U.S. patent application number 14/597119 was filed with the patent office on 2015-05-14 for methods of stabilizing molecular weight of polymer stents after sterilization.
The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Byron Lambert, Xiao Ma, Derek Mortisen, Fuh-Wei Tang, Yunbing Wang.
Application Number | 20150128527 14/597119 |
Document ID | / |
Family ID | 46147733 |
Filed Date | 2015-05-14 |
United States Patent
Application |
20150128527 |
Kind Code |
A1 |
Wang; Yunbing ; et
al. |
May 14, 2015 |
METHODS OF STABILIZING MOLECULAR WEIGHT OF POLYMER STENTS AFTER
STERILIZATION
Abstract
Methods of stabilizing the molecular weight of polymer stents
scaffolds after E-beam sterilization are disclosed. The molecular
weight of the polymer of the irradiated scaffolds is stabilized
through exposure to gas containing oxygen.
Inventors: |
Wang; Yunbing; (Sunnyvale,
CA) ; Mortisen; Derek; (Palo Alto, CA) ; Ma;
Xiao; (Santa Clara, CA) ; Tang; Fuh-Wei;
(Temecula, CA) ; Lambert; Byron; (Temecula,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Family ID: |
46147733 |
Appl. No.: |
14/597119 |
Filed: |
January 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13103890 |
May 9, 2011 |
8966868 |
|
|
14597119 |
|
|
|
|
Current U.S.
Class: |
53/425 |
Current CPC
Class: |
A61F 2/0095 20130101;
B29C 71/009 20130101; B29C 2035/0877 20130101; A61F 2240/001
20130101; A61L 2/082 20130101; A61L 2/081 20130101; B65B 55/16
20130101; A61F 2/82 20130101; A61L 2/087 20130101; B29C 71/04
20130101 |
Class at
Publication: |
53/425 |
International
Class: |
B65B 55/16 20060101
B65B055/16 |
Claims
1. (canceled)
2. A method of making a stent, comprising: providing a polymeric
stent scaffolding disposed on a catheter; exposing the scaffolding
to E-beam radiation for sterilization, wherein the scaffolding is
exposed to a gas containing oxygen during the exposure, wherein the
exposure to the gas containing oxygen is performed at least until a
free radical concentration of the gas is less than 5.times.10.sup.7
DI/mg and/or at least until the number average molecular weight
(Mn) of the scaffolding is stabilized, wherein an oxygen content of
the gas is 1% or greater; and followed by packaging the scaffolding
in an inert gas environment.
3. The method of claim 2, wherein the oxygen-containing gas is
air.
4. The method of claim 2, an oxygen content of the gas is 1 to
10%.
5. The method of claim 2, wherein the inert gas environment has an
oxygen content of less than 0.002%.
6. The method of claim 2, wherein the polymeric stent scaffolding
is exposed 8 to 24 hr to the oxygen-containing gas after the E-beam
exposure.
7. The method of claim 2, wherein during sterilization, the
scaffolding is within a package that allows permeation of air into
the package.
8. The method of claim 2, wherein a dose of the radiation exposure
is between 20-50 kGy.
9. The method of claim 2, wherein stabilizing comprises less than a
10% change in Mn over a selected time period.
10. The method of claim 9, wherein the selected time period is at
least 30 days, 30 to 60 days, or greater than 60 days.
11. The method of claim 2, wherein: prior to E-beam exposure: the
scaffolding is sealed in a package permeable to and comprising air,
wherein oxygen in the air quenches free radicals generated by the
radiation exposure, and after the radiation exposure: the package
is disposed in a gas impermeable package, the air is removed from
the packages, and the packages are filled with an inert gas and
sealed.
12. A method of making a stent, comprising: providing a polymeric
stent scaffolding; exposing the scaffolding to E-beam radiation for
sterilization, wherein the scaffolding is exposed to an inert gas
environment during sterilization; exposing the irradiated
scaffolding to air to quench free radicals generated by the
radiation exposure and stabilize a molecular weight of the
scaffolding polymer, wherein the exposure to the air is performed
at least until the free radical concentration is less than
5.times.10.sup.7 DI/mg and/or the stabilized scaffolding polymer
has less than a 10% change in Mn over a selected time period; and
after stabilizing, packaging the scaffolding in an inert gas
environment.
13. The method of claim 12, wherein the radiation exposure is
between 20-50 kGy.
14. The method of claim 12, wherein the selected time period is at
least 30 days, 30 to 60 days, or greater than 60 days.
15. A method of making a stent, comprising: packaging a polymeric
stent scaffolding in a sealed gas impermeable package for storage
until use, wherein the package contains a mixture of inert gas and
oxygen and a content of the oxygen in the gas mixture is 0.5% to
2%; and exposing the packaged scaffolding to E-beam radiation for
sterilization, wherein the oxygen in the gas mixture quenches free
radicals in the scaffolding polymer generated during radiation
exposure and stabilizes the molecular weight of the scaffolding
polymer such that a number average molecular weight (Mn) of the
stabilized scaffolding polymer changes less than 10% during
storage.
16. The method of claim 15, wherein the free radical concentration
is less than 5.times.10.sup.7 DI/mg in less than 2 days after
exposure.
17. A method of making a stent, comprising: disposing a polymeric
stent scaffolding in a gas-impermeable package; vacuum evacuating
the package followed by backfilling of the package with an inert
gas; repeating the evacuation and backfill process to further
reduce oxygen content in the package; exposing the package to
E-beam radiation for sterilization of the scaffolding, wherein an
oxygen content in the package during the exposing is 0.5 to 3%; and
releasing the sterilized package for storage and/or shipping.
18. The method of claim 17, wherein a required dose of the
radiation for sterilization is 20-50 kGy.
19. The method of claim 17, wherein the package is exposed to a
required dose for sterilization in multiple passes of E-beam
exposure.
