U.S. patent application number 14/226734 was filed with the patent office on 2014-07-24 for coated stent and method of making the same.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Matthew J. Gillick, Dudley Shelton Jayasinghe, Hung T. Nguyen, Dennis R. Orosa, Stephen D. Pacetti, John E. Papp.
Application Number | 20140205740 14/226734 |
Document ID | / |
Family ID | 42117764 |
Filed Date | 2014-07-24 |
United States Patent
Application |
20140205740 |
Kind Code |
A1 |
Orosa; Dennis R. ; et
al. |
July 24, 2014 |
Coated Stent and Method of Making the Same
Abstract
A coated implantable medical device and a method of coating an
implantable medical device is disclosed, the method includes
applying a composition onto the device and drying the composition
at elevated temperature in an environment having increased relative
humidity. A pre-screening method for a manufacturing lot of coated
stents to determine the number of drug coating layers for a desired
drug release rate is disclosed. The method including coating and
testing small groups of stents, and applying the results of the
tests to determine the number of drug coating layers to apply to
the manufacturing lot of stents.
Inventors: |
Orosa; Dennis R.; (San
Diego, CA) ; Papp; John E.; (Temecula, CA) ;
Nguyen; Hung T.; (San Diego, CA) ; Pacetti; Stephen
D.; (San Jose, CA) ; Jayasinghe; Dudley Shelton;
(Murrieta, CA) ; Gillick; Matthew J.; (Murrieta,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
42117764 |
Appl. No.: |
14/226734 |
Filed: |
March 26, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12563045 |
Sep 18, 2009 |
8715771 |
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14226734 |
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12112935 |
Apr 30, 2008 |
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12563045 |
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11825443 |
Jul 5, 2007 |
8007855 |
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12563045 |
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10375497 |
Feb 26, 2003 |
7255891 |
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11825443 |
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60915355 |
May 1, 2007 |
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61186726 |
Jun 12, 2009 |
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61186742 |
Jun 12, 2009 |
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61227114 |
Jul 21, 2009 |
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Current U.S.
Class: |
427/2.25 |
Current CPC
Class: |
A61L 2420/02 20130101;
A61L 2420/08 20130101; A61F 2/82 20130101; A61L 31/10 20130101;
A61L 31/16 20130101; A61L 2300/608 20130101 |
Class at
Publication: |
427/2.25 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1. A method of coating a stent comprising: providing a stent body;
applying a coating composition comprising a lactide polymer, a
solvent, and novolimus added thereto to the stent body; and drying
the stent body in about 20% to about 100% relative humidity,
temperature of 30 deg. C. to 110 deg. C., and for 10 minutes to 240
minutes; wherein after the act of drying, a coating is formed that
has a residual solvent level less than [(stent length
(mm)).times.(2.634)]-(36.08) as measured in .mu.g.
Description
CROSS-REFERENCE
[0001] This application is a continuation of application Ser. No.
12/563,045, filed on Sep. 18, 2009. Application Ser. No. 12/563,045
is a continuation-in-part of U.S. application Ser. No. 12/112,935,
filed Apr. 30, 2008, which claims the benefit of U.S. Provisional
Application No. 60/915,355, filed May 1, 2007; application Ser. No.
12/563,045 is also a continuation-in-part of U.S. application Ser.
No. 11/825,443, filed Jul. 15, 2007, now U.S. Pat. No. 8,007,855,
which is a divisional application of application Ser. No.
10/375,497, filed Feb. 26, 2003, now U.S. Pat. No. 7,255,891;
application Ser. No. 12/563,045 also claims the benefit of U.S.
Provisional Application No. 61/186,726, filed Jun. 12, 2009, and
U.S. Provisional Application No. 61/186,742, filed Jun. 12, 2009,
and U.S. Provisional Application 61/227,114, filed Sep. 18, 2009,
the entire content of all of the above applications and patent
incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods for coating drug delivery
devices.
[0004] 2. Description of the Background
[0005] In the field of medical technology, there is frequently a
necessity to administer drugs locally. To provide an efficacious
concentration to the treatment site, systemic administration of
medication often produces adverse or toxic side effect for the
patient. Local delivery is a preferred method in that smaller total
levels of medication are administered in comparison to systemic
dosages, but are concentrated at a specific site. Thus, local
delivery produces fewer side effects and achieves more effective
results.
[0006] The drug-eluting stent also provides for the local
administration of a therapeutic substance at the diseased site. In
order to provide an efficacious concentration to the treated site,
systemic administration of such medication often produces adverse
or toxic side effects for the patient. Local delivery is a
preferred method of treatment in that smaller total levels of
medication are administered in comparison to systemic dosages, but
are concentrated at a specific site. As such, local delivery thus
produces fewer side effects and achieves more favorable
results.
[0007] Peripheral artery disease affecting the lower extremities is
common in an aging population, affecting 10-14% of men over the age
of 65, and 20% of men and women reaching the age of 75. The
progression of lower extremity arterial disease can lead to loss of
mobility, limb pain, gangrene and amputation, as well as increased
mortality. Mortality rates at five years in patients with
Peripheral Vascular Disease (PVD) are approximately 30%; these
rates reach 44% in patients with severe peripheral artery disease.
The superficial femoral artery (SFA) is the most commonly diseased
blood vessel in the peripheral (lower limb) vasculature, due to its
characteristics: a long vessel surrounded by flexion points, with
few collateral vessels. These characteristics promote more diffuse
disease, and slow flow and flow dynamics.
[0008] Prevention of restenosis after endovascular treatment in the
peripheral arteries is a major challenge for the interventionalist,
particularly in the superficial femoral artery (SFA), in which
long, heavily calcified, and/or chronically occluded lesions are
often present. Self-expanding stents, with their elastic
properties, have been shown to be of benefit in the
revascularization of the SFA. Stent implantation, by providing a
permanent scaffold for the vessel, reduces vessel recoil and
remodeling, two of the contributing factors in restenosis. However,
neointimal hyperplasia, the major mechanism of restenosis, remains
a significant problem in the peripheral arteries.
[0009] Accordingly, to reduce the partial or total occlusion of the
artery by the collapse of arterial lining, and to reduce the chance
of the development of thrombosis and restenosis, an expandable,
intraluminal prosthesis coated with a therapeutic or beneficial
agent, one example of which includes a drug-eluting stent, is
implanted in the lumen to maintain the vascular patency.
[0010] One method of medicating a stent is with the use of a
polymer coating incorporating a drug. To fabricate the polymer
coating, a suitable polymer is usually dissolved in a solvent or
blend of solvents, followed by applying the solution onto the
stent, for example, by spraying or dipping. To complete the process
of fabricating the stent coating, the stent is dried and/or baked
to remove the solvent.
[0011] Examples of solvents currently used to dissolve
biocompatible polymers for fabricating stent coatings include
dimethylacetamide (DMAC), dimethylsulfoxide (DMSO),
dimethylformamide (DMF), and formamide. These solvents or similar
solvents with relatively high boiling points, for example, above
120.degree. C. at ambient pressure, and/or low volatility, for
example, having vapor pressure under 15 Torr at room temperature,
have a tendency to evaporate very slowly. Prolonged period of time
may be needed to allow the solvent to fully evaporate from the
coating because residual or trace amounts of the solvent may remain
in the coating composition, which may produce an adverse response
subsequent to the stent implantation. Baking of the stent at
relatively high temperatures may be needed to facilitate the
process of the solvent removal. The baking temperatures used for
this purpose, should not exceed the temperature at which the drug
can be adversely affected, however. The embodiments of the present
invention provide methods for facilitating the evaporation of the
solvent from the coating composition.
[0012] Therefore, a need exists for a drug eluting implantable
medical device, with a low residual solvent content, that via local
application of therapeutic agents provides for an effective
pharmacokinetic (PK) profile of drug tissue concentration over time
and successfully inhibits or reduces restenosis in peripheral
arteries.
SUMMARY
[0013] A method for coating an implantable medical device is
provided, the method comprises applying a polymer composition onto
the device, the polymer composition including a solution of a
polymer in a solvent, and drying the polymer composition for a
period of time at a drying temperature higher than the room
temperature in a humid environment. The drug is present at an
amount of at least 150 .mu.g/cm.sup.2 of stent surface area and the
final stent coating has been dried in a humid environment. The
resulting residual solvent level in .mu.g is less than [(stent
length (mm)).times.(2.634)]-(36.08). Useful polymers are vinyl
polymers, urethane-based polymers, polyesters, and
polysaccharides.
[0014] A method of coating a manufacturing lot of medical devices
is disclosed, the method comprising the utilization of pre-screen
devices subjected to coating and loading procedures to allow
adjustment in the coating process such that the manufacturing lot
will have the desired properties when subjected to the same
processes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The disclosed subject matter will now be described in
conjunction with the accompanying drawings in which:
[0016] FIG. 1 is an planar view, partially in section, showing the
expanded stent within the vessel in accordance with one embodiment
of the invention;
[0017] FIG. 2 is a planar view of a flattened stent in accordance
with an embodiment of the of the present invention, which
illustrates the serpentine pattern including peaks and valleys
which form the cylindrical elements of the stent;
[0018] FIG. 3 is an enlarged partial view of the stent of FIG. 2
depicting the serpentine pattern along with the peaks and valleys
which form an embodiment of a cylindrical element made in
accordance with the present invention;
[0019] FIGS. 4A and 4B are process flow diagrams illustrating the
manufacturing process for coating drugs in a polymer matrix onto a
stent in accordance with the present invention;
[0020] FIGS. 5A and 5B are illustrations of a microbalance useful
in accordance with the present invention;
[0021] FIG. 6 is a flow chart illustrating a stent spraying process
according to an embodiment of the present invention;
[0022] FIG. 7 is a graph illustrating the coating anomalies in
stents with and without primer coats;
[0023] FIG. 8 is a graph illustrating the residual solvent in a
coating verses the baking time in an oven; and
[0024] FIG. 9 is a process flow chart illustrating a manufacturing
process from stent preparation through final packaging according to
an embodiment of the present invention.
