
acids, polyethylenes, polypropylenes, polyaliphatics,
polyvinylalcohols, polyvinylacetates, hydrophobic/hydrophilic
copolymers, alkylvinylalcohol copolymers, ethylenevinylalcohol
copolymers (EVAL), propylenevinylalcohol copolymers,
polyvinylpyrrolidone (PVP), combinations thereof, polymers having
monomers thereof, or the like. Additionally, the coating can
include hydrophilic and/or hydrophobic compounds, polypeptides,
proteins, amino acids, polyethylene glycols, parylene, heparin,
phosphorylcholine, or the like.
[0087] The coatings can also be provided on the endoprosthesis to
facilitate the loading or delivery of beneficial agents or drugs,
such as therapeutic agents, pharmaceuticals and radiation
therapies. As such, the endoprosthetic material and/or holes can be
filled and/or coated with a biodegradable material.
[0088] Accordingly, the polymeric coating material can contain a
drug or beneficial agent to improve the use of the endoprosthesis.
Such drugs or beneficial agents can include antithrombotics,
anticoagulants, antiplatelet agents, thrombolytics,
antiproliferatives, anti-inflammatories, agents that inhibit
hyperplasia, inhibitors of smooth muscle proliferation,
antibiotics, growth factor inhibitors, or cell adhesion inhibitors,
as well as antineoplastics, antimitotics, antifibrins,
antioxidants, agents that promote endothelial cell recovery,
antiallergic substances, radiopaque agents, viral vectors having
beneficial genes, genes, siRNA, antisense compounds,
oligionucleotides, cell permeation enhancers, and combinations
thereof. Another example of a suitable beneficial agent is
described in U.S. Pat. No. 6,015,815 and U.S. Pat. No. 6,329,386
entitled "Tetrazole-containing rapamycin analogs with shortened
half-lives", the entireties of which are herein incorporated by
reference.
[0089] In addition to various medical devices, the coatings on
these devices may be used to deliver therapeutic and pharmaceutic
agents including: anti-proliferative/antimitotic agents including
natural products such as vinca alkaloids (i.e. vinblastine,
vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins
(i.e. etoposide, teniposide), antibiotics (dactinomycin
(actinomycin D) daunorubicin, doxorubicin and idarubicin),
anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin)
and mitomycin, enzymes (L-asparaginase which systemically
metabolizes L-asparagine and deprives cells which do not have the
capacity to synthesize their own asparagine); antiplatelet agents
such as G(GP) II.sub.b/III.sub.a inhibitors and vitronectin
receptor antagonists; anti-proliferative/antimitotic alkylating
agents such as nitrogen mustards (mechlorethamine, cyclophosphamide
and analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes-dacarbazinine (DTIC);
anti-proliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate), pyrimidine analogs (fluorouracil,
floxuridine, and cytarabine), purine analogs and related inhibitors
(mercaptopurine, thioguanine, pentostatin and
2-chlorodeoxyadenosine {cladribine}); platinum coordination
complexes (cisplatin, carboplatin), procarbazine, hydroxyurea,
mitotane, aminoglutethimide; hormones (i.e. estrogen);
anti-coagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory (breveldin); anti-inflammatory: such as
adrenocortical steroids (cortisol, cortisone, fludrocortisone,
prednisone, prednisolone, 6.alpha.-methylprednisolone,
triamcinolone, betamethasone, and dexamethasone), non-steroidal
agents (salicylic acid derivatives i.e. aspirin; para-aminophenol
derivatives i.e. acetaminophen; indole and indene acetic acids
(indomethacin, sulindac, and etodalac), heteroaryl acetic acids
(tolmetin, diclofenac, and ketorolac), arylpropionic acids
(ibuprofen and derivatives), anthranilic acids (mefenamic acid, and
meclofenamic acid), enolic acids (piroxicam, tenoxicam,
phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds
(auranofin, aurothioglucose, gold sodium thiomalate);
immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus
(rapamycin), everolimus, azathioprine, mycophenolate mofetil);
angiogenic agents: vascular endothelial growth factor (VEGF),
fibroblast growth factor (FGF); angiotensin receptor blockers;
nitric oxide donors; antisense oligionucleotides and combinations
thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor
receptor signal transduction kinase inhibitors; retenoids;
cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors
(statins); and protease inhibitors. Also, it should be recognized
that many active agents have multiple pharmaceutical uses other
than those specifically recited.
[0090] In one configuration, the external surfaces of an
endoprosthesis can include a coating comprised of
polytetrafluorethylene (PTFE), expanded PTFE (ePTFE), Dacron, woven
materials, cut filaments, porous membranes, harvested vessels
and/or arteries, or others such materials to form a stent graft
prosthesis. Similarly, a medical device, such as a valve, a flow
regulator or monitor device, can be used with the endoprosthesis,
such that the endoprosthesis functions as an anchor for the medical
device within the body lumen.
[0091] In one configuration, different external surfaces of an
endoprosthesis, such as a low stress zone less susceptible to
flexing, can be coated with functional layers of an imaging
compound or radiopaque material. The radiopaque material can be
applied as a layer at low stress zones of the endoprosthesis. Also,
the radiopaque material can be encapsulated within a biocompatible
or biodegradable polymer and used as a coating. For example, the
suitable radiopaque material can be palladium platinum, tungsten,
silver, stainless steel, gold, tantalum, bismuth, barium sulfate,
or a similar material. The radiopaque material can be applied as
layers on selected surfaces of the endoprosthesis using any of a
variety of well-known techniques, including cladding, bonding,
adhesion, fusion, deposition or the like.
III. Superelastic Everolimus Eluting Stent With
Ethylenevinylalcohol Coating
[0092] In one embodiment, the present invention can include a drug
eluting stent that is self expanding. The stent can have a
structural body that is prepared from a superelastic material that
has shape memory, such as nitinol or the like. The structural body
can be coated with at least one polymeric coating, such as
ethylenevinylalcohol copolymer (i.e., EVAL), that functions as a
drug delivery system that controls the release of drug contained
therein. The drug contained within the polymer coating can be an
anti-restinoic drug (e.g., rapamycin, everolimus, analogs thereof,
and the like) or other drug useful for inhibiting cell
proliferation within the vascular lumen. The drug can be any drug
having a therapeutic benefit for treating and/or preventing a
disease or condition. The polymer coating that contains the drug
can also be coated by another layer of the same or different
polymer that further controls the drug release profile from the
stent.
[0093] In one embodiment, the stent of the present invention is an
everolimus-eluting self-expanding nitinol stent with a elution
rate-controlling polymeric coating prepared from
ethylenevinylacetate copolymers. The stent was designed to address
and overcome three potential shortcomings of prior self-expanding
DES, namely (1) inadequate drug delivery to the target tissue, (2)
short profiles of elution leading to transiently high systemic drug
concentrations, and (3) a tendency towards strut fracture when
implanted into the SFA. The design features of the present
invention that address these drawbacks are detailed below.
[0094] In one embodiment, a coated stent can be loaded with a
relatively high overall drug content (e.g., 225 .mu.g
everolimus/cm.sup.2 stent area) as compared to other coronary
stents that elute analogs of everolimus (e.g., 140 .mu.g
sirolimus/cm.sup.2 or 160 .mu.g zotarolimus/cm.sup.2). Everolimus
(40-O-(2-hydroxyethyl)-rapamycin; Novartis Pharmaceuticals
Corporation, Basel, Switzerland) is a macrolide immunosuppressant
analog of rapamycin (i.e., sirolimus) that, in conjunction with
cyclosporine, has been shown to be effective in inhibiting chronic
rejection episodes of solid organ transplants. Its oral formulation
is marketed outside the United States under the trade name
Certican.RTM.. Everolimus effectively inhibits neointimal
hyperplasia in animal models and, when formulated onto coronary
stents at a dose of 150 .mu.g everolimus/cm.sup.2 stent area, it
reduces restenosis as compared to bare metal or paclitaxel-eluting
stents. The amount of 225 .mu.g everolimus/cm.sup.2 stent area is
an exemplary dose for the drug eluting stent embodiment as this
dose roughly represents a 2:1 increase in dose/mm.sup.2 arterial
area as compared to the coronary DES formulation.
[0095] In one embodiment, the drug eluting stent in accordance with
the present invention, which is referred to herein as "STENT A" is
characterized as follows: a structural body made of nitinol or
other similar superelastic alloy; having a maximum diameter when
expanded of 3 mm to about 20 mm, more preferably from about 3.5 mm
to about 15 mm, and most preferably from about 4 mm to about 12 mm;
having a minimum inner diameter when in a deployable of 0 um (i.e.,
touching) to about 1000 um, more preferably from about 0 um to
about 500 um, and most preferably from about 0 um to about 200 um;
and having a polymeric coating of ethylenevinylalcohol at a
thickness of about 2 um to about 50 um, more preferably from about
4 um to about 25 um, even more preferably from about 5 um to about
20 um, and most preferably from about 13 to about 15 um.