20. The method of claim 17, wherein the scaffolding comprises PLLA.
Description
[0001] This application is a continuation application of U.S.
application Ser. No. 13/103,890 and is incorporated by reference
herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods of manufacturing polymeric
medical devices, in particular, stents.
[0004] 2. Description of the State of the Art
[0005] This invention relates to radially expandable
endoprostheses, that are adapted to be implanted in a bodily lumen.
An "endoprosthesis" corresponds to an artificial device that is
placed inside the body. A "lumen" refers to a cavity of a tubular
organ such as a blood vessel. A stent is an example of such an
endoprosthesis. Stents are generally cylindrically shaped devices
that function to hold open and sometimes expand a segment of a
blood vessel or other anatomical lumen such as urinary tracts and
bile ducts. Stents are often used in the treatment of
atherosclerotic stenosis in blood vessels. "Stenosis" refers to a
narrowing or constriction of a bodily passage or orifice. In such
treatments, stents reinforce body vessels and prevent restenosis
following angioplasty in the vascular system. "Restenosis" refers
to the reoccurrence of stenosis in a blood vessel or heart valve
after it has been treated (as by balloon angioplasty, stenting, or
valvuloplasty) with apparent success.
[0006] Stents are typically composed of scaffolding that includes a
pattern or network of interconnecting structural elements or
struts, formed from wires, tubes, or sheets of material rolled into
a cylindrical shape. This scaffolding gets its name because it
physically holds open and, if desired, expands the wall of the
passageway. Typically, stents are capable of being compressed or
crimped onto a catheter so that they can be delivered to and
deployed at a treatment site.
[0007] Delivery includes inserting the stent through small lumens
using a catheter and transporting it to the treatment site.
Deployment includes expanding the stent to a larger diameter once
it is at the desired location. Mechanical intervention with stents
has reduced the rate of restenosis as compared to balloon
angioplasty. Yet, restenosis remains a significant problem. When
restenosis does occur in the stented segment, its treatment can be
challenging, as clinical options are more limited than for those
lesions that were treated solely with a balloon.
[0008] Stents are used not only for mechanical intervention but
also as vehicles for providing biological therapy. Biological
therapy uses medicated stents to locally administer a therapeutic
substance. Effective concentrations at the treated site require
systemic drug administration which often produces adverse or even
toxic side effects. Local delivery is a preferred treatment method
because it administers smaller total medication levels than
systemic methods, but concentrates the drug at a specific site.
Local delivery thus produces fewer side effects and achieves better
results.
[0009] A medicated stent may be fabricated by coating the surface
of either a metallic or polymeric scaffolding with a polymeric
carrier that includes an active or bioactive agent or drug.
Polymeric scaffolding may also serve as a carrier of an active
agent or drug.
[0010] The stent must be able to satisfy a number of mechanical
requirements. The stent must be capable of withstanding the
structural loads, namely radial compressive forces, imposed on the
stent as it supports the walls of a vessel. Therefore, a stent must
possess adequate radial strength. Radial strength, which is the
ability of a stent to resist radial compressive forces, relates to
a stent's radial yield strength and radial stiffness around a
circumferential direction of the stent. A stent's "radial yield
strength" or "radial strength" (for purposes of this application)
may be understood as the compressive loading, which if exceeded,
creates a yield stress condition resulting in the stent diameter
not returning to its unloaded diameter, i.e., there is
irrecoverable deformation of the stent. When the radial yield
strength is exceeded the stent is expected to yield more severely
and only a minimal force is required to cause major
deformation.
[0011] Once expanded, the stent must adequately maintain its size
and shape throughout its service life despite the various forces
that may come to bear on it, including the cyclic loading induced
by the beating heart. For example, a radially directed force may
tend to cause a stent to recoil inward. In addition, the stent must
possess sufficient flexibility to allow for crimping, expansion,
and cyclic loading.
[0012] Some treatments with stents require its presence for only a
limited period of time. Once treatment is complete, which may
include structural tissue support and/or drug delivery, it may be
desirable for the stent to be removed or disappear from the
treatment location. One way of having a stent disappear may be by
fabricating a stent in whole or in part from materials that erodes
or disintegrate through exposure to conditions within the body.
Stents fabricated from biodegradable, bioabsorbable, and/or
bioerodable materials such as bioabsorbable polymers can be
designed to completely erode only after the clinical need for them
has ended.
[0013] However, there are several challenges making a bioabsorbable
polymeric stent. These include making a stent with sufficient
radial strength, stiffness, and toughness or resistance to
fracture. Another challenge is maintaining the properties of the
finished stent from the end of manufacturing to the time of
implantation. Medical devices are typically stored for an
indefinite or variable period of time after fabrication. Since
storage time will vary for each device that is made, the problem of
product consistency arises if properties change over time.
INCORPORATION BY REFERENCE
[0014] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference, and as if each said individual publication or patent
application was fully set forth, including any figures, herein.
SUMMARY OF THE INVENTION
[0015] Various embodiments of the present invention include a
method of making a stent, comprising: providing a polymeric stent
scaffolding disposed on a catheter; exposing the scaffolding to
E-beam radiation for sterilization, wherein the scaffolding is
exposed to a gas containing oxygen during the exposure, wherein an
oxygen content of the gas is greater than 1%; and packaging the
scaffolding in an inert gas environment.
[0016] Further embodiments of the present invention include a
method of making a stent, comprising: providing a polymeric stent
scaffolding disposed on a catheter, wherein the scaffolding is
sealed in a package permeable to and comprising air; and exposing
the packaged scaffolding to E-beam radiation for sterilization;
after the radiation exposure, disposing package in a gas
impermeable package, wherein oxygen in the air quenches free
radicals generated by the radiation exposure; removing the air from
the packages; and filling the packages with an inert gas and
sealing the packages.