DETAILED DESCRIPTION
[0025] A coating for an implantable medical device, such as a
stent, can include an optional primer layer, a drug-polymer layer,
and an optional topcoat layer. The drug-polymer layer can be
applied directly onto the stent surface to serve as a reservoir for
an active agent or a drug which is incorporated into the
drug-polymer layer. An optional primer layer can be applied between
the stent and the drug-polymer layer to improve the adhesion of the
drug-polymer layer to the stent. An optional topcoat layer can be
used to reduce the rate of release of the drug from the
reservoir.
[0026] Medical Device Structure
[0027] The devices and methods presented can be used for treating
the lumen of a patient. 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. In accordance with a preferred
embodiment, the implantable medical device is a stent. Preferably,
the present invention includes a drug-eluting stent that has a
stent body, a polymeric coating, and a therapeutic agent.
Preferably, the therapeutic agent is a cytostatic agent. The
polymeric coating is provided on the stent to facilitate the
loading or delivery of the therapeutic agent. In accordance with a
preferred embodiment, the polymeric coating is a
poly(ethylene-co-vinyl alcohol).
[0028] The structural body of the stent can be coated with at least
one polymeric coating, such as poly(ethylene-co-vinyl alcohol)
(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 a cytostatic drug 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 release of the
drug
[0029] For purpose of illustration and not limitation, FIGS. 1-3
illustrate an exemplary stent that can be used in accordance with
the present invention. As illustrated in FIG. 1, the stent 10
serves to hold open the artery 16 after delivery catheter is
withdrawn. Due to the formation of stent 10, the undulating
component of the cylindrical elements of stent 10 is relatively
flat in a transverse cross-section so that when stent 10 is
expanded, cylindrical elements 12 are pressed into the wall of
artery 16 and as a result do not interfere with the blood flow
through artery 16. Cylindrical elements 12 of stent 10 that are
pressed into the wall of artery 16 will eventually be covered with
endothelial cell growth that further minimizes blood flow
turbulence. The serpentine pattern of cylindrical sections 12
provide good tacking characteristics to prevent stent movement
within the artery. Furthermore, the closely spaced cylindrical
elements 12 at regular intervals provide uniform support for the
wall of artery 16.
[0030] The stresses involved during expansion from a low profile to
an expanded profile are generally evenly distributed among the
various peaks and valleys of stent 10. Referring now to FIGS. 2 and
3, each expanded cylindrical element 12 embodies a serpentine
pattern having a plurality of peaks and valleys that aid in the
even distribution of expansion forces. In this exemplary
embodiment, interconnecting members 13 serve to connect adjacent
valleys of each adjacent cylindrical element 12 as described above.
The various peaks and valleys generally have U, W and inverted-U
shapes, in a repeating pattern to form each cylindrical element 12.
It should be appreciated that the cylindrical element 12 can be
formed in different shapes without departing from the spirit and
scope of the present invention.
[0031] The cylindrical element 12 of this stent 10 includes
double-curved portions (W) 21 located in the region of the valley
where each interconnecting member 13 is connected to an adjacent
cylindrical element 12. The peak portions (inverted-U) 22 and the
valley portions (U) 23 also form the cylindrical element 12 of the
stent 10. A shoulder region 24 extending from each valley portion
to peak portion (inverted U) 22 allows the peak portion to be
nested in a tight formation next to an adjacent cylindrical element
12. This shoulder region 24 provides a transition region between
the peak portions (inverted U) 22 and the valley portions (U) 23
and double-curved portion (W) 21 to allow adjacent cylindrical
elements to nest within one another and thereby better support the
artery walls with smaller gaps between stent struts. In this
manner, the shoulder region 24 provides more dense coverage of the
serpentine pattern of the cylindrical element to create a fairly
uniform strut pattern which fully supports the walls of the
diseased artery. For this reason, there are no or few areas of the
stent wall which do not have struts for supporting the wall of the
artery. Each of the valley portions (U) 23 forms a Y-shaped member
when connected to an interconnecting member 13. As can be seen in
this particular design, each of the valley portions (W's and U's)
21 and 23 have an interconnecting member which connects that
cylindrical element 12 to an adjacent cylindrical element. As a
result, each cylindrical element 12 is connected to an adjacent
cylindrical element by at least four interconnecting members 13.
The peak portions (inverted "U") 22 are not directly connected to
any adjacent cylindrical element to allow for radial expansion. The
eight interconnecting members 13 which are connected to each
cylindrical element 12 are discontinuous with each other to produce
a highly flexible stent that does not kink upon bending. This
particular design allows the stent 10 to be placed in tortuous
anatomy, where the stent 10 will conform to the particular anatomy
of the patient. For example, if the stent 10 is placed in a curved
portion of an artery, then the flexibility of the stent will allow
it to take on the same curved shape without kinking and will still
be capable of fully supporting the artery. Additionally, the
stent's resistance to kinking helps prevent occlusion of the vessel
lumen by the stent struts. Even though the stent 10 is flexible, it
is still rigid when collapsed so that it can be placed on the
delivery catheter and moved into the desired location in the
patient's vasculature.
[0032] The stent 10 also includes end rings 25 and 26 which
comprise all "W" shaped portions 27 to provide additional strength
to the ends of the stent 10. This "W" pattern also helps to
increase the overall radiopacity of the stent by virtue of the
additional material needed to create such a "W" pattern. As a
result, the stent 10 should be easily observable by a physician
using imaging instrumentation, such as a fluoroscope.
[0033] It should be appreciated that the present design can be made
with a number of peaks and valleys, preferably ranging from 4 to
16. The number of peaks and valleys will depend upon the particular
physical characteristics desired, along with the particular
application to which the stent will be used.
[0034] While the stent design of the present invention has
practical applications for procedures involving vessel diameters
from about 3.0 to 14.0 millimeters, it should be appreciated that
the stent pattern could also be successfully used in procedures
involving larger lumens of the body. Due to the increase of the
longitudinal flexibility provided by the present stent design, such
applications could include larger diameter vessels where added
flexibility in reaching the vessel is needed.
[0035] While FIGS. 1-3 illustrate 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, FIGS. 1-3 are 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 effective drug delivery into
the lumen adjacent to the endoprosthesis.
[0036] 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.
[0037] In one configuration, the endoprothesis 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,
Ti6A14V, 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. Details of expandable stents can be found in U.S.
Pat. No. 3,868,956 to Alfidi et al.; U.S. Pat. No. 4,512,1338 to
Balko et al.; U.S. Pat. No. 4,553,545 to Maas, et al.; U.S. Pat.
No. 4,733,665 to Palmaz; U.S. Pat. No. 4,762,128 to Rosenbluth;
U.S. Pat. No. 4,800,882 to Gianturco; U.S. Pat. No. 5,514,154 to
Lau, et al.; U.S. Pat. No. 5,421,955 to Lau et al.; U.S. Pat. No.
5,603,721 to Lau et al.; U.S. Pat. No. 4,655,772 to Wallstent; U.S.
Pat. No. 4,739,762 to Palmaz; and U.S. Pat. No. 5,569,295 to
Lam.
[0038] Furthermore, details of self-expanding stents can be found
in U.S. Pat. No. 4,580,568 to Gianturco; U.S. Pat. No. 4,830,003 to
Wolff, et al.; U.S. patent application Ser. No. 10/158,362 to
Denison; and U.S. Pat. Nos. 6,537,311 and 6,814,749 to Cox, et
al.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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 be 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(p-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.
[0043] 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.
[0044] 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 in its entirety by 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.
[0045] 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.
[0046] Additional materials that can be used are described in U.S.
Publication 2009/0093875, which is incorporated by reference herein
in its entirety.
[0047] 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.
[0048] The stents of the present invention can be made in many
ways. However, the preferred method of making the stent is to cut a
thin-walled tubular member, such as Nitinol tubing to remove
portions of the tubing in the desired pattern for the stent,
leaving relatively untouched the portions of the metallic tubing
which are to form the stent. It is preferred to cut the tubing in
the desired pattern by means of a machine-controlled laser.
[0049] A suitable composition of Nitinol used in the manufacture of
a self-expanding stent of the present invention is approximately
55% nickel and 44.5% titanium (by weight) with trace amounts of
other elements making up about 0.5% of the composition. The
austenite transformation temperature is between about -15.degree.
C. and 30.degree. C. in order to achieve superelasticity. The
austenite temperature is measured by the bend and free recovery
tangent method. The upper plateau strength is about a minimum of
60,000 psi with an ultimate tensile strength of a minimum of about
155,000 psi. The permanent set (after applying 8% strain and
unloading), is approximately 0.5%. The breaking elongation is a
minimum of 10%. It should be appreciated that other compositions of
Nitinol can be utilized, as can other self-expanding alloys, to
obtain the same features of a self-expanding stent made in
accordance with the present invention.
[0050] The stent of the present invention can be laser cut from a
tube of super-elastic (sometimes called pseudo-elastic) nickel
titanium (Nitinol) whose transformation temperature is below body
temperature. All of the stent diameters can be cut with the same
stent pattern, and the stent is expanded and heat treated to be
stable at the desired final diameter. The heat treatment also
controls the transformation temperature of the Nitinol such that
the stent is super elastic at body temperature. The transformation
temperature is at or below body temperature so that the stent will
be superelastic at body temperature. The stent can be electro
polished to obtain a smooth finish with a thin layer of titanium
oxide placed on the surface. The stent is usually implanted into
the target vessel which is smaller than the stent diameter so that
the stent applies a force to the vessel wall to keep it open.