[0096] Equally important as the total bulk dose of everolimus
contained on the stent is its kinetic release profile. Using an
EVAL (i.e., ethylene vinyl alcohol) copolymer system, the
everolimus eluting stent embodiment was designed to release drug
over a longer period of time as compared to coronary stents. In
contrast to coronary DES, which release drug over .about.30 days,
the everolimus eluting stent embodiment can release everolimus more
slowly, and thereby eluting approximately 80% of its drug load over
the first days 90 days. A comparison of drug release rates for
STENT 1, STENT 2, STENT 3, and the everolimus eluting stent
embodiment (i.e., stent A) of the present invention is shown in
FIG. 2A. The comparatively prolonged everolimus release rate of the
stent A embodiment is intended to roughly match the kinetics of
nitinol stent expansion. For example, oversized self-expanding
nitinol stents continue to enlarge to their nominal diameter and
potentially remodel the human arterial wall for at least six
months.
[0097] The relatively high drug load and slow release profile of
the stent A embodiment can assure that the vessel walls of treated
peripheral target arteries will contain more everolimus for longer
periods of time compared to coronary arteries treated with coronary
DES. This is shown in FIG. 2B, which compares porcine arterial drug
content for the STENT A embodiment, STENT 2, and STENT 3 treated
vessels.
[0098] A second salient feature of the slow drug release of the
STENT A embodiment is that the potential for systemic everolimus
overexposure is minimized. In part, this is because everolimus is
released slowly, and thereby the maximum systemic blood
concentration of everolimus in stented patients was much lower
(e.g., 3-4 ng/ml for a 100 mm stent having about 3.8 mg drug) one
hour post-procedure than the recommended upper therapeutic limit in
transplanted patients (e.g., 8 ng/ml) and considerably lower than
the C.sub.max of patients treated with 5 mg everolimus per day in
safety studies (e.g., 114 ng/ml).
[0099] In one embodiment, the present invention utilizes a
well-characterized nitinol stent. As a result, there are ample in
vitro and clinical data to suggest that the stent is able to
withstand the chronic mechanical forces inherent to the SFA. For
example, in a comparative retrospective study of three different
peripheral stents, radiographic strut fracture within the nitinol
stent was observed in only 1.8% of cases after a mean follow-up of
15.+-.9 months. However, fractures of some nitinol stents were
observed in 28% and 19% of cases, respectively (mean follow-up of
32.+-.16 months and 43.+-.24 months, respectively). Similarly, in a
randomized, prospective, single-center study of percutaneous
transluminal angioplasty (PTA) alone v. PTA with the nitinol stent
embodiment, the nitinol stent fracture was observed in only 2% of
patients. Finally, in a multicenter single-arm prospective
registry, strut fracture of the nitinol stent embodiment was
observed in 2.1% (3/143) stents after one year. Taken together, the
results of these three studies suggest that the nitinol stent is
well-suited to the environment of the SFA, and that chronic
implantation is not associated with high rates of fracture. A
nitinol stent can be configured to include a polymer having a drug
so as to be a drug eluting stent in accordance with the present
invention.
[0100] In one embodiment, the present invention includes an
everolimus-eluting, self-expanding nitinol stent. Such a stent can
be used to inhibit restenosis after endovascular intervention in
the SFA by selectively eluting everolimus into the vasculature
tissue in an amount significantly higher than systemic elution into
the bloodstream. As provided herein, there is ample in vitro, in
vivo, experimental, and clinical evidence to suggest that the
everolimus-eluting, self-expanding nitinol stent (1) delivers a
relatively high concentration of everolimus to the target vascular
tissue over a prolonged therapeutic interval, (2) minimizes
potential systemic exposure to everolimus through a slow systemic
(e.g., blood) release profile, and (3) can withstand and adapt to
the rigorous mechanical environment of the SFA.
[0101] In one embodiment, the present invention provides a
drug-eluting stent having a prolonged elution profile with high
local concentration and low systemic concentration. The stent can
include any stent body that is balloon or self expandable. The
stent body includes a first coating layer disposed therein, which
includes a mixture of polymer and drug. The first coating layer
includes a second coating layer of polymer disposed thereon. The
first coating layer can be configured to allow the everolimus to be
controllably released from the stent. The second coating layer can,
optionally with the first coating layer, control the release of the
drug in a manner that prolongs the release profile.
[0102] In one aspect, the polymeric coatings can cooperate so as to
control elution of the drug from the stent. This can include
facilitating elution into the tissue adjacent to the stent and
inhibiting elution into the bloodstream, thereby inhibiting
systemic drug. The controlled elution can be accomplished by the
coatings and artery tissues establishing a diffusion pathway having
a steep concentration gradient with respect to the drug so as to
induce the drug to diffuse through the diffusion pathway. The steep
concentration gradient is accomplished by the coatings having a
high concentration of drug and the tissue having a low
concentration of drug, which thereby promotes diffusion through the
diffusion pathway. Also, the coatings, drug, and tissue can provide
lipophilic and/or hydrophilic diffusion pathways with the tissue
being a sink to promote diffusion of the drug into the tissue.
[0103] Additionally, the diffusion pathway into the vascular tissue
can be enhanced by the stent being placed in a blood vessel that
passes blood. Blood, while containing some lipid-based components,
is significantly more aqueous that than lipidic because the blood
includes a significant amount of water. As such, a lipophilic drug
will preferentially diffuse through a lipophilic diffusion pathway
over an aqueous pathway. The lipophilic drug preferentially
diffusing through the lipophilic diffusion pathway into the tissue
adjacent to the stent over diffusion into the blood attributes to
the vascular tissue adjacent to the stent obtaining a therapeutic
concentration of drug and the system concentration being
significantly below a therapeutic concentration and toxic
concentration. Accordingly, systemic effects of the drug can be
inhibited by maintaining an extremely low systemic drug
concentration, thereby inhibiting the adverse effects of prolonged
systemic drug. This can also be accomplished with hydrophilic
and/or amphophilic drugs and polymer components because tissues
inherently have water as a major component.
[0104] In one embodiment, the coating/drug combination is
configured to provide an extended elution profile that can elute
substantially constant levels of drug over 3 months, more
preferably over 6 months, and most preferably over 9 months. The
slow elution kinetics attribute to the significantly inhibited
systemic elution of the drug and helps to maintain the systemic of
the drug below any therapeutic and/or toxic index. Additionally,
the slow elution kinetics attributes to the drug preferentially
diffusing through the lipophilic diffusion pathway because slow
elution kinetics further drive the lipophilic drug through a
lipophilic diffusion pathway over diffusing into the blood. Also,
the slow elution kinetics can enable the tissue to retain sink-like
properties with respect to the drug so as to provide a continuously
steep concentration gradient through the lipophilic diffusion
pathway.
[0105] In embodiments of the present invention that include
self-expanding stents, the stent continually applies pressure to
the vascular tissue. This continual application of pressure can
cause the tissue to form troughs that receive the stent elements
therein so that the contact area between the tissue and the stent
is increased. Also, it is possible that such continuous pressure
actually facilitates preferential diffusion of the drug through the
lipophilic diffusion pathway. This can occur by the pressure
shortening the diffusion pathway between the stent and the tissue
by compression of the lipid membranes and/or compression of the
coating layers.
[0106] It is thought, without being bound thereto, that the
coating/drug combination that provides preferential diffusion of
the drug through the lipophilic diffusion pathway over diffusion
into the systemic blood supply cooperates with natural
physiological processes in order to further differentiate the
amount of drug in the vascular tissue adjacent to the sent compared
to systemic drug. The difference in drug diffusion pathways that
result in extremely low systemic concentrations is supplemented by
the physiological functions of drug metabolism. Drug metabolism
occurs mainly in organs that are removed from the vascular tissue,
and preferentially not in the vascular tissue. This physiological
process naturally further reduces the systemic concentration of
drug without reducing the concentration of drug in the vascular
tissue.
[0107] In one embodiment, the polymer/drug combination that is
configured for prolonged elution can also allow for a substantially
greater amount of drug loading on the stent. Previously, drug
elution profiles have only allowed for low quantities of drug to be
applied to the stent so as to prevent excessively high elution
rates and thereby excessively high local and systemic drug
concentrations. Some of the previously used stents with low drug
loading concentrations have caused higher systemic drug
concentrations. Now, the polymer/drug combination of the present
invention can allow for substantially increased drug loading on the
stent with reduced systemic concentrations. For example, stents
that produce excessive systemic concentrations of drug have had
relatively lower amounts of drug, such as the following: stent 2
having 140 .mu.g/cm.sup.2; stent 3 having 100 .mu.g/cm.sup.2; and
stent 1 having 90 .mu.g/cm.sup.2. However, the polymer/drug
combination of the present invention can allow for the stents to
have a substantially higher amount of drug loading with lower
systemic blood concentrations. For example, the present invention
can have a drug loading preferably greater than or equal to about
150 .mu.g/cm.sup.2, more preferably greater than or equal to about
200 .mu.g/cm.sup.2, and most preferably greater than or equal to
about 225 .mu.g/cm.sup.2.
[0108] Similarly, the stents of the present invention can have
substantially more total drug per stent than the stents that
produce excessive systemic drug concentrations. For example, stents
that produce excessive systemic concentrations of drug have had
relatively lower amounts of total drug. However, the polymer/drug
combination of the present invention can allow for the stents to
have a substantially higher amount of total drug loading. For
example, the present invention can have a total drug loading
preferably greater than or equal to about 1-3 mg total drug for a
short stent, more preferably greater than or equal to about 3-6 mg
total drug for a medium length stent, and most preferably greater
than or equal to about 6-12 .mu.g total drug for a long stent.