[0017] Additional embodiments of the present invention include a
method of making a stent, comprising: providing a polymeric stent
scaffolding; exposing the scaffolding to E-beam radiation for
sterilization, wherein the scaffolding is exposed to an inert gas
environment during sterilization; exposing the irradiated
scaffolding to air to quench free radicals generated by the
radiation exposure and stabilize a molecular weight of the
scaffolding polymer; and after the period of time, storing
scaffolding in an inert gas environment.
[0018] Other embodiments of the present invention include a method
of making a stent, comprising: providing a package having an inner
gas permeable layer and an outer gas impermeable layer, wherein the
inner layer and the outer layer have an inert gas environment
within and the inner layer and outer layer are sealed, wherein a
polymer scaffolding is disposed within the inner layer; exposing
the scaffolding to E-beam radiation for sterilization; allowing
fluid communication between ambient air and the outer layer to
expose the scaffolding to air for a period of time; after the
period of time, removing air from and sealing the gas impermeable
package; and storing the scaffolding in an inert gas
environment.
[0019] Further embodiments of the present invention include a
method of making a stent, comprising: providing a polymeric stent
scaffolding; exposing the scaffolding to E-beam radiation for
sterilization, wherein during the exposure the scaffolding is in a
sealed gas impermeable package containing a gas mixture of oxygen
and an inert gas, wherein the oxygen content of the gas mixture is
1% or less; and storing the scaffolding in the gas mixture until
use of the scaffolding, wherein the oxygen in the gas mixture
quenches free radicals in the scaffolding polymer and stabilizes
the molecular weight of the scaffolding polymer.
[0020] Additional embodiments of the present invention include a
method of making a stent, comprising: providing a polymeric stent
scaffolding; selecting a final Mn of the polymer of the
scaffolding; irradiating the scaffolding with E-beam radiation for
sterilization in an inert gas environment, wherein the polymer of
the scaffolding has an initial Mn after the irradiation; allowing
the Mn of the irradiated scaffolding to increase from the initial
Mn to the final Mn in the inert gas environment; exposing the
scaffolding to an oxygen-containing gas to stabilize the Mn of the
scaffolding at the final Mn; and storing the stabilized scaffolding
in an inert gas environment.
[0021] Further embodiments of the present invention include a
method of making a stent, comprising: providing a package having a
first side that is impermeable and a second side that is gas
permeable, wherein the first side has an inert gas environment
within and the second side has ambient air, wherein a polymeric
scaffolding is disposed within the first side, where the sides are
connected by a movable sealer that allows movement of the
scaffolding from the first side to the second side without fluid
communication between the sides; exposing the scaffolding to E-beam
radiation for sterilization; after a period of time after
sterilization, shifting the scaffolding with the movable sealer to
the second side to expose the stent to air; and after a selected
stabilization time, shifting the scaffolding to the first side to
the inert gas environment; and resealing the first side with inert
gas.
[0022] Additional embodiments of the present invention include a
method of making a stent, comprising: providing a package having a
first side and a second side that are both gas impermeable, wherein
the first side has an inert gas environment and the second side has
a mixture of an inert gas and oxygen, wherein a polymeric
scaffolding is disposed within the first side, wherein the sides
are connected by a valve that allows fluid communication between
the first side to the second side when the valve is open; exposing
the scaffolding to E-beam radiation for sterilization; after a
period of time after sterilization, opening the valve to allow
fluid communication between the first side and the second side to
expose the scaffolding to oxygen and terminate free radicals in the
scaffolding; and after a selected stabilization time, closing the
valve and replacing the inert gas and mixture in the first side
with an inert gas environment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 depicts a stent.
[0024] FIG. 2 depicts a normalized free radical decay profile of
PLLA scaffolding samples stored under different environments (argon
vs. oxygen) after E-beam sterilization in argon.
[0025] FIG. 3 depicts the Mn versus time of a PLLA scaffolding
after radiation sterilization aged in argon.
[0026] FIG. 4 depicts a normalized free radical decay of E-beam
irradiated PLLA scaffolding samples sterilized and aged in a sealed
foil pouch in argon and samples sterilized and aged in a Tyvek.RTM.
pouch.
[0027] FIG. 5A depicts a schematic representation of a Tyvek.RTM.
pouch with a stent contained within.
[0028] FIG. 5B depicts the Tyvek.RTM. pouch of FIG. 5B disposed
within an aluminum pouch.
[0029] FIG. 6 depicts a schematic representation of a
double-layered pouch.
[0030] FIG. 7 depicts the free radical decay in irradiated PLLA
scaffolding samples sterilized and stored in containers with
different oxygen concentrations, 0%, 0.002%, and 1%.
[0031] FIG. 8 depicts the Mn versus time of a PLLA scaffolding that
is not irradiated with E-beam radiation.
[0032] FIG. 9 depicts the Mn versus time for irradiated PLLA
scaffolding samples under different packaging environments.
[0033] FIG. 10 depicts a schematic representation of a two-sided
pouch having an aluminum side and a Tyvek.RTM. side, which has air
within.
[0034] FIG. 11 depicts a schematic representation of a pouch with a
first aluminum side and a second aluminum side.
DETAILED DESCRIPTION OF THE INVENTION
[0035] Various embodiments of the present invention relate to
manufacture of polymeric implantable medical devices. In
particular, the embodiments include methods of stabilizing the
properties of polymer stents after radiation sterilization.
[0036] The methods described herein are generally applicable to any
amorphous or semi-crystalline polymeric implantable medical device,
especially those that have load bearing portions when in use or
have portions that undergo deformation during use. In particular,
the methods can be applied to tubular implantable medical devices
such as self-expandable stents, balloon-expandable stents, and
stent-grafts.
[0037] A stent may include a pattern or network of interconnecting
structural elements or struts. FIG. 1 depicts a view of a stent
100. In some embodiments, a stent may include a body, backbone, or
scaffolding having a pattern or network of interconnecting
structural elements 105. Stent 100 may be formed from a tube (not
shown). The structural pattern of the device can be of virtually
any design. The embodiments disclosed herein are not limited to
stents or to the stent pattern illustrated in FIG. 1. The
embodiments are easily applicable to other patterns and other
devices. The variations in the structure of patterns are virtually
unlimited.