[0051] The stent tubing of a self-expanding stent made in
accordance with the present invention may be made of suitable
biocompatible material besides super-elastic nickel-titanium (NiTi)
alloys. In this case the stent would be formed full size but
deformed (e.g. compressed) to a smaller diameter onto the balloon
of the delivery catheter to facilitate intra luminal delivery to a
desired intra luminal site. The stress induced by the deformation
transforms the stent from an austenite phase to a martensite phase,
and upon release of the force when the stent reaches the desired
intra luminal location, allows the stent to expand due to the
transformation back to the more stable austenite phase. Further
details of how NiTi super-elastic alloys operate can be found in
U.S. Pat. Nos. 4,665,906 and 5,067,957 to Jervis, the entire
disclosures of which are incorporated by reference herein.
[0052] The tubing also may be made of suitable biocompatible
material such as stainless steel. The stainless steel tube may be
alloy-type: 316L SS, Special Chemistry per ASTM F138-92 or ASTM
F139-92 grade 2.
[0053] The stent diameters are very small, so the tubing from which
it is made must necessarily also have a small diameter. For PTCA
applications, typically the stent has an outer diameter on the
order of about 1 mm (0.04-0.09 inches) in the unexpanded condition,
the same outer diameter of the hypotubing from which it is made,
and can be expanded to an outer diameter of 40 mm or more. The wall
thickness of the tubing is about 0.076-0.381 mm (0.003-0.015
inches). For stents implanted in other body lumens, such as PTA
applications, the dimensions of the tubing are correspondingly
larger. While it is preferred that the stents be made from laser
cut tubing, those skilled in the art will realize that the stent
can be laser cut from a flat sheet and then rolled up in a
cylindrical configuration with the longitudinal edges welded to
form a cylindrical member.
[0054] Coating Composition
[0055] In accordance with one embodiment of the invention, the
stent is coated with at least one polymeric coating. Preferably,
the coating functions as a drug delivery system that controls the
release of the drug contained therein. Examples of such
biocompatible polymeric materials can include a suitable hydrogel,
hydrophilic polymer, hydrophobic polymers, bioabsorbable polymers,
and monomers thereof. Examples of such polymers can include nylons,
poly(alpha-hydroxy esters), polylactic acids, polylactides,
poly-L-lactide, polyDL-lactide, poly-L-lactide-co-DL-lactide,
polyglycolic acids, polyglycolide, polylactic-coglycolic acids,
polyglycolide-co-lactide, polyglycolide-co-DL-lactide,
polyglycolide-co-Llactide, 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, poly(ethylene-co-vinyl
alcohol) (EVAL), poly(vinyl alcohol), poly(N-vinylpyrrolidone)
(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. In accordance with a preferred embodiment, the polymeric
coating includes poly(ethylene-co-vinyl alcohol) (EVAL).
[0056] Examples of solvents that can be used with EVAL include
DMAC, DMSO, DMF, formamide, N-methyl-2-pyrrolidone (NMP),
sulfolane, benzyl alcohol, cyclohexanol, phenol, formic acid,
m-cresol, p-cresol, trifluoroacetic acid, glycerol, ethylene
glycol, propylene glycol, and mixtures thereof.
[0057] The polymeric coating can contain a therapeutic agent. The
coating facilitates the loading or delivery of the therapeutic
agent. In accordance with a preferred embodiment, the therapeutic
agent is a cytostatic agent. Some non-limiting examples of
cytostatic therapeutic agents include marcrolide immunosuppressive,
macrolide antibiotics, rapamycin, protaxel, taxanes, docetaxel,
zotaroliums, novolimus, zotarolimus, everolimus, sirolimus,
biolimus, myolimus, deforolimus, tacrolimus, or temsirolimus
compounds, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, structural derivatives and functional analogues of
zotarolimus, sirolimus, biolimus, myolimus, deforolirnus,
tacrolimus, or temsirolimus compounds.
[0058] Further examples of drugs include antiproliferative
substances such as actinomycin D, or derivatives and analogs
thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., or
COSMEGEN available from Merck). Synonyms of actinomycin D include
dactinomycin, actinomycin IV, actinomycin I.sub.1, actinomycin
X.sub.1, and actinomycin C.sub.1. The active agent can also fall
under the genus of antineoplastics and antimitotic. Examples of
such antineoplastics and/or antimitotics include paclitaxel (e.g.
TAXOL.RTM. by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel
(e.g. Taxotere.RTM., from Aventis S.A., Frankfurt, Germany),
methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,
doxorubicin hydrochloride (e.g. Adriamycin.RTM. from Pharmacia
& Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such
antiplatelets, anticoagulants, antifibrin, and antithrombins
include sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, and thrombin inhibitors such as Angiomax.TM. (Biogen,
Inc., Cambridge, Mass.). Examples of such cytostatic or
antiproliferative agents include angiopeptin, angiotensin
converting enzyme inhibitors such as captopril (e.g. Capoten.RTM.
and Capozide.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.),
cilazapril or lisinopril (e.g. Prinivil.RTM. and Prinzide.RTM. from
Merck & Co., Inc., Whitehouse Station, N.J.); calcium channel
blockers (such as nifedipine), colchicine, fibroblast growth factor
(FGF) antagonists, fish oil (omega 3-fatty acid), histamine
antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a
cholesterol lowering drug, brand name Mevacor.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such
as those specific for Platelet-Derived Growth Factor (PDGF)
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, steroids,
thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist),
and nitric oxide. An example of an antiallergic agent is
permirolast potassium. Other therapeutic substances or agents which
may be appropriate include alpha-interferon, genetically engineered
epithelial cells, and dexamethasone
[0059] For example and not limitation, the coating can include a
therapeutic agent in addition to the cytostatic drug or instead of
the cytostatic drug. In this regard, the therapeutic agent can
include anti-proliferative, anti-inflammatory, antineoplastic,
antiplatelet, anti-coagulant, anti-fibrin, antithrombotic,
antimitotic, antibiotic, antiallergic and antioxidant compounds,
HMG-CoA reductase inhibitors, and peroxisome proliferator-activated
receptor .alpha. (PPAR .alpha.) agonists such as fenofibrates
(clofibrate, ciprofibrate, benzafibrate, and Tricor and Trilipix
ABT-335). Thus, the therapeutic agent can be, again without
limitation, a synthetic inorganic or organic compound, a protein, a
peptide, a polysaccharides and other sugars, a lipid, DNA and RNA
nucleic acid sequences, an antisense oligonucleotide, an
antibodies, a receptor ligands, an enzyme, an adhesion peptide, a
blood clot agent including streptokinase and tissue plasminogen
activator, an antigen, a hormone, a growth factor, a ribozyme, and
a retroviral vector.
[0060] In accordance with a preferred embodiment of the invention,
the drug eluting stent is self-expanding. In accordance with a
preferred embodiment, 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 poly(ethylene-co-vinyl
alcohol) (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 a cytostatic drug, 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.
[0061] 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
poly(ethylene-co-vinyl alcohol). The stent was designed to address
and overcome three potential shortcomings of prior self-expanding
drug eluting stent (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.
[0062] 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 other drugs (e.g., 140 .mu.g sirolimus/cm.sup.2
or 160 .mu.g zotarolimus/cm.sup.2). 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 dosage 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.
[0063] In one embodiment, the drug eluting stent in accordance with
the present invention 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 .mu.m (i.e., touching) to about 1000
.mu.m, more preferably from about 0 .mu.m to about 500 .mu.m, and
most preferably from about 0 um to about 200 .mu.m; and having a
polymeric coating of poly(ethylene-co-vinyl alcohol) at 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 to about 15
.mu.m.
[0064] In one embodiment, the stent has an unconstrained, nominal
diameter of 5 mm, 6 mm, 7 mm or 8 mm. Representative lengths for
each diameter are 28 mm, 30 mm, 40 mm, 60 mm, 80 mm, or 100 mm, 120
mm, 150 mm, or 200 mm long. In some embodiments, each of the above
lengths may vary by about .+-.4.0 mm.
[0065] Equally important as the total bulk dose of everolimus
contained on the stent is its kinetic release profile. Using an
EVAL (i.e., poly(ethylene-co-vinyl alcohol)) system, the everolimus
eluting stent embodiment was designed to release drug over a longer
period of time as compared to coronary stents. In a broad sense, a
coronary DES, as opposed to a periphery DES, releases drugs over
about 30 days. In this embodiment, 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.
[0066] The relatively high drug load and slow release profile of
the everolimus-eluting stent of the present invention 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.
[0067] A second salient feature of the slow drug release of the
everolimus-eluting stent with the poly(ethylene-co-vinyl alcohol)
coating embodiment is that the potential for systemic everolimus
overexposure is minimized.
[0068] 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% after a mean follow-up of 32.+-.16 months, and 19%
after a mean follow-up of 43.+-.24 months. Similarly, in a
randomized, prospective, single-center study of percutaneous
transluminal angioplasty (PTA) alone versus 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.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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. Some 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, 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.
[0076] 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.
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.
[0077] 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. The coating may have a primer layer of the same or
different polymer, or no primer layer.
[0078] In one embodiment, the polymeric coating can have 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, even more
preferably about 60%, and most preferably about 63% 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.