[0109] Additionally, the stents of the present invention can have
substantially more drug per area of artery into which the drug is
to diffuse compared to prior stents. For example, stents that
produce excessive systemic concentrations of drug have had
relatively lower amounts of drug per area of artery, such as the
following: stent 2 having 0.86 to 1.3 .mu.g/mm.sup.2; stent 3
having 0.49 to 63 .mu.g/mm.sup.2; and stent 1 having about 0.57 to
0.66 .mu.g/mm.sup.2. However, the polymer/drug combination of the
present invention can allow for the stents to have a substantially
higher amount of drug per area of artery. For example, the present
invention can have a drug loading preferably greater than or equal
to about 1.25 .mu.g/mm.sup.2 of artery, more preferably greater
than or equal to about 1.5 .mu.g/mm.sup.2 of artery, and most
preferably greater than or equal to about 2.0 .mu.g/mm.sup.2 of
artery.
[0110] In one embodiment, the polymeric coating can have a
thickness of about 2 .mu.m to about 50 .mu.m, more preferably from
about 4 .mu.m to about 25 .mu.m, even more preferably from about 5
.mu.m to about 20 .mu.m, and most preferably from about 13 .mu.m to
about 15 .mu.m. The coating can be uniform or divided into discrete
layers.
[0111] In one embodiment, the polymeric coating can having a primer
coating against the metal, a drug-loaded coating disposed on the
primer coating, and a topcoat disposed on the drug-loaded coating.
This can include the primer coating being from about 1% to about
20% of the total coating thickness, more preferably from about 3%
to about 15% of the total coating thickness, even more preferably
from about 5% to about 10% of the total coating thickness, and most
preferably about 7% of the total coating thickness. This can also
include the drug-loaded coating being from about 25% to about 90%
of the total coating thickness, more preferably from about 40% to
about 80% of the total coating thickness, even more preferably
about 50% to about 70% of the total coating thickness, and most
preferably about 60% of the total coating thickness. Additionally,
this includes the topcoat being from about 5% to about 50% of the
total coating thickness, more preferably from about 15% to about
40% of the total coating thickness, more preferably from about 25%
to about 35% of the total coating thickness, and most preferably
about 30% of the total coating thickness.
[0112] In one example, a 28 mm stent is coated with 234 .mu.g of
primer coating, 3160 .mu.g of drug-loaded coating, and 600 .mu.g of
topcoat. The ratio of primer/drug/topcoat layers can be about
1/14/3.
[0113] In one embodiment, the prevent invention includes a nitinol
stent having a first ethylenevinylalcohol-everolimus coating on the
nitinol body and a second ethylenevinyl alcohol coating thereon. In
one aspect, the everolimus can be included at 1070 .mu.g for a
10.times.28 mm stent so as to produce a blood Cmax of less than or
about 0.72 ng/ml with a Tmax of 7 days, a tissue Cmax of about
greater than or about 6607 ng/g with a Tmax of 3 days, and a half
life (t.sub.1/2) of about 16.3 days. In another aspect, the
everolimus can be included at 1070 .mu.g for a 8.times.28 mm stent
so as to produce a blood Cmax of less than or about 2.29 ng/ml with
a Tmax of 1 day, a tissue Cmax of greater than or about 12946 ng/g
with a Tmax of 3 days, and a half life of 11.70 days. In another
aspect, the everolimus can be included at 1070 .mu.g for a
8.times.28 mm stent so as to produce a blood Cmax of less than or
about 2.70 ng/ml with a Tmax of 3 days, a tissue Cmax of greater
than or about 8709 ng/g with a Tmax of 3 days, and a half life of
11.51 days. In another aspect, the everolimus can be included at
3209 .mu.g for a 8.times.28 mm stent so as to produce a blood Cmax
of less than or about 3.35 ng/ml with a Tmax of 3 days, a tissue
Cmax of greater than or about 22027 ng/g with a Tmax of 3 days, and
a half life of 21.26 days. In another aspect, the everolimus can be
included at 3777 .mu.g for a 7.times.100 mm stent so as to produce
a blood Cmax of less than or about 9.6 ng/ml with a Tmax of 0.042
days, a tissue Cmax of greater than or about 16347 ng/g with a Tmax
of 3 days, and a half life of 19.8 days, and which produces a
kidney Cmax of less than or about 25.6 ng/g, a lung Cmax of less
than or about 22.8 ng/g, a muscle Cmax of less than or about 13.5
ng/g, a liver Cmax of less than or about 15.1 ng/g, and a spleen
Cmax of less than or about 23.1 ng/g.
IV. Method of Making Endoprostheses
[0114] Various different manufacturing techniques are well known
and may be used for fabrication of the drug eluting endoprosthesis
of the present invention. Such manufacturing techniques can be
employed to make the different annular elements of the drug eluting
endoprosthesis. For example, the different annular elements or
entire endoprosthesis can be formed from a hollow tube using a
known technique, such as laser cutting, EDM, milling, chemical
etching, hydro-cutting, and the like. Also, the different annular
elements or endoprosthesis can be prepared to include multiple
layers or coatings deposited through a cladding process such as
vapor deposition, electroplating, spraying, or similar processes.
Also, various other processes can be used such as those described
below and or others known to those skilled in the art in light of
the teaching contained herein.
[0115] Optionally, the different annular elements or endoprosthesis
can be fabricated from a sheet of suitable material, where the
sheet is rolled or bent about a longitudinal axis into the desired
tubular shape. Additionally, either before or after being rolled
into a tube, the material can be shaped to include endoprosthetic
elements by being shaped with well-known techniques such as
laser-cutting, milling, etching or the like. If desired, the
lateral edges of the structure can be joined together, such as by
welding or bonding, to form a closed tubular structure, or the
lateral edges can remain unattached to form a coiled, rolled sheet
or open tubular structure. Such fabrication techniques are
described in more detail below and known to those skilled in the
art.
[0116] A. Sintering
[0117] A method of making different annular elements or
endoprosthesis in accordance with the present invention can include
sintering sinterable particles to provide a sintered article having
the shape of the endoprosthesis. The sintering can be conducted in
molds that are in the shape of an endoprosthesis.
[0118] In one configuration, the sintered body can be obtained from
a molded green body prepared by molding a mixture of sinterable
particles with or without a binder into the shape of different
annular elements or endoprosthesis or body intermediate. Sintering
a molded green body that has the shape of different annular
elements or endoprosthesis can provide a sintered body that can
function as an endoprosthesis with no or minimal further
processing. Alternatively, after the green body has been formed in
the mold and sintered into a hardened endoprosthesis, the process
can include shaping the sintered body with a stream of energy
and/or matter in order to obtain a desired shape. Thus, sintering a
green body in a mold can result in an endoprosthesis that is either
ready for use, or requires additional processing or finishing.
[0119] Additionally, the sintered body can be shaped into an
endoprosthesis as described herein. Also, the endoprosthesis can be
further processed after sintering and/or shaping such as by
grinding, sanding, or the like to provide enhanced surface
characteristics.
[0120] B. Drawing Concentric Tubes
[0121] In one configuration, multilayered annular elements or
endoprosthesis in accordance with the present invention can be
prepared by a drawing process that draws two or more distinct
concentric tubes into a single tube having two or more layers.
Additionally, such a drawing process can combine multiple
concentric tubes into a single multilayered tube. The drawing
process can be configured to produce junctions separating adjacent
layers or bonds that bond adjacent layers. As such, the
sequentially-adjacent concentric tubes can be drawn together and
progressively reduced in a cross-sectional profile until the
desired size and residual clamping stress is attained.
[0122] Accordingly, a metallurgical bond can be prepared with
elements of each sequentially-concentric tube diffusing together
and bonding so as to form a strong metallurgical bond. Such a
metallurgical bond can be achieved by applying significant pressure
and heat to the tubes. As such, a metallurgical bond can form a
diffusion layer at the interface between sequentially-adjacent
concentric tubes (i.e., layers). The characteristics of these
diffusion layers can be controlled by the proper heat treatment
cycle. In part, this is because the heat treatment, temperature,
and time of processing can control the rates of transfer of the
diffusing elements that produce the diffusion layers. Also, the
pressure at the interface between layers can be developed so as to
result in the residual radial clamping stress in the tube after
drawing. A similar process can be used in order to couple the
adjacent different annular elements or endoprostheses together to
form the hybrid segmented endoprosthesis.
[0123] In one example of this process, an outer tube of nitinol, a
middle tube of tantalum, and an inner tube of nitinol can be
arranged to form the composite structure. The multilayered material
can be produced to result in bonding between the layers so as to
achieve a residual clamping stress of at least about 50 p.s.i.
Accordingly, the annealing process can be performed within a
limited range of time and temperatures. For example, the lower
limit can be at least about 1550.degree. F. for at least six
minutes, and the upper limit can be less than about 1850.degree. F.
for less than 15 minutes. A similar process can be used in order to
couple the adjacent different annular elements together to form the
endoprosthesis.