[0038] A stent such as stent 100 may be fabricated from a polymeric
tube or a sheet by rolling and bonding the sheet to form the tube.
A tube or sheet can be formed by extrusion or injection molding. A
stent pattern, such as the one pictured in FIG. 1, can be formed in
a tube or sheet with a technique such as laser cutting or chemical
etching. The stent can then be crimped on to a balloon or catheter
for delivery into a bodily lumen.
[0039] An implantable medical device of the present invention can
be made partially or completely from a biodegradable,
bioresorbable, bioabsorbable, or biostable polymer. A polymer for
use in fabricating an implantable medical device can be biostable,
bioresorbable, bioabsorbable, biodegradable or bioerodable.
Biostable refers to polymers that are not biodegradable. The terms
biodegradable, bioresorbable, bioabsorbable, and bioerodable are
used interchangeably and refer to polymers that are capable of
being completely degraded and/or eroded into different degrees of
molecular levels when exposed to bodily fluids such as blood and
can be gradually resorbed, absorbed, and/or eliminated by the body.
The processes of breaking down and absorption of the polymer can be
caused by, for example, hydrolysis and metabolic processes.
[0040] A stent made from a biodegradable polymer is intended to
remain in the body for a duration of time until its intended
function of, for example, maintaining vascular patency and/or drug
delivery is accomplished. After the process of degradation,
erosion, absorption, and/or resorption has been completed, no
portion of the biodegradable stent, or a biodegradable portion of
the stent will remain. In some embodiments, very negligible traces
or residue may be left behind.
[0041] The duration of a treatment period depends on the bodily
disorder that is being treated. In treatments of coronary heart
disease involving use of stents in diseased vessels, the duration
can be in a range from several months to a few years. The duration
is typically up to about six months, twelve months, eighteen
months, or two years. In some situations, the treatment period can
extend beyond two years.
[0042] As indicated above, a stent has certain mechanical
requirements such as high radial strength, high stiffness or high
modulus, and high fracture toughness. A stent that meets such
requirements greatly facilitates the delivery, deployment, and
treatment of a diseased vessel. With respect to radial strength and
stiffness, a stent must have sufficient radial strength to
withstand structural loads, namely radial compressive forces,
imposed on the stent so that the stent can supports the walls of a
vessel at a selected diameter for a desired time period. A
polymeric stent with inadequate radial strength and/or stiffness
can result in an inability to maintain a lumen at a desired
diameter for a sufficient period of time after implantation into a
vessel.
[0043] In addition, the stent must possess sufficient toughness or
resistance to fracture to allow for crimping, expansion, and cyclic
loading. These aspects of the use of the stent involve deformation
of various portions of the stent. Sufficient toughness is important
to prevent cracking or fracture during use which could lead to
premature mechanical failure of the stent.
[0044] The strength to weight ratio of polymers is usually smaller
than that of metals. To compensate for this, a polymeric stent can
require significantly thicker struts than a metallic stent, which
results in an undesirably large profile. The strength deficiency of
polymers is addressed in the present invention by incorporating a
deformation step in the stent fabrication process by subjecting the
polymer construct to deformation. Deforming polymers tends to
increase the strength along the direction of deformation, which is
believed to be due to the induced polymer chain orientation along
the direction of deformation. For example, radial expansion of a
polymeric tube construct provides preferred circumferential polymer
chain orientation in the tube. Additionally, stretching a tube
provides preferred axial orientation of polymer chains in the tube.
Thus, a stent fabrication process can include radially deforming a
polymer tube and cutting a stent from the deformed tube. The
deformation process also results in strain induced crystallization,
increasing the crystallinity of the construct which increases the
strength of the polymer.
[0045] Semi-crystalline polymers that are stiff or rigid under
biological conditions or conditions within a human body are
particularly suitable for use as a scaffolding material.
Specifically, polymers that have a glass transition temperature
(Tg) sufficiently above human body temperature which is
approximately 37.degree. C., should be rigid upon implantation.
Poly(L-lactide) (PLLA) is an example of such a polymer. These
polymers, however, may exhibit a brittle fracture mechanism in
which there is little or no plastic deformation prior to failure.
As a result, it is important not only to improve the strength of
such polymers when making a device, but also to improve the
fracture toughness for the range of use of a stent, specifically
for the range deformation during use of the stent. In particular,
it is important for a stent to have high resistance to fracture
throughout the range of use of a stent, i.e., crimping, delivery,
deployment, and during a desired treatment period after
deployment.
[0046] Exemplary biodegradable polymers for use with a
bioabsorbable polymer scaffolding include poly(L-lactide) (PLLA),
poly(D-lactide) (PDLA), polyglycolide (PGA), and
poly(L-lactide-co-glycolide) (PLGA). With respect to PLGA, the
stent scaffolding can be made from PLGA with a mole % of GA between
5-15 mol %. The PLGA can have a mole % of (LA:GA) of 85:15 (or a
range of 82:18 to 88:12), 95:5 (or a range of 93:7 to 97:3), or
commercially available PLGA products identified being 85:15 or 95:5
PLGA.
[0047] The fabrication methods of a bioabsorbable stent for use in
the methods of treatment described herein can include the following
steps:
[0048] (1) forming a polymeric tube using extrusion,
[0049] (2) radially deforming the formed tube,
[0050] (3) forming a stent scaffolding from the deformed tube by
laser machining a stent pattern in the deformed tube with laser
cutting,
[0051] (4) optionally forming a therapeutic coating over the
scaffolding,
[0052] (5) crimping the stent over a delivery balloon, and
[0053] (6) sterilization with election-beam (E-beam) radiation.
[0054] In step (2) above, the extruded tube may be radially
deformed to increase the radial strength of the tube, and thus, the
finished stent. The increase in strength reduces the thickness of
the struts required to support a lumen with the stent when expanded
at an implant site. In exemplary embodiments, the strut thickness
can be 100-200 microns, or more narrowly, 120-180, 130-170, or
140-160 microns.