[0079] In accordance with a further embodiment, the everolimus
coated drug eluting stent mounted on a balloon catheter apparatus
produces a pharmacokinetic profile that provides the therapeutic
agent to the vasculature or target tissue in a sufficient and
effective concentration. Indeed, the resulting pK profile or
decline in tissue concentration with time can provide the
therapeutic agent at a concentration necessary to prevent or
inhibit restenosis. Pharmacokinetics includes the study of the
mechanisms of absorption and distribution of an administered drug,
the rate at which a drug action begins and the duration of the
effect, the chemical changes of the substance in the body (e.g. by
enzymes) and the effects and routes of excretion of the metabolites
of the drug. Pharmacokinetic analysis is performed by
noncompartmental (model independent) or compartmental methods.
Noncompartmental methods estimate the exposure to a drug by
estimating the area under the curve of a concentration-time graph.
Compartmental methods estimate the concentration-time graph using
kinetic models. Compartment-free methods are often more versatile
in that they do not assume any specific compartmental model and
produce accurate results also acceptable for bioequivalence
studies.
[0080] Coating Procedure
[0081] In accordance with the invention, after the stent is formed
according to methods and techniques described above, a polymer
coating and therapeutic agent can be applied thereto. Some of the
methods for coating 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.
[0082] 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.
[0083] 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 heat 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.
[0084] A specific process for coating a cytostatic therapeutic
agent in a polymer, preferably in a poly(ethylene-co-vinyl
alcohol), such as EVOH, provides for adequate coating integrity and
release rate profiles. The manufacturing process for coating a
cytostatic drug in EVAL polymer onto a stent is illustrated in
FIGS. 4A and 4B.
[0085] As illustrated in FIGS. 4A and 4B, the process steps include
preparing the stent and preparing the spraying solutions to be
used. Next, an optional primer is applied, the drug/polymer coating
is applied and the final coating applied. Following the coating
process, the stents are visually inspected to confirm that there
are no defects. The acceptable stents are then collapsed, loaded
onto a delivery catheter, packaged, sterilized and packaged into a
secondary package for lot releasing testing.
[0086] Details of the process steps will be described herein.
During stent preparation, the dimensions of the stent are measured
to verify that it is within required tolerances. The stent is then
ultrasonically cleaned in sterile water, ultrasonically cleaned in
70/30 isopropyl alcohol and room air dried. The stent is then
weighed on a micro balance to establish an initial uncoated stent
weight. The coating amount (coating thickness, drug amount) has
been correlated with coating weight gain so that the change in
stent weight as the stent is coated and baked is tracked throughout
the manufacturing process. Following weighing of the stent, the
stent is subjected to an argon gas plasma discharge under vacuum to
prepare the surface for maximum polymer adhesion.
[0087] In one embodiment the stent is weighed using a microbalance
made by modifying a Mettler-Toledo UMX2 Microbalance available from
Mettler-Toledo International Inc. (Columbus, Ohio). The modified
microbalance has a horizontal balance weighing pan and a stent
lifter to facilitate loading the stent on the balance. As seen in
FIGS. 5A and 5B, the microbalance has an enclosure 64 with an
enclosure lid 63 and a stent lifter 61 which allows the stent 60 to
be easily loaded onto the weighing pan 62. FIG. 5A shows the
microbalance in the loading position, and FIG. 5B shows the
microbalance in the weighing position with the enclosure lid 63
closed.
[0088] In an embodiment, the poly(ethylene-co-vinyl alcohol) may be
purified by processing the typically available pellet form
(available from Aldrich Chemicals) into a powder. The resulting
material has more consistent and reproducible properties. The
purifying procedure removes impurities, obtains desired molecular
weight distribution, and achieves faster process time (fast
solubility in solvents), thereby reducing the time when using the
material in manufacturing. The molecular weight distribution may be
more consistent because smaller molecular fragments are
removed/reduced. A resulting coating may have a more predictable
and less variable drug release properties.
[0089] In an example of the purification procedure for the
poly(ethylene-co-vinyl alcohol), although the procedure may be
applied to other polymers, a 10% by weight stock solution was
prepared by dissolving the stock polymer into >99% N,N-dimethyl
acetamide (Aldrich #271012-2L). Chilling the dimethyl acetamide
solution of the polymer and adding cyclohexane drop wise produced a
gel-like mass, swollen by solvent. The supernatant was pipetted off
and the polymer gel was re-dissolved in N,N-dimethyl acetamide. The
solution was then added to 100 ml of ethanol drop wise with
vigorous mixing. After the addition was completed, the solution was
allowed to stand at room temperature overnight. Then the solution
was filtered off the white solid and the white solid was washed
with cyclohexane overnight. The solution was again filtered off of
the washed solid and dried to produce a fine, free flowing powder.
The process above may be used with different solvent/polymer
combinations to achieve similar results.
[0090] In accordance with another embodiment, the EVAL purification
process involves multiple washes of EVAL pellets with Ethanol at
59.degree. C. A mixture of EVAL/Ethanol at 1:7 ratio (w/w) is
heated in a flask at 59.degree. C. with continuous stirring for
approximately 24 hours. The flask is built with a jacket to
circulate heated water to maintain the temperature of the
EVAL/ethanol mixture at 59.degree. C. At the end of the 24 hr
period, the ethanol is drained out, EVAL pellets are rinsed with
fresh ethanol and the wash cycle is repeated with fresh ethanol for
a total of 4 washes. At the end of fourth wash cycle, the ethanol
is collected and the EVAL pellets are vacuum dried at 120.degree.
C. Both EVAL and the last ethanol rinse are tested for total
volatiles using thermogravimetric analysis, impurities in the final
rinse using Fourier transform infrared spectroscopy, and metal
impurities using an inductively coupled plasma (ICP) analysis for
Mg, Pb, Ni, Hg, Al, K, P, and Na. The purified EVAL is stored in
wide mouth type 3 soda lime glass ultra clean bottles with Teflon
PTFE lined closures.
[0091] In an embodiment, preparation of a primer/topcoat polymer
solution and drug/polymer solution starts with a stock solution of
EVAL in DMA. Purified EVAL pellets and DMA are weighed into a type
3 soda lime ultra clean clear glass bottle to give 1:9 (w/w)
EVAL/DMA ratio; the bottle is then capped with a Teflon PTFE lined
closure. The mixture is heated in an oven at 80.degree. C. for
approximately 1.5 hours with continuous stirring. Heating is used
to help dissolve the EVAL in DMA. The EVAL stock solution is stored
at ambient temperature for a minimum six hours before using it for
the preparation of coating solutions as described below. Typically
the stock solution is used within 6 to 48 hours.
[0092] In a further embodiment, to prepare the primer/topcoat
solution of EVAL, the stock solution of EVAL (10% EVAL in DMA)
prepared as above is diluted with DMA to obtain 4.5% (w/w) EVAL in
DMA. This may be achieved by weighing an appropriate amount of EVAL
stock solution and DMA into an ultra clean type 3 soda lime clear
glass bottle and stirring for approximately 10 minutes with a
magnetic stirrer. For example, to prepare 100 g of primer/topcoat
solution, 45 g of EVAL stock solution is mixed with 55 g of DMA.
The solution may be stored at ambient temperature. Shelf life is
typically about 2 weeks, but may be extended if the solution is
refrigerated.
[0093] In another embodiment, the preparation of the drug/polymer
solution comprises weighing a desired amount of Everolimus drug
substance, EVAL stock solution, and DMA solvent into a type 3 soda
lime ultra clean amber glass bottle to give 1:1.6 ratio of
drug/polymer in the mixture. The mixture is then stirred with a
magnetic stirrer for approximately 10 minutes. Depending on the
amount of solution desired, the amount of each component may be
varied. Drug/polymer solutions may be stored at ambient
temperature. Shelf life is typically about 2 weeks at ambient
temperature, but may be extended if the solution is
refrigerated.
[0094] In accordance with one embodiment, the stent is initially
coated with a primer coating consisting of a poly(ethylene-co-vinyl
alcohol) in dimethylacetamide (DMA) solvent. The coating process
includes rotating a stent on a spraying mandrel and passing the
rotating stent under the spray nozzle for the length of the stent,
for one pass. The stent is then passed under the spray nozzle in
the opposite direction for the length of the stent for another
pass. Following the second pass, the stent is moved to a drying
station where the stent is dried, for example, by passing hot
nitrogen gas over and through the rotating stent. The stent can be
sprayed with several cycles, each cycle including two spray passes
and a drying step. In accordance with an embodiment, the cycles can
range from 1 to 10 cycles, preferably, 2-4 cycles. A summary of
machine settings and minimum to maximum settings for applying the
primer polymer coating is disclosed in Table A.
TABLE-US-00001 TABLE A Settings for Spraying Stent with Primer
Polymer Coat Normal Min. to Max. Machine Settings Settings Settings
Stent rotation (RPM) 100 50-250 Stent linear speed (mm/sec) 6 2-20
Drying Temperature at Stent (.degree. C.) 50 30-100 Drying time
(sec) 20 5-60 Number of spray passes/cycle 2 1-10 Number of cycles
3 1-10 Start Position (mm) 40 10-60 Spray Length (mm) Adjusted per
10-120 stent length
[0095] Following the spraying step, the stent is weighed to
determine the weight of the primer coating. This weight can be used
to adjust spraying rates. The stent is then inspected to ensures
that there are no coating defects. All acceptable stents are then
baked to remove excess solvent. The temperature at which the stent
bakes ranges from 50 to 180.degree. C., preferably from 130 to
150.degree. C. The stent is baked for 5-120 minutes, preferably
from 40-80 minutes. Following baking, the stent is then weighed to
determine the primer coated stent weight gain. The stent is then
placed in a sealed glass vial to control the stent's
environment.
[0096] In accordance with an alternative embodiment, therapeutic
agent can also be added to the primer coating.