[0124] In another configuration, a metallic interleaf layer can be
placed between separate tubes so as to bond the tubes together and
form a multilayered material. The multiple tubes separated by the
metallic interleaf layer can be drawn together and progressively
reduced until the desired cross-sectional profile and residual
clamping stress is attained, as described above. The drawn tubes
can be heat-treated to form a diffusion bond between the separate
layers. As such, the metallic interleaf layer can enhance the
diffusion rate or type of diffusing atoms that are transported
across a diffusion region between one layer and the interleaf
layer. A similar process can be used in order to couple the
adjacent different annular elements together to form the
endoprosthesis.
[0125] In one configuration, a multilayered sheet can be prepared
to have separate layers of different materials or the same
material. For example, the multilayered sheet can have a top layer
of nitinol, a middle layer of tantalum, and a bottom layer of
nitinol. The sheet can be prepared by metallurgically bonding the
layers prior to a deep drawing process, which is well known in the
art. During the deep drawing process, the sheet can be placed over
a die and forced into the die, such as by a punch or the like. A
tube having a closed end and a defined wall thickness can be formed
in the die. This process can be repeated using a series of dies
that have progressively decreasing diameters until a multilayered
tube is formed having the desired diameter and wall thickness. For
certain material combinations, intermediate heat treatments can be
performed between the progressive drawing operations to form a
multilayered material that is resistant to delaminating. Once a
multilayered tube of desired thickness and dimensions has been
formed, the closed end and the curved edges can be cut off. Then,
the tube can be heat treated, as described above, until proper
inter-metallic bonds are formed between the layers.
[0126] C. Shaping
[0127] Accordingly, an endoprosthetic material can be shaped by
various methods as described in more detail below. Such shaping
techniques can utilize streams of energy and/or streams of matter
in order to impart shapes into the endoprosthetic material. The
streams of energy include photons, electromagnetic radiation,
atomic, and sub-atomic materials, as described above. On the other
hand, the streams of matter are considered to include materials
larger than atomic scale particles, and can be microscopic or
macroscopic in size. In any event, the shaping can be designed to
direct a stream of energy or a stream of matter at the
endoprosthetic material to form an endoprosthetic element and/or
holes therein.
[0128] In one configuration, a stream of energy can cut, shape,
and/or form a tube into an endoprostheses by generating heat at the
site where the stream intersects the material, as is well known in
the art. The thermal interaction can elevate the local temperature
to a point, which can cut, melt, shape, and/or vaporize portions of
the endoprosthetic material from the rest of the material.
[0129] Accordingly, one configuration of the stream-cutting
apparatus can operate and shape the endoprosthetic material by
thermal interactions. As such, any of the thermal processes
described herein can be used for thermal-cutting. For example, such
thermal interactions can arise from laser beam treatment, laser
beam machining, electron beam machining, electrical discharge
machining, ion beam machining, and plasma beam machining.
[0130] In one configuration, by knowing the thermal properties of
the endoprosthetic material, precise energy requirements can be
calculated so that the thermal beam provides the appropriate or
minimum energy for melting and/or vaporizing the material without
significantly melting undesirable portions of the material. For
example, laser beams are a common form of a stream of energy that
can be used to shape the endoprosthetic material. Additionally,
there are instances where a laser is preferred over all other
cutting techniques because of the nature of the resulting
endoprosthesis as well as the characteristics of the endoprosthetic
material.
[0131] In one configuration, an endoprosthesis may be manufactured
as described herein using a femtosecond laser. A femtosecond laser
may be desirable in producing an endoprosthesis in accordance with
the multilayered composite structure of the present invention
because it produces a smaller heat influence zone HIZ or heat
affected zone HAZ compared to other lasers, or it can substantially
eliminate the HIZ or HAZ. In comparison, cutting an endoprosthesis
using known methods can result in the tubular material being melted
away, and thereby forming the pattern in the tubular member. Such
melting can result in embrittlement of some materials due to oxygen
uptake into the HIZ.
[0132] In one configuration, electrical discharge machining is used
to shape endoprosthetic material and/or form holes in the
endoprosthetic material as desired. As such, electrical discharge
machining can be capable of cutting all types of conductive
materials such as exotic metal including titanium, hastaloy, kovar,
inconel, hard tool steels, carbides, and the like. In electrical
discharge, the main interaction between the stream of energy and
the endoprosthetic material is thermal, where heat is generated by
producing electrical discharges. This can lead to the
endoprosthetic material being removed by melting and evaporation.
Some examples of electrical discharge machining include wire
electron discharge machining, CNC-controlled electrical discharge
machining, sinker electrical discharge machining, small hole
discharge machining, and the like.
[0133] In another configuration, a charged particle beam can be
used for shaping the endoprosthetic material, wherein electron
beams and ion beams exemplify charged particle beams. A charged
particle beam is a group of electrically-charged particles that
have approximately the same kinetic energy and move in
approximately the same direction. Usually, the kinetic energies are
much higher than the thermal energies of similar particles at
ordinary temperatures. The high kinetic energy and the
directionality of these charged beams can be useful for cutting and
shaping of the green bodies, as described herein. Additionally,
there are some instances where electron beams or ion beams are
preferred over other cutting techniques.
[0134] In one configuration, a stream of chemical matter can be
used in order to shape or form holes in the endoprosthetic
material. Chemical-jet milling, for example, provides selective and
controlled material removal by jet and chemical action. As such,
the process is similar to water-jet cutting, which is described in
more detail below. In any event, chemical-jet milling can be useful
for shaping various types of endoprosthetic materials, which
provides intricate shaping capabilities.
[0135] In another configuration, electrochemical shaping can be
based on a controlled electrochemical dissolution process similar
to chemical-jet milling an endoprosthetic material. As such, the
endoprosthetic material can be attached to an electrical source in
order to allow an electrical current to assist in the shaping.
[0136] In one configuration, hydro-cutting or water-jet cutting can
be used to shape an endoprosthetic material. Hydro-cutting is
essentially a water-jet technology that uses the high force and
high pressure of a stream of water directed at the endoprosthetic
material in order to cut and shape the material as desired.
Hydro-cutting can be preferred over some of the other
stream-cutting technologies because it can be free of heat, flame,
and chemical reactions, and can provide a precise cold shaping
technique. Also, heated water with or without being doped with
reactive chemicals can also be used. Hydro-cutting is particularly
suitable for polymeric endoprostheses, but can be used for metal
materials when combined with abrasive particles, as described
below.
[0137] Additionally, hydro-cutting can be enhanced by the
introduction of particulate materials into the water feed line. As
such, some hydro-cutting techniques utilize garnet or other rigid
and strong materials in order to apply an abrasive cutting force
along with the force applied by the water itself. Also, the
hydro-cutting process in the present invention can be used with or
without inclusion of such abrasives.
[0138] Additionally, one of the benefits of hydro-cutting is the
ability to reutilize and recycle the spent water-jet material. As
such, the endoprosthetic material can be easily separated from the
spent water, thereby enabling the recycling and reuse of the water
during the hydro-cutting process.
[0139] In one configuration, sandblasting, which fits into the
regime of stream of matter cutting, can be used to shape an
endoprosthetic material by projecting a high energy stream of sand
particles at the material. Sandblasting cuts materials in a manner
similar to hydro-cutting, especially when the water-jet is doped
with abrasive particulates. Additionally, various other particulate
streams other than sand can be used in the stream-cutting
techniques and machinery.
[0140] D. Additional Processing
[0141] An additional step of passivation can be performed during
the manufacturing stage of the endoprosthesis in order to form a
homogeneous oxide layer for corrosion-resistance. The passivation
process may be performed prior to installation of the markers in
accordance with the present invention or it may be performed after
installation of the radiopaque markers. It can also be done before
or after the different annular elements or endoprostheses are
coupled together. Alternatively, multiple passivation processes may
be performed, once prior to application of the markers, and again
after insertion of the markers.
[0142] As originally shaped and/or fabricated, the annular elements
or endoprosthesis can correspond to a delivery configuration, to a
deployed configuration, or to a configuration therebetween. The
annular elements or endoprosthesis can be fabricated with a
configuration at least slightly larger than the delivery
configuration. In this manner, the endoprosthesis can be crimped or
otherwise compressed into its delivery configuration in a
corresponding delivery device.
[0143] In another configuration, the annular elements or
endoprosthesis can be originally fabricated from a tube having a
diameter corresponding to the deployed configuration. In this
manner, the longitudinally-free portions of the annular elements
(e.g., elbow or foot not at a connection location) and
circumferentially-free portions (e.g., the toe and/or heel portion
of the foot extensions) can be maintained within the general
cylindrical shape (e.g., diameter) of the endoprosthesis when
deployed, so as to avoid such portions from extending radially
inward when in the deployed configuration. The endoprosthesis can
be designed to match the target vessel in which the endoprosthesis
is to be deployed. For example, a stent can be provided with an
outer diameter in the deployed configuration ranging from about 1
mm for neurological vessels to about 25 mm for the aorta.
Similarly, a stent can be provided with a length ranging from about
5 mm to about 200 mm. Variations of these dimensions will be
understood in the art based upon the intended application or
indication for the endoprosthesis.