[0055] Detailed discussion of the manufacturing process of a
bioabsorbable stent can be found elsewhere, e.g., U.S. Patent
Publication No. 20070283552, which is incorporated by reference
herein.
[0056] A packaged stent and catheter are sterilized to reduce the
bioburden of the stent and delivery system to a specified level.
Bioburden refers generally to the number of microorganisms with
which an object is contaminated. The degree of sterilization is
typically measured by a sterility assurance level (SAL) which
refers to the probability of a viable microorganism being present
on a product unit after sterilization. The required SAL for a
product is dependent on the intended use of the product. For
example, a product, such as a stent, to be used in the body's fluid
path is considered a Class III device and requires an SAL of
10.sup.-6. SAL's for various medical devices can be found in
materials from the Association for the Advancement of Medical
Instrumentation (AAMI) in Arlington, Va.
[0057] A stent is typically sterilized after mounting the stent at
the end of a catheter by crimping. Prior to sterilization, the
stent-catheter assembly is placed in a package and sealed. The
package is typically made of a gas-impermeable material such as
aluminum foil. The package remains sealed after sterilization until
the time of implantation. The interior of the packaging is
typically an inert gas such as argon.
[0058] An inert gas refers generally to a non-reactive gas. Inert
gases include noble gases such as argon and helium. Inert gases
also include compound gases that are non-reactive due to the
valence, the outermost electron shell, being complete, such as
diatomic nitrogen. The inert gas environment or atmosphere may have
0% oxygen or may contain a small amount of oxygen, for example,
less than 0.01%, 0.005%, 0.002, or less than 0.001% oxygen. The
content of gases is expressed in mole percent, unless otherwise
specified.
[0059] The packaging of the stent in an inert gas may be achieved
by vacuum evacuation of the packaging followed by a backfill of the
packaging with an inert gas such as argon. The evacuation and
backfill process can be repeated to assure complete removal of
oxygen. The final oxygen content of the packaging atmosphere may be
approximately 0.002% or less, 0.002% to 0.01%, 0.01% to 0.015%,
0.015% to 0.02%, or 0.02% to 0.04%.
[0060] The packaging is designed to prevent exposure of the stent
to any bioburden such as bacteria as well as non-inert gases such
as oxygen as well as moisture. Oxygen and moisture may adversely
affect the properties of a drug delivery coating, and thus, the
drug delivery profile. Additionally, moisture can also cause
degradation of the scaffolding. Unless otherwise specified,
"oxygen" refers to diatomic oxygen. Irradiation can convert
diatomic oxygen to ozone, which can quench free radicals.
[0061] The sterilization can be performed by exposing the stent and
catheter to radiation, for example, electron beam (E-beam), gamma
ray, and x-ray sterilization. A sterilization dose can be
determined by selecting a dose that provides a required SAL. A
sample can be exposed to the required dose in one or multiple
passes. An exemplary radiation dose for sterilization of a stent
may be 20-50 kGy or any value between, for example, 25 kGy.
[0062] During E-beam irradiation of a bioabsorbable scaffolding,
such as a PLLA scaffolding, energy is deposited uniformly across
the device. The irradiation leads to polymer chain scission,
excitation of the macromolecules, and the formation of free
radicals. Free radicals refer to atomic or molecular species with
unpaired electrons on an otherwise open shell configuration. Free
radicals can be formed by oxidation reactions. These unpaired
electrons are usually highly reactive, so free radicals are likely
to take part in chemical reactions, including chain reactions.
These free radicals generated proceed to react with each other or
initiate further reactions within the polymer chains. The outcomes
of these reactions will be recombination, branching, crosslinking,
chain scission, or propagation.
[0063] The immediate effect of the irradiation arises from chain
scission since a decrease in molecular weight is observed after
exposure to the radiation. For example, a PLLA stent scaffolding
with a number average molecular weight (Mn)=260 kDa before E-beam
sterilization decreases to an Mn between 70-80 kDa immediately
after a radiation dose of 27.5 kGy. The immediate decrease in the
molecular weight is not generally a problem, as long at the
molecular weight after sterilization is at a desired level. A
desired post-sterilization molecular weight may be obtained by
adjusting the molecular weight resin. The Mn of a PLLA scaffolding
post-sterilization may be 60 to 65 kDa, 65-70 kDa, 70 to 80 kDa, or
80 to 90 kDa.
[0064] Thus, it was known to the inventors that radiation
sterilization of a bioabsorbable stent scaffolding causes a drop in
molecular weight immediately after exposure. It was also known that
radiation sterilization causes the generation of free radicals in
the polymer. However, decay mechanism of the free radicals in the
polymer scaffolding was not. Nor was the impact of the free
radicals or radiation sterilization in general on stent properties,
beyond the immediate changes, over a longer term (e.g., hours,
days, weeks, months after irradiation.
[0065] Given the potential of free radicals to alter the long term
properties of a bioabsorbable polymer scaffolding, it is important
to accurately detect free radical type, level, and especially its
change with time after sterilization. This offers very valuable
information for design and modification of a bioabsorbable polymer
scaffolding.
[0066] Electron spin resonance spectroscopy (ESR) technique has
been used for the detection of free radicals. The original
implementation of this method originally used by the inventors was
used commonly in various industrial applications. According to that
original method, a stent is sterilized in an inert gas environment
in a pouch, the stent is taken out of the pouch, and stored in a
glass container. Then the information about free radical level,
type and its change with time is detected and estimated based on
measurement of the spins of unpaired electrons in a magnetic field.
All the previous ESR results based on this original method showed
that the half-life of the generated free radicals is very short,
and therefore, based on these results would not be expected to
cause any significant impact on final stent product properties.