[0097] Following the primer coating, the stent is coated with the
therapeutic agent coating. In accordance with a preferred
embodiment, the stent is coated with a drug coating consisting of
therapeutic agent, (e.g., everolimus), in an EVAL copolymer matrix
with a DMA solvent. Prior to mounting the stent having the primer
coat thereon, the stent is visually inspected. The stent is then
loaded and rotated on a spraying mandrel. The coating process
includes rotating a stent on a spraying mandrel and passing the
rotating stent under the spray nozzle for the length of the stent,
for one pass. The stent is then passed under the spray nozzle in
the opposite direction for the length of the stent for another
pass. Following the second pass, the stent is moved to a drying
station where the stent is dried, for example, by passing hot
nitrogen gas over and through the rotating stent. The stent can be
sprayed with several cycles, each cycle including two spray passes
and a drying step. In accordance with a preferred embodiment, the
cycles can range from 1 to 50 cycles, preferably, 20-40 cycles. A
summary of machine settings and minimum to maximum settings for
applying the drug coating is disclosed in Table B.
TABLE-US-00002 TABLE B Settings for Spraying Scent with Drug
Coating Normal Min. to Max. Machine Settings Settings Settings
Stent rotation (RPM) 100 50-250 Stent linear speed (mm/sec) 6 2-20
Drying Temperature at Stent (.degree. C.) 50 30-100 Drying time
(sec) 20 5-60 Number of spray passes/cycle 2 1-10 Number of cycles
27 1-50 Start Position (mm) 40 10-60 Spray Length (mm) Adjusted per
10-120 stent length
[0098] Following the spraying step, the stent is weighed to
determine the weight of the drug coating. This weight can be used
to adjust spraying rates. The stent is then inspected to ensure
that there are no coating defects. All acceptable stents are then
baked to remove excess solvent. The temperature at which the stent
bakes ranges from 50 to 180.degree. C., preferably from 60 to
80.degree. C. The stent is baked for 5-120 minutes, preferably from
20-40 minutes. Following baking, the stent is then weighed to
determine the drug coated stent weight gain. The stent is then
placed in a sealed glass vial to control the stent's
environment.
[0099] Following applications of the primer coating and the drug
coating, the stent is coated with a final coat of polymer. In
accordance with a preferred embodiment, the final coating consists
of an EVAL copolymer in a DMA solvent. Prior to mounting the stent
having a primer coating and a drug coating, the stent is visually
inspected and, in accordance with a preferred embodiment, also
weighed. The stent is then loaded and rotated on a spraying
mandrel. The coating process includes rotating a stent on a
spraying mandrel and passing the rotating stent under the spray
nozzle for the length of the stent, for one pass. The stent is then
passed under the spray nozzle for the opposite direction for the
length of the stent for another pass. Following the second pass,
the stent is moved to a drying station where the stent is dried,
for example, by passing hot nitrogen gas over and through the
rotating stent. The stent can be sprayed with several cycles, each
cycle including two spray passes and a drying step. In accordance
with a preferred embodiment, the cycles can range from 1 to 50
cycles, preferably, 10 to 20 cycles. A summary of machine settings
and minimum to maximum settings for applying the final coating to
the stent is disclosed in Table C.
TABLE-US-00003 TABLE C Settings for Spraying Stent with Final
Polymer Coating Normal Min. to Max. Machine Settings Settings
Settings Stent rotation (RPM) 100 50-250 Stent linear speed
(mm/sec) 6 2-20 Drying Temperature at Stent (.degree. C.) 50 30-100
Drying time (sec) 20 5-60 Number of spray passes/cycle 2 1-10
Number of cycles 14 1-50 Start Position (mm) 40 10-60 Spray Length
(mm) Adjusted per 10-120 stent length
[0100] Following the spraying step, the stent is weighed to
determine the final coating weight gain. This weight can be used to
adjust spraying rates and for process control. The stent is then
inspected to ensure that there are no coating defects. All
acceptable stents are then baked to remove excess solvent. The
temperature at which the stent bakes ranges from 50 to 180.degree.
C., preferably from 70 to 90.degree. C. The stent is baked for
5-120 minutes, preferably from 20-40 minutes. Following baking, the
stent is then weighed to determine the final coat weight gain. The
stent is then placed in a sealed glass vial to control the stent's
environment.
[0101] In accordance with an alternative embodiment, the primer
coating can be eliminated from the manufacturing steps. The typical
purpose of a primer coat is to enhance adhesion between the metal
stent and the drug coating. As seen FIG. 6, the typical stent
spraying process may have a significant reduction in the number of
manufacturing steps if the primer coat is removed. Primer removal
provides a simpler design, reduces the amount of implanted EVAL
polymer into a patient, and enhances manufacturing.
[0102] A measure of the adhesion of the drug coating to the metal
stent is represented by the coating integrity. A coating integrity
test measures the coating anomalies, or area of damaged coating
after a stent has been deployed from a catheter and expresses this
damages as a % of the total stent surface area. Typically, the drug
release of the DES is not significantly affected when the coating
anomaly is <7%. The graph in FIG. 7 shows that stents with a
primer and stents without a primer have similar coating anomalies,
and are both below the typical specification requirement of <7%.
Each Study had 10 samples, with Study A and Study B having a primer
coat, and Study C and Study D not having a primer coat. Further
testing of drug release rate, drug total content, and impurity
content has shown no significant impact from primer coat
removal.
[0103] In accordance with an alternative embodiment, the primer
coating and/or the final polymer coating can be eliminated from the
manufacturing steps. Furthermore, although the preferred process
includes spraying of the primer, drug and final coatings, the
coatings can also be applied by dipping, painting, droplet, or
continuous bead methods, and plasma deposition, as known to those
skilled in the art. In yet another alternative, the weighing step
after the baking step can also be eliminated by validating the
weight loss through the baking process. Alternatively, the weighing
step after the spraying step can be eliminated by validating the
consistency of the spraying process. In yet another alternative, a
vacuum oven is used to remove solvent instead of ovens discussed
above.
[0104] Following application of the final coating, the stents can
be loaded onto the delivery system. Prior to initiating the loading
process, the stent is visually inspected. The stent is then coated
with silicone medical fluid lubricant to reduce friction and
possible damage in subsequent steps. The stent is cooled, collapsed
to the delivery system diameter, and then transferred into a
collapse sheath. This sheath holds the stent in the collapsed state
until it is loaded into the delivery system. The stent is pushed
from the collapse sheath and loaded onto the delivery catheter. The
deployment force is then tested by applying a measured force to the
delivery system to move the stent a few millimeters. The force to
move the stent must be within a specified limit. Following the
testing of the deployment force, the stent is pushed back to its
fully loaded position. The assembled stent/catheter product is
measured, tested and visually inspected for correct assembly. The
final produce is placed in a protective coil and is sealed inside a
sterile barrier Tyvek header bag. Subsequently, the product is
sterilized, preferably subjected to Eta sterilization, and returned
for final packaging. The sterilized header bag is placed into a
foil pouch, the pouch is evacuated and then filled with argon gas
to protect the drug product from light, moisture and oxygen.
[0105] Alternative Coating Fabrication
[0106] Some drug eluting stent manufacturing processes require the
removal of solvents that have a high boiling point. Solvent removal
for certain polymer/solvent combinations cannot be fully removed by
dry baking alone. The dry baking occurs after the application of
the drug coat and then again after the application of a final coat.
A humidity bake process may be used to minimize the amount of
solvent remaining inside of the coated layers after the completion
of the spray coating and dry baking of the stents. If humidity is
added to the dry baking processes, then the separate humidity bake
step at the end may be eliminated.
[0107] To fabricate a stent coating, for example, a polymer can be
dissolved in a solvent or in a system comprising a mixture of
solvents to form the polymer solution. One example of a suitable
polymer is poly(ethylene-co-vinyl alcohol) (EVAL). The polymer
solution can then be applied onto the surface of the stent by a
conventional method, e.g., by spraying or dipping, to form the
coating. In one embodiment, the solvent can have boiling point
greater than about 120.degree. C., for example, above about
130.degree. C. at atmospheric pressure. In another embodiment, the
solvent can have vapor pressure at 20.degree. C. of less than about
15 Torr, for example, below about 10 Torr. In yet another
embodiment, the solvent can have both boiling point and vapor
pressure described above.
[0108] In an embodiment, the concentration of EVAL in the polymer
solution can be between about 1 and 5 mass %, for example, about 2
mass %. An EVAL solution can be prepared by combining EVAL with a
solvent or a mixture of solvents described above and by stirring
the composition for about 2 to 4 hours at a temperature between
about 75.degree. C. and about 85.degree. C., for example, about
80.degree. C. EVAL can be used to manufacture of the primer layer,
drug-polymer layer, and/or the topcoat layer.
[0109] According to embodiments of the present invention, the
coating can be baked in an oven at an elevated temperature, while
the oven environment has a high relative humidity. The baking
temperature can be within a range of between about 30.degree. C.
and about 110.degree. C., for example, about 80.degree. C.
[0110] The high humidity atmosphere can be created in the baking
oven, for example, by having a tray or pan of water inside the
oven, spraying or misting water inside the oven, or passing into
the oven a water fog or mist that is generated outside the oven.
The elevated humidity can be created during, and/or prior to, the
baking process. The relative humidity of the oven environment where
the stent coating is baked can be within a range of between about
20% and about 100%, preferably about 40% to 80%, for example about
60%, or in another example about 80%. In another embodiment, the
relative humidity is about 40% to about 100%, preferably about 60%
to about 100%, and more preferably about 60% to about 80%. The
baking time can be between about 10 minutes and about 240 minutes,
for example, about 30 minutes. Among other benefits, the method of
forming the stent coating according to embodiments of the present
invention allows for faster drying time without substantial
increase in the baking temperature. It is believed that this
process will facilitate acceptable reduction of any residual or
trace amounts of the solvent from the coating.