[0144] Also, the geometry of each component of the endoprosthesis
or endoprosthetic element, such as the width, thickness, length and
shape of the strut elements, interconnectors, crossbars,
connectors, elbows, foot portions, ankle portions, toe portions,
heel portions and the like can be selected to obtain predetermined
expansion, flexibility, foreshortening, coverage scaffolding, and
cross-sectional profile characteristics. For example, longer
crossbars and/or connectors can promote greater radial expansion or
scaffolding coverage. The phase difference or circumferential
alignment between adjacent annular elements likewise can be altered
to control coverage and flexibility. Similarly, the number and
placement of connection locations and, if present, the connectors,
between longitudinally-adjacent annular elements can be selected to
obtained the desired flexibility of the endoprosthesis. The number
of elbows and/or foot extensions between connection locations also
can be varied to achieve desired performance characteristics.
[0145] E. Coatings
[0146] After the endoprosthesis body is formed, a polymeric coating
can be applied thereto. The coating can be applied as is well known
in the art of drug eluting stents were polymers are used to retain
the drug and allow for diffusion therefrom. Some of the methods for
coating endoprostheses (e.g., stents) with polymers includes
dipping, spraying, inkjetting, painting, brushing, rolling, or
otherwise depositing the polymeric coating on the endoprosthesis
body. This can include such processes for one or more concentric
layers of polymeric coating materials.
[0147] In one embodiment, the drug is mixed into a polymeric
solution that is applied to the endoprosthesis by an acceptable
method of application. Alternatively, a first layer of polymer can
be applied to the stent and then a drug layer can be applied
thereto with a topcoat of polymer being applied over the drug
layer. In another alternative. A coated stent can be dipped into a
drug solution so that the drug diffuses into the polymeric coating
to achieve the desired amount of drug. In yet another alternative,
a bare endoprosthesis can have a layer of drug applied thereto with
at least one layer of polymer applied thereto.
[0148] After application of a fluid or gelatinous coating, the
endoprosthesis can be dried so that the coating can be
substantially solidified. Such drying can accomplished by passive
or active drying. Passive drying includes retaining the coated
stent in normal or ambient conditions so that a natural drying
process occurs. Active drying includes the use of head or forced
air to cause the solvent in the liquid coating to evaporate from
the coating, and thereby harden the coating so as to be
substantially solid.
[0149] In one embodiment, the coating or plurality of coatings are
applied by a plurality of spray layers. For example, the primer
coating can be formed from about 2-3 passes of spraying polymer,
the drug-loaded coating can be formed from about 26 passes of
spraying polymer, and the topcoat can be formed from about 13
passes of spraying polymer.
V. Method of Delivering Hybrid Segmented Endoprosthesis
[0150] Generally, the drug eluting endoprosthesis of the present
invention can be delivered into a body of a subject by any method
known or developed. For example, the method of using catheters to
deploy self-expandable or balloon-expandable stents can be
employed.
[0151] In one embodiment, the endoprostheses of the present
invention are configured for use in a body lumen. As such, the
present invention includes a method of delivering the
endoprosthesis into a body lumen of a subject. Such a method
includes: providing an endoprosthesis as described herein;
orienting the endoprosthesis into a delivery orientation with a
cross section that is smaller than the body lumen; inserting the
endoprosthesis in the delivery orientation into a delivery device,
such as a deliver catheter that can be configured substantially as
a catheter for delivering a stent; delivering the endoprosthesis to
a desired deployment site within the body lumen of the subject;
removing the endoprosthesis from the delivery device; and expanding
the endoprosthesis so as to have an enlarged dimension that applies
radial forces to an inner wall of the body lumen.
[0152] FIGS. 5A-5B are side Views illustrating an embodiment of a
drug endoprosthesis and methods of deploying such an endoprosthesis
into a body lumen in accordance with the present invention. The
endoprosthesis 120a is a drug eluting stent, which is depicted in
FIG. 5C to show 3 different layers as follows: a stent body layer
124, a polymer/drug coating 122, and a polymeric topcoat 126 that
controls drug diffusion from the stent, where 122a, 124a, and 126a
designate the delivery configuration and 122b, 124b, and 126b
designate the deployed configuration.
[0153] FIG. 5A is a schematic representation illustrating a
delivery system 100 for delivering a drug eluting endoprosthesis
120a into a body lumen 140, such as a blood vessel like the vena
cava. The delivery system includes an endoprosthesis delivery
catheter 102 configured for delivering a drug eluting
endoprosthesis 120a that is retained by the catheter 102 in a
delivery orientation (e.g., radially compressed). The delivery
catheter 102 includes a delivery member 104 that defines a delivery
lumen 107 that is shaped and dimensioned to retain the
endoprosthesis 120a in the delivery orientation. Accordingly, the
delivery member 104 is substantially tubular and configured
similarly as any delivery catheter member. An internal surface 106
defined by the delivery member 104 holds the endoprosthesis 120a
within the delivery catheter 102.
[0154] The delivery system 100 delivers the endoprosthesis 120a
with a catheter 102 similarly to the method of delivering other
endoprostheses into a body lumen. As such, an insertion site (not
shown) is formed through the skin (not shown) that traverses into a
body lumen 140. A guidewire (not shown) is then inserted through
the insertion site, through the body lumen 140, to the delivery
site 144. A catheter (not shown) is then inserted into the body
lumen 140 to the delivery site 144 over the guidewire, and the
guidewire is optionally extracted. The delivery catheter 102 is
then inserted through the catheter (not shown) until reaching the
delivery site 144 and the catheter is withdrawn.
[0155] Optionally, the catheter is the delivery catheter 102, and
in this instance, the delivery catheter 102 is retained at the
delivery site 144 and the endoprosthesis 120a is delivered to the
delivery site 144 through the lumen 107 of the delivery catheter
102. An optional pusher or stop 110, having a lumen (not shown) to
receive the guidewire (not shown), can be used to push the
endoprosthesis 120a within the lumen 107 of the delivery catheter
102 to the delivery site 144 or limit proximal movement of the
endoprosthesis 120a as the delivery catheter 102 is moved
proximally to deploy the endoprosthesis 120a.
[0156] Accordingly, the delivery system 100 is inserted through
percutaneous insertion site (not shown) that traverses from the
skin (not shown) into the body lumen 140 until reaching the
delivery site 144. The pusher 110 includes a distal end 112 that
pushes the endoprosthesis 120a from the distal end 108 of the
delivery member 104. Alternatively, the endoprosthesis 120a can be
disposed at the distal end 108 of the delivery member 104, and the
pusher 110 holds the endoprosthesis 120a at the delivery site 144
and the delivery member 104 is retracted over the endoprosthesis
120a and pusher 110. Thus, the pusher 110 can push the
endoprosthesis 120a from the delivery catheter 102 or the delivery
member 104 can be withdrawn over the endoprosthesis 120a and pusher
110 in order to deploy the endoprosthesis 120a. Combinations of
these are also possible.
[0157] FIG. 5B illustrates the endoprosthesis 120b in the deployed
configuration at the delivery site 144 within the body lumen 140.
As such, the endoprosthesis 120b is radially expanded so as to
contact the inner wall 142 of the body lumen 140.
[0158] In one embodiment, the present invention can include a
method of extracting the endoprosthesis from the body lumen, which
can include: inserting an endoprosthesis-extracting medical device
into the body lumen so as to come into contact with the
endoprosthesis; engaging the endoprosthesis-extracting medical
device with the endoprosthesis; radially compressing the
endoprosthesis so as to have a reduced dimension with a cross
section that is smaller than the body lumen; and retrieving the
endoprosthesis from the desired deployment site within the body
lumen of the subject. Optionally, the endoprosthesis can be
received into the endoprosthesis extracting medical device, which
can be substantially similar to a catheter.
[0159] In one embodiment, at least one of delivering or retrieving
the endoprosthesis is performed with a catheter. Catheters
configured for delivering and/or retrieving endoprostheses from a
body lumen can be adapted for delivering and/or retrieving the
endoprosthesis of the present invention.
VI. Lumen Filter
[0160] In one embodiment, the medical device of the present
invention having the drug-loaded polymer coating can be a lumen
filter, such as a vena cava filter. The drug-loaded polymer coating
can provide substantially the same drug elution profile with
increased local tissue concentration and decreased blood and
systemic concentration as described herein.
[0161] In one embodiment, the lumen filter is configured for a use
other than filtering clots from the lumen; however, such a function
can also be performed. The lumen filter embodiment is configured to
deliver the drug loaded in the polymer to the lumen in which the
filter is disposed without a substantial amount of systemic
delivery. As such, the delivery profile from the lumen filter can
be substantially as shown herein.
[0162] As shown in FIGS. 6A-6C, the lumen filter 200 can include a
substantially tubular or conical-shaped body 210, the walls of
which can be partitioned by a slot pattern, web, latticework or the
like rendering the body radially expandable. Additionally, a
plurality of tines can be included in the body 210 in substantially
uniform circumferential spacing about the proximal end of said
tubular body. In a filter intended for femoral vein introduction
into the vena cava the tines can be elongated appendages having
hooked terminal ends. In a filter intended for jugular vein
introduction the tines can be short spikes. The filter can be
delivered to the inferior vena cava by catheters as is well known
in the art, including through the technique and structures
discussed above with respect to endoprosthesis 120a.