[0067] The inventors then considered a hypothesis that sample
storage gas environment might have a potential impact on free
radical decay. While the stent scaffolding is stored in an argon
sealed pouch prior to implantation, the test samples in the
original ESR method were stored in a regular glass container filled
with air.
[0068] The inventors considered whether ESR measurement methods
that would mimic the storage environment would show a free radical
decay profile different from the original method. In one
alternative method, the ESR measurements may be performed on a
sample in a specially designed container filled with an inert gas
such as argon. Such a method may mimic the real packaging
environment in the pouch.
[0069] Another alternative method was applied to generating a free
radical decay profile of irradiated PLLA scaffolding. In this
method, a set of irradiated samples were stored in separate sealed
gas impermeable aluminum pouches. The samples were taken out of a
pouch at different times. After a sample was taken out of pouch, it
would immediately be placed in the ESR equipment for free radical
detection. By running ESR using samples stored in the argon sealed
pouch at different times and collecting all received data together,
a free radical decay profile was obtained.
[0070] Free radical decay profiles for PLLA scaffoldings sterilized
in an inert argon atmosphere were generated according to the
alternative method described above. The results surprisingly show
the presence of moderately persistent free radicals. FIG. 2 depicts
a normalized free radical decay profile of E-beam irradiated PLLA
scaffolding using the alternative method of samples aged in a
sealed pouch with argon. FIG. 2 also shows free radical decay
profile of samples aged in air. The results from the alternative
method in FIG. 2 clearly show that the free radicals exist in the
scaffolding more than 3 weeks after electron beam processing of the
scaffolds while in the samples exposed to air, the free radicals
decay to near zero in about 1 day.
[0071] During the relatively long period of free radical decay in
the former, it is believed that the free radicals are related to
temporal changes in molecular weight, thereby increasing
variability of the product. Measurements according to the original
method show that a decay to zero in about 1 day, and thus is not a
reflection of the decay of a PLLA scaffolding in an inert gas
environment.
[0072] These results showed that the long term free radical decay
might cause continued molecular weight change of scaffolding after
E-beam sterilization. The inventors have found surprisingly the
molecular weight of a PLLA scaffolding continues to increase up to
about 40 days after E-beam sterilization. FIG. 3 depicts the Mn
versus time of a PLLA scaffolding after radiation sterilization
with a dose of 27.5 kGy and aged in argon. As indicated above, the
Mn is shown to increase from an initial value after radiation
exposure to about 110 kDa 40 days after exposure. The decay profile
of the free radicals suggests the molecular weight change may be
associated with free radicals generated from sterilization.
[0073] The significance of the time scale of such changes is the
impact on product consistency. It is desired generally for the
properties of a medical device to be independent of the storage
time. More importantly, it is desirable for the performance of the
device to be independent of storage time. Changes in some
properties may not significantly affect the performance of the
device, while other changes may.
[0074] The consistency of molecular weight at implantation is
important since the inventors have recognized that the initial
molecular weight, specifically Mn, is a major component in
determining the degradation profile of the scaffolding. In order to
heal a diseased vessel, a scaffolding must have a proper
degradation profile. The scaffolding should maintain radial
strength for a period of time to allow healing of the vessel. After
this period, the scaffolding radial strength may decrease and the
stent should absorb away as quickly and safely as possible. The
inventors have found that molecular weight is one of several
variables that impact total resorption time. Increasing the
consistency of molecular weight will therefore reduce variability
in the total resorption time.
[0075] One way to address the product stability and consistency
issue, or equivalently, addressing the control of the
post-sterilization molecular weight change, is to condition a
sterilized final product for a period of time after sterilization
prior to release. For example, the product may be conditioned 3
weeks at room temperature or 7-10 days at an elevated temperature
such as 30.degree. C. This conditioning would stabilize the Mn or
level off Mn change before release of the product. In this case,
the properties of the released product would be stable, but the
conditioning would result only in a molecular weight at the final
high end.
[0076] Various embodiments of the present invention include methods
of stabilizing the properties of a polymeric stent scaffolding and
coating and preventing changes in properties as a function of time
caused by radiation sterilization. The methods include exposing the
scaffolding to oxygen during, after, or both during and after
radiation sterilization to stabilize molecular weight and other
properties. The exposure may be and is desirable performed in a
manner that preserves the degree of sterility of the stent or
reduction in bioburden of the stent provided by the radiation
sterilization. The sterility can be maintained by allowing the
oxygen exposure through a gas permeable material or package that
allows gas permeation while prevent permeation of bioburden.
Exposure to oxygen or oxygen-containing gas according to the
present invention does not refer to exposure to a gas with a
residual oxygen content, for example, in evacuated and inert gas
backfilled containers typically used for post-sterilization storage
which can be about 0.002% or less oxygen content.
[0077] Exposing sterilized stents to oxygen is contrary the
generally accepted practice in the art which focuses on isolating
pre- and post-sterilized stent from non-inert environment, e.g.,
reactive gases and moisture. Specifically, it is believed that
exposing stents to atmospheric levels of oxygen causes may cause an
additional drop in the molecular weight of PLLA. As used herein,
"oxygen" refers to diatomic oxygen, O.sub.2. Stabilizing the
molecular weight may refer to less than a 10% change in Mn over a
period after radiation exposure of at least 30 days, 30 to 60 days,
or greater than 60 days.
[0078] The inventors have found from several studies that exposing
the stent scaffolding to an oxygen-containing gas such as air
during or after radiation exposure reduces or prevents further
changes in molecular weight and other properties with time. It is
believed from these studies that oxygen reacts with the free
radicals which renders the free radicals non-reactive or terminates
the free radicals. Therefore, the free radicals react with and are
terminated by the oxygen rather than reacting with the polymer
chains of the stent polymer. The termination or quenching of the
free radicals occurs over a much shorter time frame than the decay
of the free radicals in an inert environment.