[0111] In one embodiment, EVAL is used along with DMAC solvent.
DMAC is a relatively non-volatile solvent with a boiling point of
166.degree. C. EVAL may be dried at about 80.degree. C., and if
higher temperatures are used, it may degrade. When dry, EVAL is
very impermeable, even to gases such as oxygen, but the
permeability of EVAL is very dependent on its moisture content.
Therefore, drying stents in the presence of high humidity
effectively removes the residual solvent while retaining the
integrity of drugs, such as everolimus. The following Table 1
demonstrates the difference between the amount of residual solvent
using a conventional stent drying process versus a humidity bake
process.
TABLE-US-00004 TABLE 1 Test # A B Description EVAL EVAL Size 8
.times. 100 mm 8 .times. 100 mm Process Existing Process Existing
Process w/ (dry) (pre-sterile) 24 hr Humidity Bake (pre-sterile)
Oven Time/ 80.degree. C./30 min/ambient 80.degree. C./30 min (2
cycles) + Temp/RH: (2 cycles) 50.degree. C./24 hrs/90% + RH
Residual Solvent (.mu.g) Residual Solvent (.mu.g) 322.9 2.0 353.2
1.0 314.1 0.8 317.3 0.7 318.0 1.4 336.0 327.2 367.1 321.2 332.3
Average: 330.9 1.2 StDev: 17.13 0.53 Cumulative 6 hrs - 30% 6 hrs -
19% Release Rate (% 24 hrs - 50% 24 hrs - 36% of Target Total 168
hrs - 75% 168 hrs - not tested Content, Mean) (6/24/168 hrs)
[0112] Table 2 and FIG. 8 demonstrate how the residual solvent
content decreases with increased baking time at 50.degree. C. and
80% relative humidity.
TABLE-US-00005 TABLE 2 Bake Time 2 4 6 8 12 16 24 RS 92.5 45.9 31
13.9 10.5 7.2 1.6 99.2 41.6 32.5 16.9 7.7 4.9 0.8 95.9 47.4 20.9
24.8 6.9 4.7 1.4 90.2 38.7 40.7 16.4 8.2 6.6 1.7 114.3 39.3 30.4
16.7 11.5 3.4 0.4 Aver- 98.4 42.6 31.1 17.7 9.0 5.4 1.2 age St.
9.51 3.91 7.05 4.13 1.95 1.53 0.56 Dev. % 9.7% 9.2% 22.7% 23.3%
21.8% 28.6% 47.3% RSD
[0113] Bake Time in Hrs. RS=Residual Solvent (.mu.g)
[0114] The maximum amount of remaining residual solvent depends on
the size, and in particular, the length of the stent because the
diameters are similar. In one embodiment, the maximum residual
solvent level for a 30 mm long stent is 45.0 .mu.g; 40 mm long
stent is 70.0 .mu.g, 60 mm long stent is 116.0 .mu.g; 80 mm long
stent is 177.0 .mu.g; and a 100 mm long stent is 228.0 .mu.g. In
another embodiment, the maximum residual solvent in .mu.g=[(stent
length (mm)).times.(2.634)]-(36.08).
[0115] In addition to EVAL, the formulation for making the
drug-polymer layer can additionally include an active agent or a
drug which can be incorporated into the EVAL solution. The amount
of the drug can be between about 0.1 and about 10 mass % of the
total mass of the formulation used to make the drug-polymer layer.
The drug can include any substance capable of exerting a
therapeutic or prophylactic effect for a patient. The drug may
include small molecule drugs, peptides, proteins, oligonucleotides,
and the like. The drug could be designed, for example, to inhibit
the activity of vascular smooth muscle cells. It can be directed at
inhibiting abnormal or inappropriate migration and/or proliferation
of smooth muscle cells to inhibit restenosis.
[0116] The method of the present invention can be used for
fabricating stent coatings including polymers that absorb at least
about 1 mass % of water when exposed to relative humidity of about
100%. EVAL, which absorbs up to 5 mass % of water when exposed to
relative humidity of about 100%, is just one example of a polymer
that can be used. Examples of suitable polymers other than EVAL
include poly(N-vinylpyrrolidone)(PVP), ethyl cellulose, cellulose
acetate, carboxymethyl cellulose, cellulosics, chitin, chitosan,
poly(vinyl alcohol), heparin, dextran, dextrin, dextran sulfate,
collagen, gelatin, hyaluronic acid, chondroitan sulfate,
glycosaminoglycans, poly[(2-hydroxyethyl)methylmethacrylate],
polyurethanes, poly(ether urethanes), poly(ester urethanes),
poly(carbonate urethanes), thermoplastic polyesters, solvent
soluble nylons, poly(acrylamide), poly(acrylic acid), copolymers of
acrylic acid and acrylates, poly(methacrylic acid), copolymers of
methacrylic acid and methacrylates, and blends thereof. Table 3 is
a summary demonstrating which solvents can be used in conjunction
with particular polymers in order to fabricate coatings according
to embodiments of the present invention.
TABLE-US-00006 TABLE 3 Examples of Polymer-Solvent Compositions
Example Polymer Solvents 1 EVAL DMSO, DMAC, DMF, NMP, formamide,
cyclohexanol, sulfolane, benzyl alcohol, phenol, formic acid,
m-cresol, p-cresol, trifluoroacetic acid, glycerol, ethylene
glycol, propylene glycol 2 Sodium Heparin DMSO, DMAC, DMF, NMP,
formamide, benzyl alcohol 3 PVP Propylene glycol, ethylene glycol,
formamide, glycerol, DMSO 4 Hyaluronic Acid DMF, DMSO, formamide 5
Poly(vinyl alcohol) DMSO, formamide 6 TECOFLEX 80A DMAC, DMF
poly(ester urethane)
[0117] Pre-Screen Process
[0118] According to several embodiments of the invention, to ensure
that a given lot of drug eluting stents (DES) produces results
within specifications, one or more of the following controls may be
used including 1) testing raw materials before using them to insure
that the materials meet particular specifications; 2) applying
tight tolerances on process parameters, such as temperature and
pressure control; and 3) testing the intermediate products
throughout the manufacturing process to insure that they are
meeting specifications.
[0119] One of the critical quality attributes related to DES
performance is in vitro release rate. The in vitro release rate
correlates to in vivo release rate. The release of the drug at
therapeutic levels over a designed time period provides the means
to prevent restenosis.
[0120] According to one embodiment of the invention, a process is
used to provide an accurate means of controlling the release rate
for an individual manufactured DES lot. The manufacturing process
comprises applying an optional polymer primer coat, a drug/polymer
coat, and a polymer final coat to a bare metal stent. The release
rate is primarily dependent on the polymer top coat thickness. When
the thickness is obtained by spraying several coats at a certain
.mu.g weight gain per coat, then the release rate is a function of
the number of coats.
[0121] According to an embodiment, the pre-screen process involves
determining the correct number of top coats that will yield the
specified release rate at product lot release. The coating
thickness correlates to the number of thin coats applied to make up
the total thickness. The pre-screen processes a group of stents
through the normal manufacturing process and uses the same drug,
polymer and solvent as the manufacturing lot to be built. In some
embodiments, different groups of the pre-screen samples are coated
with different numbers of final coats and each pre-screen group of
stents is then tested for drug release rate. The group with the
desired release rate determines how many coats need to be applied.
Analysis of the data is fed back to the manufacturing line
indicating how many final coats to apply. The main production run
then continues to completion.
[0122] According to one embodiment, the manufacturing process from
stent preparation through final packaging is illustrated in FIG. 9
and as follows:
[0123] Step 1:--All stents for the manufacturing build are
inspected and prepared for spraying.
[0124] Step 2:--Primer coating is started, first for the pre-screen
stents and then continued for the manufacturing build.
[0125] Step 3:--Drug coating is started, first for the pre-screen
stents and then continued for the manufacturing build.
[0126] Step 4:--At this point only the pre-screen stents are
processed further. All other stents for the manufacturing build are
put on hold until pre-screen results are returned.
[0127] Step 5:--Pre-screen stents are processed through the final
coat process. Typically 7 stents (3 min to 30 max.) are coated
with, e.g., 10 thin coats. This is repeated for, e.g., 12, 14, 16,
and 18 coats.
[0128] Step 6:--The pre-screen stents go through a final stent and
coating inspection
[0129] Step 7:--At this stage there are several alternative methods
for pre-screen conditioning. One embodiment will be explained here.
Other options, including quick sterilization and no sterilization
will be discussed below. [0130] The pre-screen stents are
collapsed, loaded onto catheters, and TYVEK packaged per the normal
manufacturing process. [0131] The assemblies are sterilized per the
normal manufacturing process
[0132] Step 8:--Pre-screen stents are tested for release rate. The
data is analyzed and the number of coats that produces a release
rate closest to the release rate specification mean is fed back to
the manufacturing line.
[0133] Step 9:--The manufacturing lot is then coated with the
pre-screen predicted number of final coats. [0134] The
manufacturing lot is completed, sterilized, and lot release tested
per normal procedures.
[0135] Process Advantages:
[0136] Small variations of the quality of raw materials and solvent
can be corrected for e.g., in the case of polymer, changes in
molecular weight distribution and water content can affect the
release rate. This is important when the polymer undergoes any
additional processing, such as purification, prior to being used.
The drug and solvent combination is also susceptible to moisture
effects. Another advantage is that products are produced with
consistent test results for release rates. A further advantage is
to minimize failed lots due to out of a specification release
rates.