[0163] The filter can be delivered substantially as described in
for the endoprosthesis 120a in FIGS. 5A-5B, and the elements
thereof are include in FIGS. 6B-6C. For example, after the proper
location is obtained within the body lumen, i.e., the delivery site
144 of FIG. 6B is attained, the filter 200 can be deployed from the
distal end of the catheter 102 through distal movement of the
pusher 110, proximal movement of catheter 102, or a combination of
distal and proximal movements. With the filter 200 being
self-expanding, releasing the filter 200 from the distal end of the
delivery catheter 102 allows the filter 200 to expand into the body
lumen affix the expanded filter 200 within the vena cava. After
deployment of the expanded filter 200 within the vena cava the
catheter 102 is withdrawn as shown in FIG. 6C, and the filter
elutes drug as described herein.
[0164] In one embodiment, the medical device of the present
invention, such as the drug-coated stent or lumen filter, can be
utilized to locally deliver the drug as described herein. As such,
the medical device can be used as a drug delivery system instead of
or in concurrence to being a stent or a lumen filter.
[0165] In one embodiment, the medical device of the present
invention, such as the drug-coated stent or lumen filter, can be
configured to systemically elute the drug in an amount sufficient
for maintaining a therapeutically effective amount of drug in the
blood. For example, everolimus, zotarolimus, or other rapamycin
analogs can be included in the polymeric coating of the medical
device in an amount that systemically delivers the drug into the
blood stream for systemic administration. The amount of drug
elution can be configured to be sufficient for providing the
therapeutic benefit of the drug for the treatment and/or
prophylaxis in which the drug is being used. Such amounts are
readily obtainable and the blood concentration can be achieved by
altering (e.g., increasing or decreasing) the total amount of drug
in the polymer.
[0166] In one embodiment, the medical device, such as the lumen
filter, can be configured for substantially systemic drug delivery
in addition to and/or instead of local delivery into the adjacent
tissue. In such a configuration, the medical device is configured
to preferentially elute the drug into the blood over the tissue.
This can be accomplished by any of the following: applying the
drug-loaded polymer to at least one fluid-contacting surface of the
medical device; coating the tissue-contacting surfaces of the
medical device with a coating that inhibits drug diffusion; and
combinations thereof.
[0167] In one embodiment, the medical device, which can be in the
form of a stent, lumen filter, implant, or the like, can be
configured as a drug delivery system that can be a substitute for
an oral medication regimen. This can be achieved by the medical
device in a suitable form for implantation into a body cavity,
lumen, organ, subcutaneous, or any other body part. Many medical
devices are configured specifically for placement in the body and
any of these medical devices can be configured for controlling drug
elution so as to obtain a desired systemic concentration via the
configurations described herein. That is, the drug-loaded polymer
that has a long term elution profile can be selectively applied to
the medical device. As such, the medical device becomes a systemic
drug release device instead of a device to treat an area of
stenosis. The drug release device could replace daily pills for
individuals in need of the therapy provided by the drug, such as
transplant patients. However, any drug for any condition can be
applied to the medical device in the polymer system described
herein for treatment of any disease.
EXAMPLES
Example 1
[0168] Stent in vivo experimental pharmacokinetics of the
peripheral everolimus eluting self-expanding nitinol stent (i.e.,
STENT A) were assessed in the porcine model. Briefly, stents were
implanted in the iliofemoral arteries, explanted at pre-determined
endpoints, and assayed for drug content by HPLC. The results (e.g.,
FIG. 2A) showed that the drug was slowly released from the device
over approximately three months, at a rate largely independent of
stent configuration. The three-month release rates considerably
prolonged as compared to previously developed peripheral
drug-eluting stents which elute over about one week (STENT #1) or
coronary drug-eluting stents which elute over about one month
(STENT #1 and STENT #2).
Example 2
[0169] Tissue in vivo experimental pharmacokinetics of the
peripheral everolimus eluting self-expanding nitinol stent (i.e.,
STENT A) in the porcine model. Stents were implanted in the
iliofemoral arteries. At pre-determined endpoints, stented arterial
tissue was explanted and assayed for drug content by HPLC. Drug
content following STENT A implantation, expressed in drug/g
arterial tissue, is shown in FIG. 2B comparison to porcine coronary
drug content after treatment with coronary drug-eluting stents
(STENT #2 and STENT #3). The relatively high drug content and slow
release profile of the STENT A stent assures that the vessel walls
of treated target arteries will comparatively contain more drug for
longer periods of time.
Example 3
[0170] Systemic or blood in vivo experimental pharmacokinetics of
the peripheral everolimus-eluting self-expanding nitinol stent
(e.g., STENT A) in the porcine model. As shown in FIG. 3, because
everolimus is released slowly from the device, the whole blood
concentration of everolimus in stented patients is projected to be
in the range of 1-6 ng/ml (square-marked line), lower than the
recommended upper therapeutic limit in transplanted patients (8
ng/ml) and considerably lower than the C.sub.max of patients
treated with 5 mg everolimus per day in safety studies (116 ng/ml,
zigzag line). Because of its slow release profile, whole blood
everolimus concentrations after ABSOLUTE-E stenting approximate
those of traditional coronary drug-eluting stents (circle-marked
line).
Example 4
[0171] Long-term in-vivo angiographic and histologic results of
STENT A stenting (DES) vs. bare metal stenting (BMS) were studied.
In this study, overlapped DES and BMS were implanted into the right
and left iliofemoral arteries of Yucatan Miniature swine. After six
months, the stented portion of the arteries were embedded in
methylmethylacrylate resin, sectioned, ground, polished, and
stained with Toluidine Blue and Basic Fuschin stains. As shown in
FIG. 4 in the angiographic and histologic examples, the
everolimus-eluting DES was effective in limiting neointimal
hyperplasia and in-stent restenosis as compared to the BMS.
Example 5
[0172] Nitinol stents were coated with EVAL and everolimus.
Briefly, N,N-Dimethyl acetamide was used for EVAL polymer
formulation at 4.5% (w/w). Everolimus was then formulated with
EVAL/DMA to obtain a drug to polymer ratio of about 1:1.6. The
permitted daily exposure of DMA was defined as 10.9 mg by ICH
Guidelines on Residual Solvents. Additionally, the tests and
specifications for DES indicate that DMA residual solvent is not to
exceed 40 .mu.g for a stent 8.0.times.28 mm. The coated stent was
sterilized with ethylene oxide.
Example 6
[0173] Experiments were conducted in order to determine the in vivo
release rate and drug elution profile for the drug eluting stents
of the present invention. Briefly, stents of a dimension of
10.0.times.28 mm having an EVAL coating with everolimus at 1070
.mu.g total drug were implanted into peripheral vasculature of
healthy swine. The swine were divided into 5 groups and assays at
3, 7, 14, 28, and 90 days. Concentrations of Everolimus in whole
blood and in arterial tissue in the stented vessel were measured
and pharmacokinetic parameters of Tmax, Cmax and t.sub.1/2 were
calculated. The rate of elution from the stent was determined by
measuring the amount of drug remaining on the stent at designated
times post-implant, up to 90 days. Drug concentrations in tissue
from proximal, medial and distal segments of stented arteries were
compared to assess the uniformity of elution along the length of
the stent.
[0174] Prior to surgery, animals were administered clopidogrel
bisulphate and salicylic acid, blood was drawn for a baseline
clinical pathology (CBC and Chemistry) analysis. Surgical plane
anesthesia was and the vasculature was accessed via the carotid
artery. A sheath was placed and sutured into position in order to
provide access for the test devices to be placed in to the right
and left iliac/femoral arteries. A guiding catheter and wire were
passed from the carotid to the distal vasculature using fluoroscopy
to visualize the movement of the device through the anatomy.
Measurements of the vessels were taken and recorded after reaching
the desired location. The devices were then deployed into the
best-sized vascular region of the left and right iliac/femoral
arteries.
[0175] At each interim sacrifice, designated animals were prepared
for surgery. Whole blood with EDTA was collected for complete blood
count (CBC) with differential. A blood smear was prepared. Serum
was prepared from whole blood for a standard chemistry panel. A
final angiography was performed. The vessels were measured and the
data recorded. Animals were euthanized while under anesthesia,
using an acceptable method of euthanasia. The vessels containing
the stents were then isolated and visually inspected and removed.
The artery was removed from the stent and grossly sectioned into
three segments (stented region, unstented proximal, unstented
distal). The excised vessels were collected into labeled containers
and immediately frozen and stored at (-70.degree. C.).
[0176] Analysis of drug concentration in blood and arterial tissue
was performed. The method for analysis of Everolimus in porcine
whole blood and tissues involves adding 200 .mu.L of internal
standard (IS)/precipitating solution to 100 .mu.L whole blood or
tissue homogenate. Samples are vortexed and centrifuged. Two
hundred microliters of the supernatant is transferred to an
autosampler vial. Analysis is performed by injecting 100 .mu.L of
sample onto a Zorbax SB-C18 (4.6.times.12.5 mm 5 .mu.m) cleanup
column (ambient, 5 mL/min) and then switched to an lnertsil ODS-3
(2.1.times.50 mm, 5 .mu.m) analytical column (0.4 mL/min),
maintained at 65.degree. C. The sample is loaded onto the cleanup
column using a mobile phase of 50/50 methanol/0.1% formic acid with
0.2 mM NaCl. Isocratic elution from the analytical column is
performed using a mobile phase of 65/35 acetonitrile/0.1% formic
acid containing 0.2 mM NaCl. Run time is about 6 minutes. Detection
is by mass spectroscopy. The range of the assay is 0.1-100 ng/mL in
porcine whole blood and 0.5-500 ng/g in tissue.