[0079] In certain embodiments of the present invention, a method of
making a stent includes providing a stent-catheter assembly
including a polymeric stent scaffolding disposed on a catheter. The
scaffolding is exposed to radiation, such as E-beam radiation, to
sterilize. The scaffolding is exposed to an oxygen-containing gas
during the radiation sterilization. For example, the stent-catheter
assembly is exposed to air. The oxygen-containing gas may be
sufficient to quench or terminate all or all but a residual amount
(e.g., less than 5.times.10.sup.7 DI/mg) of the free radicals in a
short period of time, for example, in less than 1 hr, 5 hrs, 12
hrs, 1 day, 2 days, or less than 5 days. The exposure to
oxygen-containing gas can continue for a period of time after the
radiation exposure, for example, until the free radicals are
terminated, equivalently, the free radicals have decayed to zero or
below a level at which the molecular weight of the scaffolding
polymer is stabilized for a long term, such as 2 weeks, 1 month, or
longer than 1 month. The stent may then be stored in an inert gas
atmosphere indefinitely, for example, until implantation. An
exemplary molecular weight profile according to these embodiments
is illustrated by study D in Table 1 and FIG. 9.
[0080] FIG. 4 depicts the free radical decay profiles of irradiated
PLLA scaffolding for two cases, (1) sterilized in a sealed foil
pouch in argon and (2) sterilized and aged in a gas permeable
Tyvek.RTM. pouch, thus exposed to air. The Tyvek.RTM. pouch allows
permeation of air, while preserving sterility. The expanded time
scale compared to FIG. 2 illustrates the dramatic unexpected
difference in the decay of free radicals in an inert atmosphere
compared to an oxygen-containing environment.
[0081] The above stabilization methods may be accomplished in a
number of ways. In an exemplary embodiment, in a first step, prior
to sterilization, the stent is placed in a gas permeable pouch such
as a Tyvek.RTM. pouch. FIG. 5A depicts a schematic representation
of a Tyvek.RTM. pouch 120 with a stent 122 contained within. The
pouch will allow oxygen to pass through to terminate any free
radicals generated during sterilization to prevent any
post-sterilization molecular weight change associated with free
radicals, while preserving the sterility level of the stent.
Materials other than Tyvek.RTM. that are gas permeable and that
also preserve a sterility level may be used in this embodiment and
others described herein. Although the pouch is permeable to air, it
will block the permeation of bioburden to maintain the sterility
level post-sterilization. The stent may be kept in the pouch a
period of time until the molecular weight of the scaffolding
polymer of the stent is stabilized by the oxygen exposure. In a
second step, the gas permeable pouch can be disposed within a gas
impermeable pouch, such as an aluminum pouch. FIG. 5B depicts
Tyvek.RTM. pouch 120 disposed within aluminum pouch 124. The gas
impermeable pouch may then be evacuated, backfilled with an inert
gas, and sealed for long term storage or until implantation.
[0082] Other embodiments of the present invention include exposing
the scaffolding to radiation in an inert gas environment. Following
radiation exposure in the inert gas environment, the scaffolding is
exposed to an oxygen-containing gas. The exposure the
oxygen-containing gas can continue for a period of time after the
radiation exposure. The period of time may be sufficient to prevent
any further molecular weight change. The stent may then be stored
in an inert gas atmosphere indefinitely, for example, until
implantation. An exemplary molecular weight profile according to
these embodiments is illustrated by study E in Table 1 and FIG.
9.
[0083] The inventors have observed that exposure of polymer
scaffolding to air during sterilization results in a greater drop
in Mn than sterilization in an inert gas environment (see FIG. 9).
E-beam radiation in a gas with high oxygen content may generate
ozone which is highly reactive and can react with polymer chains of
the stent or with a drug in the stent.
[0084] These other embodiments involving exposure to
oxygen-containing gas after radiation exposure may be accomplished
in a variety of ways. In an exemplary embodiment, a method involves
packaging a stent in a double-layered pouch. The first or inner
layer is gas permeable, such as a Tyvek.RTM. pouch, and the second
or outer layer is gas impermeable, such as an aluminum pouch. FIG.
6 depicts a schematic representation of a double-layered pouch 130.
Pouch 130 has an inner gas permeable Tyvek.RTM. layer 132 and an
outer gas impermeable aluminum layer 134. Stent 136 is disposed
within the inner Tyvek.RTM. layer. Prior to and during E-beam
sterilization the outer layer is sealed and contains an inert gas
environment ant the stent is sealed within the Tyvek.RTM. layer,
also in an inert gas environment. Post-sterilization, the aluminum
layer is opened, or more generally, fluid communication is allowed
between the outer pouch and ambient air to allow air into the
pouches, which exposes the stent to air. Outer pouch 134 has a
sealable opening 138 that can be open and closed to allow exposure
to air and sealed from exposure to air, respectively. For example,
sealable opening 138 has a foil seal 138A and a Tyvek.RTM. window
139B that allows air to enter pouch 134. The stent is exposed to
the air for at least a period of time to stabilize the molecular
weight of the stent scaffolding polymer. The foil pouch may then be
backfilled with inert gas and resealed. Alternatively, an
additional foil pouch may be added outside of the double layer
pouch, evacuated, backfilled with inert gas, and resealed.
[0085] The inventors have found that the cumulative free radicals
terminated depend on the time of exposure to the oxygen-containing
gas. Thus, the oxygen exposure may continue until the concentration
of free radicals levels decays below a selected value. For example,
the selected concentration can be 5.times.10.sup.7 DI/mg.
[0086] Following the exposure to oxygen for the period of time, the
scaffolding may then be disposed into an inert gas environment or
the gas may be removed from the packaged backfilled with an inert
gas.
[0087] The oxygen-containing gas can have any concentration of
oxygen that stabilizes (e.g., within 10%) the molecular weight (Mn)
as observed over a period of at least 2 weeks, 1 month, or 2
months. Alternatively or additionally, the oxygen-containing can
have any concentration of oxygen that causes the free radical
concentration to decay to below a certain level (e.g.,
5.times.10.sup.7 DI/mg) in less than 1 hr, 5 hrs, 12 hrs, 1 day, 2
days, or less than 5 days.