[0137] Testing Method for Pre-Screen Process
[0138] Release rate testing for lot release involves continuous
dipping of DES units in a medium and testing samples at different
time points. In one approach, the time points include 2, 6, 12, 24,
36, 48, 72, 96 . . . 168 hr and then every 24 hr until 80% of drug
is released. For the pre-screen process, an abbreviated method may
be used where sample are tested only at a single time point of 24
hr. This allows faster turn around time yet provides a method of
estimating the release profile.
[0139] Variations to the Pre-Screen Process
[0140] The pre-screen process provides accurate final coat feedback
for the manufacturing lot, however it puts the manufacturing build
on hold until the pre-screen stents are processed, tested, and the
analyzed results are fed back to the manufacturing line. This is of
particular concern as coating solutions have shelf lives. Therefore
the coating needs to be completed before the solutions' shelf lives
expire. The following are various alternatives that are used to
shorten the pre-screen cycle time:
[0141] Quick Sterilization
[0142] ETO sterilization typically has a 7 to 14 day turn around
time. A shorter sterilization cycle that eliminates the
preconditioning and/or aeration times can reduce the cycle time to
1 day. To use this pre-screen method several trials are needed to
correlate the release rate difference between the two cycles. The
offset difference can then be applied to the pre-screen results to
predict the manufactured lot release rate. For example, several
groups of stents with the same coating formulation within each
group, with each group having a different coating formulation, are
tested for release rate at 1 day, and 7 days or 14 days depending
on how the manufacturing lot will be treated. Assuming that the 14
day sterilization is desired, then the 1 day results are compared
with the 14 day results. The coating composition on the group of
stents that ultimately had the desired release rate after 14 days
of sterilization indicate the desired group of day 1 stents, and
hence the desired coating composition after 1 day of
sterilization.
[0143] No Sterilization
[0144] In the same way as for quick sterilization, pre-screened
stents can be analytically tested as soon as they are final coated
and collapsed, or immediately after being final coated. In these
cases new offset values are obtained by separate testing. These
methods eliminate the 1 to 14 day delays due to sterilization.
[0145] Some embodiments of the present invention are illustrated by
the following Examples.
Example 1
[0146] A polymer solution containing about 4.0 mass % EVAL and the
balance, a solvent blend of DMAC and pentane, with a mass ratio
between DMAC and pentane of about 4:1 can be prepared. To prepare
the polymer solution, EVAL can be combined with DMAC and the
mixture can be stirred for about 2 hrs at a temperature of about
80.degree. C. The solution can be applied onto a 13-mm TETRA stent
(previously available from Guidant Corp., now Abbott Vascular) to
form a primer layer. An additional stent to which the coating may
be applied is the ABSOLUTE.TM.: Self-Expandable Peripheral Nitinol
Stent (available from Abbott Vascular). To apply the primer layer,
a spray apparatus, such as an EFD 780S spray nozzle with a
VALVEMATE 7040 control system, manufactured by EFD, Inc. of East
Providence, R.I. can be used. The EFD 780S spray nozzle is an
air-assisted external mixing atomizer. The composition can be
atomized by air and applied to the stent surfaces. The atomization
pressure can be about 0.1 MPa (15 psi). During the process of
applying the composition, the stent can be rotated about its
longitudinal axis, at a speed of about 120 rpm. The stent can be
also linearly moved along the same axis during the application.
[0147] The EVAL solution can be applied to the 13-mm TETRA in a
series of 10-second passes, to deposit about 10 .mu.g of coating
per spray pass. Instead of the 13-mm TETRA stent, other suitable
stents can also be used, for example, a 12-mm VISION stent
(available from Abbott Vascular). Between the spray passes, the
stent can be dried for about 10 seconds using flowing air with a
temperature of about 60.degree. C. Five spray passes can be
applied, followed by baking the primer layer in an oven. As the
primer layer contains no active agent, the primer layer can be
baked at a temperature at about 140.degree. C. for about 1 hour.
Optionally, the relative humidity in the oven during baking can be
about 60%. As a result, a primer layer can be formed having a
solids content of about 50 .mu.g. "Solids" means the amount of the
dry residue deposited on the stent after all volatile organic
compounds (e.g., the solvent) have been removed.
[0148] A drug-containing formulation can be prepared comprising
about 4.0 mass % EVAL, about 1.33 mass % everolimus, and the
balance, a solvent blend, the blend comprising DMAC and pentane in
a mass ratio of about 4:1. EVAL can be combined with DMAC and the
mixture can be stirred for about 2 hrs at a temperature of about
80.degree. C. Pentane and everolimus can then be added to the EVAL
solution.
[0149] The drug-containing formulation can be sprayed to the primed
stent. In a manner identical to the application of the primer
layer, 26 spray passes can be performed, depositing about 20 .mu.g
of the wet drug-polymer layer per each pass. The wet drug-polymer
layer can then be baked in an oven at about 50.degree. C. for about
1 hour, while relative humidity in the oven is maintained at about
60%, to form the dry drug-polymer layer having a solids content of
about 460 .mu.g.
Example 2
[0150] A primer solution can be prepared and coated onto a 13 mm
TETRA stent as described in Example 1. An additional stent to which
the coating may be applied is the ABSOLUTE.TM.: Self-Expandable
Peripheral Nitinol Stent (available from Abbott Vascular). A
drug-containing formulation can be prepared comprising about 4.0
mass % EVAL, about 2.0 mass % paclitaxel, and the balance, a
solvent blend of DMAC and tetrahydrofuran (THF), the blend having a
mass ratio between DMAC and THF of about 3:2. EVAL can be combined
with DMAC and the mixture stirred for about 2 hours at a
temperature of about 80.degree. C. THF and paclitaxel can then be
added to the EVAL solution.
[0151] The drug containing formulation can be sprayed onto the
primed stent. In a manner identical to the application of the
primer layer, nine spray passes can be performed, depositing about
20 .mu.g of the wet formulation per each spray pass. The wet
drug-polymer layer can then be baked in an oven at about 60.degree.
C. for about one hour, while the relative humidity in the oven is
maintained at about 60%, to form a the drug-polymer layer having a
solids content of about 150 .mu.g.
[0152] A topcoat formulation can be prepared comprising about 2.2
mass % EVAL, about 1.5 mass % sodium heparin, and the balance, a
solvent blend of formamide, methanol and DMAC, the blend having a
mass ratio between formamide, methanol and DMAC of about 1:1:3.
EVAL can be combined with DMAC and the mixture can be stirred for
about 2 hours at a temperature of about 80.degree. C. Sodium
heparin can be dissolved in the blend of formamide and methanol.
The EVAL solution can then be added to the heparin solution. This
topcoat formulation can be sprayed onto the dry drug-polymer layer.
In a manner identical to the application of the primer and
drug-polymer layers, four spray passes can be performed, depositing
about 20 .mu.g of the wet topcoat per spray pass. The wet topcoat
layer can then be baked in an oven at about 60.degree. C. for about
one hour, while the relative humidity in the oven is maintained at
about 60%, to form a topcoat layer having a solids content of about
60 .mu.g.
Example 3
[0153] A polymer solution containing about 2.0 mass % of poly(butyl
methacrylate) (PBMA) and the balance, a blend of acetone and xylene
having a mass ratio between acetone and xylene of about 3:2 can be
prepared. To prepare the polymer solution, PBMA can be combined
with acetone and the mixture can be stirred for about 1 hour at
60.degree. C., followed by adding xylene. The solution can be
sprayed onto a stent to form a primer layer as described in Example
1. The PBMA solution can be applied to a 13-mm TETRA stent in a
series of 10-second passes, to deposit about 10 .mu.g of the
polymer solution per spray pass. An additional stent to which the
coating may be applied is the ABSOLUTE.TM.: Self-Expandable
Peripheral Nitinol Stent (available from Abbott Vascular). Between
passes, the stent can be dried at ambient temperature for about 10
seconds using flowing air. Five spray passes can be applied,
followed by baking the wet primer layer in an oven at about
80.degree. C. for about 30 minutes. As a result, a primer layer can
be formed having a solids content of about 50 .mu.g.
[0154] A drug-containing formulation can be prepared comprising
about 4.0 mass % BIONATE 55D, about 2.0 mass % rapamycin, and the
balance, a solvent blend of DMAC and THF, the blend having a mass
ratio between DMAC and THF of about 1:1. BIONATE 55D is a trade
name of a thermoplastic polycarbonate-urethane elastomer formed as
the product of the reaction between a hydroxyl-terminated
polycarbonate, an aromatic diisocyanate, and a low molecular weight
glycol used as a chain extender. BIONATE 55D is available from The
Polymer Technology Group Incorporated of Berkeley, Calif. BIOANATE
55D can be combined with DMAC and the mixture can be stirred for
about 6 hrs at a temperature of about 80.degree. C. THF and
rapamycin can then be added to the BIONATE 55D solution.
[0155] The drug containing formulation can be sprayed onto the
primed stent. In a manner identical to the application of the
primer layer, 27 spray passes can be performed, depositing about 20
.mu.g per spray pass. The wet drug-polymer layer can then be baked
in an oven at about 60.degree. C. for about one hour, while the
relative humidity in the oven is maintained at about 60%, to form a
the drug-polymer layer having a solids content of about 500
.mu.g.
Example 4
[0156] A primer solution can be prepared and coated onto a 13 mm
TETRA stent as described in Example 1. An additional stent to which
the coating may be applied is the ABSOLUTE.TM.: Self-Expandable
Peripheral Nitinol Stent (available from Abbott Vascular). A
drug-containing formulation can be prepared and coated on the stent
as described in Example 2, except the baking of the wet
drug-polymer layer can be carried out at about 100% relative
humidity in a sealed vessel. First, a sealed vessel containing
deionized water can be placed in an oven set to about 50.degree. C.
and allowed to equilibrate. The stent having wet drug-polymer layer
coated thereon can be placed into the vessel, followed by closing
the vessel and baking at about 50.degree. C. for two hours. The
stent is positioned in the vessel in such as way as to not make
contact with the deionized water.