[0177] Analysis of drug remaining on excised stents was performed.
To determine the amount of drug remaining on excised stents, each
explanted stent was sonicated at ambient temperature for 15 minutes
in 3.5-13 ml N,N-Dimethyl Acetamide (DMA) to elute the drug polymer
from the stent. An aliquot of extract is then diluted to a final
composition of 50% DMA, 50% water, by volume. Analysis is performed
by injecting 50 .mu.l onto a C18 (3.times.150 mm, 5 .mu.m particle
size) column and a UV or photodiode array detector. The isocratic
mobile phase is composed of 50/50 (v/v) Acetonitrile/water at 1.2
mL/min. The column temperature is maintained at 50.degree. C. while
the samples are maintained at 50.degree. C., and the
chromatographic analysis is monitored at 277 nm. Run time is about
25 minutes. The range of the assay is 2.5-60 .mu.g/ml in DMA/water
stent extract. Using this method, the total amount of drug is
determined as the sum of both 6 and 7 member ring isomers of
Everolimus. The amount of drug release in-vivo at each time
interval is calculated by subtracting residual drug from the
theoretical amount target total content of drug on the stent. The
in-vivo release rates are reported as percent of target total
content.
[0178] The drug concentration in whole blood at each interim time
point was determined to be as follows: 0.72 ng/ml at 7 days; 0.23
ng/ml at 14 days; 0.12 ng/ml at 28 days, and below 0.1 ng/ml at 90
days. The drug concentration in tissues in proximity (e.g.,
proximal to stented region, stented region, and distal to stented
region) to the stent at each interim time point was determined to
be as follows: at 3 days proximal to stented region was 100 ng/g,
stented region was 6607 ng/g, and distal to stented region was 278
ng/g; at 7 days proximal to stented region was 37 ng/g, stented
region was 5104 ng/g, and distal to stented region was 208 ng/g; at
14 days proximal to stented region was 40 ng/g, stented region was
4137 ng/g, and distal to stented region was 251 ng/g; at 28 days
proximal to stented region was 12 ng/g, stented region was 3928
ng/g, and distal to stented region was 86 ng/g; and at 90 days
proximal to stented region was 7 ng/g, stented region was 2303
ng/g, and distal to stented region was 8 ng/g.
[0179] The amount of drug remaining on each excised stent was
measured by HPLC with spectrophotometric detection. The percent of
drug released was then calculated as the amount eluted from the
excised stent, subtracted from the Target Total Content (TTC) as
specified for the device product (1070 .mu.g dose), divided by the
TTC and multiplied by 100. The percentage of Everolimus released
from the stent at each timepoint is summarized as follows: at day
3, drug remaining on stent was 900 .mu.g and percent released was
15.9%; at day 7, drug remaining on stent was 758 .mu.g and percent
released was 29.1%; at day 14, drug remaining on stent was 577
.mu.g and percent released was 46.1%; at day 28, drug remaining on
stent was 388 .mu.g and percent released was 63.7%; and at day 90,
drug remaining on stent was 150 .mu.g and percent released was
86.0%. The time at which 50% of the drug has been released is
described here as t.sub.1/2 and was calculated to be 16.3 days.
This corresponds to 67 days post-implantation for 1070 .mu.g dose
stents to achieve 80% elution. Additionally, the percent drug
released over time was compared for stents implanted in the left or
right iliac artery. Placement of the stent (in the left or right
iliac artery) did not alter the rate of drug release. The percent
Everolimus released over time was similar between stents implanted
in the left and right iliac arteries.
[0180] This study defined blood, tissue, and stent kinetic
parameters for 1070 .mu.g dose 10.0.times.28 mm stents in a porcine
model. These results indicate that the Everolimus coated
10.0.times.28 mm drug eluting stent will provide local,
time-limited delivery of drug.
Example 7
[0181] The in vivo release rate profile for everolimus from an
8.0.times.28 mm drug eluting stent coated with EVAL and everolimus
in the peripheral vasculature of healthy swine was studied.
Concentrations of everolimus in whole blood and in arterial tissue
in the stented vessel were measured and pharmacokinetic parameters
of Tmax, Cmax and t.sub.1/2 were calculated. The rate of elution
from the stent was determined by measuring the amount of drug
remaining on the stent at designated times post-implant, up to 180
days. From these data, the rate of elution was calculated. The test
article was a nitinol stent (i.e., STENT A), which was implanted
with a 120 cm delivery system. The stent is coated with an ethylene
vinyl alcohol co-polymer (i.e., EVAL) containing the drug
everolimus at 1070 .mu.g and 3209 .mu.g target total content
(henceforth referred to as dose). These doses correspond to
approximate nominal concentration per surface area values of 225
.mu.g/cm.sup.2 and 675 .mu.g/cm.sup.2, respectively. The drug
eluting stents were prepared substantially as described herein.
[0182] Animals were divided into three groups. Days 3, 7, 28, 56,
and 90 were identified as interim timepoints for determination of
kinetic parameters of drug release. For select groups, additional
timepoints were added. Group 1 (e.g., 1070 .mu.g) was additionally
sampled at day 1, 14, 56, and 180. Group 2 (e.g., 1070 .mu.g
different formulation) was additionally sampled at day 56, and
group 3 (e.g., 3209 .mu.g was additionally sampled at day 14.
Stents were deployed in four vessels per animal (both left and
right iliac/femoral region and lateral circumflex femoral region).
Implantation and analyses of drug elution were performed
substantially as described herein.
[0183] The drug concentration for group 1 in whole blood at each
interim time point was determined to be as follows: 2.29 ng/ml at 1
day; 2.14 ng/ml at 3 days; 1.07 ng/ml at 7 days; 0.27 ng/ml at 14
days; 0.13 ng/ml at 28 days; and below 0.1 ng/ml at 56 and 90 days.
The drug concentration for group 2 in whole blood at each interim
time point was determined to be as follows: 2.70 ng/ml at 3 days;
1.57 ng/ml at 7 days; and below 0.1 ng/ml at 28, 56, and 90 days.
The drug concentration for group 3 in whole blood at each interim
time point was determined to be as follows: 3.35 ng/ml at 3 days;
1.45 ng/ml at 7 days; 1.03 ng/ml at 14 days; 0.29 ng/ml at 28 days;
and below 0.1 ng/ml at 56 and 90 days.
[0184] The drug concentration in tissues in proximity (e.g.,
proximal to stented region, stented region, and distal to stented
region) to the stent for group 1 at each interim time point was
determined to be as follows: at 1 day, proximal to stented region
was 403 ng/g, stented region was 9965 ng/g, and distal to stented
region was 874 ng/g; at 3 days, proximal to stented region was 199
ng/g, stented region was 12946 ng/g, and distal to stented region
was 870 ng/g; at 7 days, proximal to stented region was 159 ng/g,
stented region was 10880 ng/g, and distal to stented region was 739
ng/g; at 14 days, proximal to stented region was 105 ng/g, stented
region was 6415 ng/g, and distal to stented region was 296 ng/g; at
28 days, proximal to stented region was 66 ng/g, stented region was
5834 ng/g, and distal to stented region was 152 ng/g; at 56 days,
proximal to stented region was 19 ng/g, stented region was 833
ng/g, and distal to stented region was 9 ng/g; at 90 days, proximal
to stented region was 12 ng/g, stented region was 833 ng/g, and
distal to stented region was 9 ng/g: at 180 days, proximal to
stented region was 4 ng/g, stented region was 209 ng/g, and distal
to stented region was 6 ng/g.
[0185] The drug concentration in tissues in proximity (e.g.,
proximal to stented region, stented region, and distal to stented
region) to the stent for group 2 at each interim time point was
determined to be as follows: at 3 days proximal to stented region
was 533 ng/g, stented region was 8709 ng/g, and distal to stented
region was 1552 ng/g; at 7 days, proximal to stented region was 104
ng/g, stented region was 3594 ng/g, and distal to stented region
was 435 ng/g; at 28 days, proximal to stented region was 50 ng/g,
stented region was 1853 ng/g, and distal to stented region was 73
ng/g; at 56 days, proximal to stented region was 10 ng/g, stented
region was 2191 ng/g, and distal to stented region was 25 ng/g; and
at 90 days, proximal to stented region was 16 ng/g, stented region
was 1271 ng/g, and distal to stented region was 11 ng/g.
[0186] The drug concentration in tissues in proximity (e.g.,
proximal to stented region, stented region, and distal to stented
region) to the stent for group 3 at each interim time point was
determined to be as follows: at 3 days, proximal to stented region
was 520 ng/g, stented region was 22027 ng/g, and distal to stented
region was 856 ng/g; at 7 days, proximal to stented region was 698
ng/g, stented region was 17200 ng/g, and distal to stented region
was 910 ng/g; at 14 days, proximal to stented region was 307 ng/g,
stented region was 16528 ng/g, and distal to stented region was
1119 ng/g; at 28 days, proximal to stented region was 136 ng/g,
stented region was 13243 ng/g, and distal to stented region was 414
ng/g; and at 90 days proximal to stented region was 55 ng/g,
stented region was 2458 ng/g, and distal to stented region was 63
ng/g.
[0187] The percentage of everolimus released from the stent at each
time-point is summarized in Table 1.
TABLE-US-00001 TABLE 1 Average Drug Release From Stent Group 1 1070
.mu.g Group 2 1070 .mu.g Drug Solution Lot #1 Drug Solution Lot #2
Group 3 3209 .mu.g Drug Percent Drug Percent Drug Percent Time
Remaining on Released Remaining on Released Remaining on Released
(days) Stent (.mu.g)* (%)* Stent (.mu.g)* (%)* Stent (.mu.g)* (%)*
1 1000 (23) 6.5 (0.6) N/A N/A N/A N/A 3 866 (48) 19.1 (1.4) 813
(40) 24.0 (4.5) 2788 (107) 13.1 (3.3) 7 663 (33) 38.0 (0.1) 705
(27) 34.1 (0.9) 2545 (47) 20.8 (1.5) 14 484 (82) 54.8 (4.9) N/A N/A
2132 (60) 33.6 (1.9) 28 311 (69) 70.9 (2.3) 299 (28) 72.1 (1.4)
1427 (42) 55.6 (1.3) 56 185 (35) 82.7 (1.4) 180 (18) 83.2 (0.1) N/A
N/A 90 123 (39) 88.5 (3.3) 120 (20) 88.8 (1.0) 411 (86) 87.2 (2.7)
180 34 (11) 96.9 (0.4) N/A N/A N/A N/A *Reported as Mean (Standard
Deviation) N/A = Not Applicable. This dose/timepoint not included
in study design.
[0188] For groups 1 and 2, t.sub.1/2 was 11.70 and 11.51 days,
respectively, confirming that Lots #1 and #2 of the 1070 .mu.g dose
stents were comparable in elution rates. For group 3, the time at
which approximately 50% of the drug had been released from the
stent was calculated as 21.26 days. This corresponds to 50-58 days
post-implantation for 1070 .mu.g dose stents to achieve 80%
elution, and approximately 80 days post-implantation for 3209 .mu.g
dose stents to achieve the same.
[0189] This study defined blood, tissue, and stent kinetic
parameters for 1070 .mu.g dose and 3209 .mu.g dose stents in a
porcine model. This study demonstrated comparable blood and tissue
concentrations, and comparable stent elution rates between lots of
1070 .mu.g dose stents. These results indicate that the Everolimus
coated 8.0.times.28 mm drug eluting stent will provide local,
time-limited delivery of drug.
Example 8
[0190] The in vivo release rate profile for everolimus from a
7.0.times.100 mm drug eluting stent coated with EVAL and everolimus
in the peripheral vasculature of healthy swine was studied.
Implantation and analyses of drug elution were performed
substantially as described herein. The drug concentration in whole
blood at each interim time point was determined to be as follows:
below 0.1 ng/ml at implantation; 9.56 ng/ml at 0.04 days; 6.25
ng/ml at 0.12 days; 4.97 ng/ml at 0.25 days; 4.94 ng/ml at 1 day;
4.13 ng/ml at 2 days; 3.52 ng/ml at 3 days; 1.64 ng/ml at 7 days;
1.14 ng/ml at 14 days; 0.27 ng/ml at 28 days; and below 0.1 ng/ml
at 90 days.
[0191] The drug concentration in tissues in proximity (e.g.,
non-stented region proximal to stented region (A), proximal stented
region (B), medial stented region (C), distal stented region (D),
and non-stented region distal to stented region(E)) to the stent at
each interim time point was determined to be as shown in Table
2.
TABLE-US-00002 TABLE 2 Mean Arterial Tissue Concentration by
Location Concentration (ng/g) Time (days) A B C D E 3 269 10892
16347 12357 263 (186) (4469) (5005) (4519) (202) 7 524 7894 11431
9633 332 (302) (1899) (1840) (6373) (156) 14 123 4825 5243 6528 353
(63) (1303) (1945) (1253) (106) 28 114 3625 4148 4275 245 (143)
(810) (1739) (828) (209) 90 50 2211 2699 2401 18 (90) (532) (657)
(413) (13) Reported as Mean (Standard Deviation)
[0192] The drug concentration in extravascular tissue (liver, lung,
kidney, gastrocnemius muscle) are summarized in Table 3.
TABLE-US-00003 TABLE 3 Extravascular Drug Concentrations
Extravascular tissue (ng/g) Group Time-point Liver Spleen Lung
Kidney Muscle 1 3 Days 15.1 (2.0) 23.1 (4.9) 22.8 (2.7) 25.6 (2.3)
13.5 (1.4) 2 7 Days 13.2 (0.7) 14.4 (3.1) 12.0 (0.4) 15.6 (1.0) 6.3
(1.3) 3 14 Days 8.2 (1.4) 11.8 (5.0) 8.7 (2.6) 11.2 (1.7) 4.8 (2.2)
4 28 Days 2.9 (0.7) 3.5 (0.7) .sup. 3.2 (1.1) 4.2 (0.7) 0.8 (0.2) 5
90 Days BLLOQ 0.7 (0.1) 0.5 (0.0) 0.8 (0.0) BLLOQ Reported as Mean
(Standard Deviation) BLLOQ = Below Lower Limit of Quantification
(0.5 ng/g)
[0193] Maximum tissue concentrations were observed at Day 3
post-implantation for all extravascular tissues sampled. Cmax
tissue values for liver, spleen, lung, kidney and gastrocnemius
muscle were 15.1, 23.1, 22.8, 25.6, and 13.5 ng/g, respectively.
Drug concentrations in kidney, lung and spleen were not
significantly different from each other and were significantly
greater than liver and gatrocnemius muscle drug concentrations at
Day 3 post-implantation (spleen versus liver p<0.01, all other
p<0.001). Liver and muscle drug concentrations were not
significantly different from each other. In all tissues except
liver, Day 7 post-implantation drug concentrations were
significantly less than at Day 3 (p<0.001). Drug concentrations
in gastrocnemius muscle were significantly less than all other
extravascular tissues sampled (p<0.001). At Day 14
post-implantation, drug concentration in muscle were significantly
lower than in kidney or spleen (p<0.01). Drug concentration in
kidney was significantly lower at Day 14 than at Day 7 (p<0.05).
In liver, drug concentration at Day 14 was also significantly lower
than at Day 7 (p<0.05). In all extravascular tissues, drug
concentration was significantly lower at Day 28 post-implantation
than at Day 14 post-implantation (p<0.05 muscle, all other
p<0.001). At Day 28 post-implantation, drug concentration in
gastrocnemius muscle was significantly lower at Day 28
post-implantation than all other extravascular tissues sampled at
this timepoint (p<0.001). At Day 28 post-implantation, drug
concentration in kidney was significantly greater than in liver
(p<0.05). At Day 90 post-implantation, drug concentrations in
liver and gastrocnemius muscle were below the lower limit of
quantification. In kidney, lung, and spleen, drug concentrations
were significantly lower at 90 Days post-implantation than at Day
28 post-implantation (spleen p<0.01, kidney and lung
p<0.001). There were no significant differences in measured drug
concentrations between kidney, lung, or spleen at Day 90
post-implantation.
[0194] The percentage of everolimus released from the stent and
amount remaining on the stent at each time-point is represented in
Table 4.
TABLE-US-00004 TABLE 4 Average Drug Release From Stent Drug
Remaining on Stent Percent Released Time (days) (.mu.g) (%) 3 33.39
12 (179) 7 2767 27 (163) 14 2212 41 (49) 15 1859 51 (148) 16 2258
40 (3) 27 1537 59 (37) 28 1613 57 (239) 90 754 80 (133)
[0195] The time at which 50% of the drug has been released is
described here as t.sub.112 and was achieved by approximately 19.8
days post-implantation. By 85.5 days post-implantation, 80 percent
of the drug on average had eluted from the stent. Using a porcine
model, this study demonstrated everolimus distribution into
extravascular tissues, with disappearance of drug from these
tissues following the rate of disappearance of everolimus from
blood. In vascular tissue, drug was found in segments immediately
adjacent and within stented regions, and from unstented vessels.
Vascular and nonvascular tissue concentrations decreased over time,
indicating no tissue accumulation. These results indicate that the
everolimus coated 7.0.times.100 mm drug eluting stent will provide
local, time-limited delivery of drug.
Example 9
[0196] The concentration of drug can range between 10
.mu.g/cm.sup.2 and 200 .mu.g/cm.sup.2, and the stent can range from
20 mm to 300 mm. Accordingly, Table 5 provides for the total amount
of drug loaded on the stent as related to the drug amount per area
and the stent length.
TABLE-US-00005 TABLE 5 Drug Conc. Total Dose (.mu.g) .mu.g/cm.sup.2
20 mm 100 mm 150 mm 300 mm 10 34 169 253 506.6667 100 338 1689 2533
5066.667 200 676 3378 5067 10133.33 500 1689 8444 12667 25333.33
1000 3378 16889 25333 50666.67 2000 6756 33778 50667 101333.3 225
760 3800 5700 11400
[0197] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. All changes which come
within the meaning and range of equivalency of the claims are to be
embraced within their scope. All references recited herein are
incorporated herein in their entirety by specific reference.
* * * * *