Example 5
[0157] The following data was obtained by replacing the dry baking
with humidity baking
TABLE-US-00007 TABLE 4 Release Rate and Residual Solvent vs. Baking
time in humidity chamber (minutes) Drug Coat Final Coat Arm
Humidity Bake Humidity Bake 24 hr. Release Residual # Time
(minutes) time (minutes) Rate Sterile (%) Solvent (.mu.g) 1 30 30
51.75 265 2 60 60 48 188 3 60 120 60.5 152 4 60 240 58.5 83
[0158] The four Arms of the experiment baked the 8 mm
diameter.times.100 mm long stents for different durations in a
humid environment through the drug and final coat processes. Listed
in Table 4 are the resultant drug release rate (RR) after 24 hours
and residual solvent (RS) content.
[0159] The minimum specification for residual solvents for this
size stent is 228 .mu.g. Arm 1, which was humidity baked for 30
minutes after the drug coat and 30 minutes after the final coat,
had residual solvents slightly higher than the specification.
However stents with higher humidity bake times had residual
solvents lower than the specification. The release rate in 24 hours
was not targeted to a particular value, and the differences are of
no concern since the final coat thickness could be adjusted to
obtain the required release rate.
[0160] The following combinations of oven baking may be employed to
reduce the residual solvents to acceptable levels and also simplify
and speed up the manufacturing process.
[0161] In one embodiment, after at least one drug coat is applied
to the stent, the coated stent is dry baked for 30 minutes. Next,
at least one final coating formulation is sprayed on top of the
drug coat, and after the desired number of coats is sprayed, the
stent with the drug coats covered by the final coats is dry baked
for 30 minutes. The stent is then collapsed, loaded onto a
catheter, and TYVEK packaged. This package is then humidity baked
for four hours.
[0162] In another embodiment, after at least one drug coat is
applied to the stent, the coated stent is humidity baked for 30
minutes. Next, at least one final coating formulation is sprayed on
top of the drug coat, and after the desired number of coats is
sprayed, the stent with the drug coats covered by the final coats
is humidity baked for 30 minutes. The stent is then collapsed,
loaded onto a catheter, and TYVEK packaged. This package is then
humidity baked for two hours.
[0163] In yet another embodiment, after at least one drug coat is
applied to the stent, the coated stent is dry baked for 30 minutes.
Next, at least one final coating formulation is sprayed on top of
the drug coat, and after the desired number of coats is sprayed,
the stent with the drug coats covered by the final coats is
humidity baked for 30 minutes. The stent is then collapsed, loaded
onto a catheter, and TYVEK packaged. This package is then humidity
baked for two hours.
[0164] In a further embodiment, after at least one drug coat is
applied to the stent, the coated stent is dry baked for 30 minutes.
Next, at least one final coating formulation is sprayed on top of
the drug coat, and after the desired number of coats is sprayed,
the stent with the drug coats covered by the final coats is dry
baked for four hours. The stent is then collapsed, loaded onto a
catheter, and TYVEK packaged. This package is not baked.
[0165] In an embodiment, after at least one drug coat is applied to
the stent, the coated stent is not baked at this point. Next, at
least one final coating formulation is sprayed on top of the drug
coat, and after the desired number of coats is sprayed, the stent
with the drug coats covered by the final coats is dry baked for
four hours. The stent is then collapsed, loaded onto a catheter,
and TYVEK packaged. This package is not baked.
[0166] Table 5 describes the current parameter settings for each of
the baking processes.
TABLE-US-00008 TABLE 5 Current Process Conditions Process
Parameters Process name Temperature (.degree. C.) Relative Humidity
(%) Dry Bake for all processes 80.degree. C. NA Humidity Bake
50.degree. C. 80%
Example 6
[0167] A clinical study to evaluate the safety and performance of
the everolimus-eluting self-expanding Nitinol stent system for the
treatment of atherosclerotic de novo or restenotic native
superficial femoral and proximal popliteal artery lesions was
performed. Performance and efficacy was determined and
pharmacokinetic evaluation was conducted.
[0168] The stent had a drug eluting layer consisting of two layers,
a primer layer and a drug/polymer layer. As discussed above, the
primer layer is applied to the surface of the stent to aid in the
adherence of the drug/polymer matrix to the stent. The drug/polymer
matrix layer is composted of EVAL polymer mixed with everolimus.
The drug/polymer matrix was applied to the sent on top of the
primer layer.
[0169] Patients had a single de novo or restenotic native disease
segment of the superficial femoral artery (SFA) or proximal
popliteal artery (located within the following parameters: 1 cm
from the femoral bifurcation of the SFA and 3 cm from the proximal
margin of the intercondylar fossa). For inclusion into the trial,
the disease segment length was between .gtoreq.3 cm (30 mm) and
.ltoreq.17 cm (170 mm), the target vessel reference diameter was
between .gtoreq.4.3 mm and .ltoreq.7.3 mm with >50% diameter
stenosis, all by visual estimation. The inflow artery had to be
free from significant lesions (>50% stenosis) by angiography.
Patients with a significant iliac artery stenosis were eligible for
inclusion into the trial, if the stenosis was successfully treated
without complication, prior to patient enrollment and treatment of
the target lesion with the investigational device. Patients were
required to have a patent popliteal artery free from significant
lesion (>50% stenosis) with at least one patent outflow artery
that provided in-line circulation to the lower leg and foot, which
was confirmed by angiography. For patients with bilateral SFA
lesions, the lesion in the highest Rutherford Clinical Category
limb was to be treated.
[0170] Patients were stented with everolimus-eluting Nitinol
stents. The length of the stent used depended on the length of the
superficial femoral or proximal popliteal lesions.
[0171] Prior to the stenting procedure, patients received one of
two medication regimens: 1) aspirin (75 mg daily) and either
clopidogrel (75 mg daily) or ticlopidine (250 mg twice a day) for
at least 3 consecutive days, or 2) a pre-loading dose of 300-600 mg
of clopidogrel or 500 mg of ticlopidine. Post-procedure, patients
were required to receive a minimum daily dose of 75 mg of aspirin
and either clopidogrel 75 mg (minimum dose) or ticlopidine 250 mg
daily (minimum dose) for at least 6 months. Clopidogrel was taken
by 97.1% of the patients with a mean duration intake of
171.6.+-.29.3 days, while aspirin was taken by 99.0% of the
patients, with a mean duration intake of 170.7.+-.32.4 days. All
subjects underwent clinical assessments at 30 days, 6 months and
will be followed for 12 months and 18 months after the stenting
procedure and annually for five years.
[0172] Two sub studies were performed; Pharmacokinetic (PK) and
Computed Tomography Angiography (CTA).
[0173] Pharmacokinetic evaluation was conducted in a subset of 26
patients who received everolimus-eluting stents. For the 26
patients, there were 18 males and 8 females. The mean age was 66
years (ranging from 50 to 82 years). The target lesion was a single
de novo superficial femoral artery (SFA) or proximal popliteal
artery with .gtoreq.50% stenosis, .gtoreq.30 mm and <170 mm
lesion length and .gtoreq.4.3 mm and .ltoreq.7.3 mm target vessel
diameter (via visual estimate). All patients received
everolimus-eluting stents implanted during the percutaneous femoral
intervention procedure.
[0174] Blood samples for the evaluation of everolimus
concentrations were collected by venpuncture prior to stent
implantation and at approximately 1, 4 and 8 hours post final stent
placement and before subject discharge from the study site
(collection times ranged from 16.92 to 166.45 hours) and at one
month after the percutaneous femoral intervention procedure.
[0175] Blood concentrations of everolimus were determined using a
validated liquid/liquid extraction high performance liquid
chromatography (HPLQ method with tandem mass spectrometric
detection (MS/MS). The lower limit of quantitation (LLOQ) for
everolimus was 0.2 ng/mL using a 0.020 mL (20 .mu.L) blood
sample.
[0176] The pharmacokinetic parameter values of everolimus were
estimated using noncompartmental methods. These included: the
maximum observed plasma concentration (Cmax) and time to Cmax
(Tmax), the area under the plasma concentration-time curve (AUC)
from time 0 to eight hours (AUC.sub.0-8), 24 hours (AUC.sub.0-24),
672 hours (AUC.sub.0-672), time of the last measurable
concentration (AUC.sub.0-last) and dose normalized Cmax, and
AUC.
[0177] All available plasma concentrations of everolimus and
pharmacokinetic parameter values were tabulated for each patient
and each dose group, and summary statistics were computed for each
sampling time and each parameter. The mean Cmax of everolimus for
these dose groups (3033, 3777, 6810 and 7554 .mu.g) ranged from
1.83 to 4.66 ng/mL. The mean AUC.sub.0-245 and AUC.sub.0-last, of
everolimus for these groups ranged from 36.31 to 72.24 ng-h/mL and
from 308.42 to 1571.96 ng-h/mL, respectively. The dose-normalized
mean Cmax of everolimus for these dose groups ranged from 0.60 to
0.65 ng/mL/mg. The dose-normalized mean AUC.sub.0-24, and
AUC.sub.0-last, of everolimus for these dose groups ranged from
7.20 to 12.74 ng-h/mL/mg and from 101.69 to 258.38 ng-h/mL/mg,
respectively.
[0178] 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. Thus, it is
intended that the present invention include modifications and
variations that are within the scope of the appended claims and
their equivalents. All references recited herein are incorporated
herein in their entirety by specific reference.
* * * * *