[0088] For example, air may be used which is 20.95 mol % oxygen.
The balance of the gas can include an inert gas(s) and possible
other residual gas impurities. The concentration of oxygen in the
gas can be less than 1%, 1 to 5%, 5-10%, more than 10% to air
concentration, air concentration to 40 mol %, 40 to 60%, 60 to 90%,
90-95%, or greater than 95%.
[0089] The inventors also found that the rate of free radical decay
depends on the concentration of oxygen. The lower the concentration
of oxygen, the longer the time required to reach a given
concentration of free radicals. Exemplary exposure times may be
less than 10 min, 10 min to 1 hr, 1 to 3 hr, 3 to 6 hr, 6 to 9 hr,
9 to 12 hr, 12 hr to 1 day, 1 to 2 days, 2 to 3 days, 3 to 5 days,
or greater than 5 days.
[0090] In further embodiments, the stent may be packaged and stored
until release and implantation in an atmosphere that is a mixture
of inert gas and oxygen. The mixture is primarily an inert gas with
a very low oxygen content that is substantially lower than that of
air, but greater than the residual content of an evacuated and
inert gas backfilled package. The packaged stent may then be
radiation sterilized and stored in the atmosphere indefinitely, for
example, until release and implantation. "Release" refers to
release or shipping from a manufacturer or contractor of the
manufacturer in a ready-to-implant condition. The storage time from
sterilization may be 1 to 10 days, 10 days to 1 month, 1 to 3
months, 3 to 6 months, 6 months to 1 year, 1 to 2 years. The
concentration of oxygen in the gas mixture may be high enough to
cause the free radical concentration to decay to below a certain
level (e.g., 5.times.10.sup.7 DI/mg) in less than 5 hrs, 12 hrs, 1
day, 2 days, or less than 5 days. The concentration of oxygen
should be low enough that storage for any of the storage ranges
disclosed will not result in adverse effects on the molecular
weight of the polymer of the stent or drug. In exemplary
embodiments, the content of oxygen may be less than 0.5%, 0.5 to
1%, 1 to 2%, 0.08 to 1.02%, 2 to 3%, 3 to 5%, 5 to 10%, less than
1%, less than 5%, less than 10%, or 10 to 20%.
[0091] In some embodiments, prior to sterilization, the scaffold is
placed in a gas impermeable package and the atmosphere in the
package, i.e., air, may be evacuated and then the package may be
backfilled with the inert gas-oxygen mixture. For example, the same
equipment may be used as that for evacuating and backfilling the
package with inert gas, which backfills the package from an argon
cylinder. In the present invention, the package may be backfilled
with the inert gas/oxygen mixture with the controlled amount of
oxygen. The molecular weight profile according to these embodiments
is illustrated by study C in Table 1 and FIG. 9.
[0092] Studies have shown for a gas mixture with an oxygen content
of 1% that no free radicals can be detected after 2 days, whereas a
signal is still detected at 28 days using an inert gas atmosphere.
FIG. 7 depicts the free radical decay in irradiated PLLA
scaffolding samples sterilized and stored in containers with
different oxygen concentrations, 0%, 0.002%, and 1%. The free
radical decay of samples in 0.002% oxygen is more rapid than the 0%
oxygen, but the long term decay is similar. The free radical decay
of the samples in 1% oxygen samples is significantly faster than in
the 0% or 0.002% oxygen.
[0093] Table 1 is a summary of the studies on the effect of E-beam
sterilization on PLLA scaffolding samples. The samples in study A
were not sterilized to provide a basis for comparison of the effect
of E-beam radiation on molecular weight. The samples in studies B-E
were sterilized with E-beam radiation with a dose of 27.5 kGy. The
sterilization and storage conditions are in Table 1 for each study.
FIG. 8 depicts the Mn versus time of a PLLA scaffolding
corresponding to study A. The Mn is fairly constant as
expected.
TABLE-US-00001 TABLE 1 Summary of studies on the effect of E-beam
radiation on PLLA scaffolding samples. Sterilization conditions
Storage conditions Study for samples for samples A Non-sterile - no
irradiation RT.sup.1 storage in sealed foil pouch in argon B
Sterilize in foil pouch in RT storage in sealed foil argon pouch in
argon C Sterilize in foil pouch in 1% RT storage in sealed foil
O.sub.2 pouch in argon D Sterilize in Tyvek .RTM. RT storage in
sealed Tyvek .RTM. pouch - exposed to air pouch in argon E
Sterilize in foil pouch in 1. Expose to samples to air for argon 24
hrs 2. Seal and repack units in foil pouch in argon .sup.1RT = Room
Temperature Data collection A-D: 0, 1, 3, 7, 14, 21, 28, 35, 56,
(180) days Data collection E: 3, 7, 14, 21, 28, 35, 56, (180)
days
[0094] FIG. 9 depicts the Mn versus time for the samples of studies
B-E. For study B, the sterilization and storage in inert gas and
the effect were discussed above. In study B, the scaffolding Mn
increased from about 80 kDa post-sterilization to above 100 kDa
after about 60 days.
[0095] The comparison between study A, FIG. 8, and study B, FIG. 9,
reveals the dramatic effect that radiation has on the long term
behavior of Mn. The profile of Mn for study C, which is
sterilization and storage in a 1% oxygen gas, in FIG. 9 shows only
a slight increase in Mn the first day or so with stable Mn after
the increase. For study D, which is sterilization in air, the
initial Mn is lower than for studies B and C and is stable
throughout the range studied. For study E, the initial molecular
weight is also lower than for studies B and C and is stable
throughout the range studied. The molecular weight for study D is
slightly higher than for study E. This presence of oxygen during
the sterilization in study D may increase the radiation induced
chain scission resulting in a lower Mn.
[0096] A preferred embodiment used in the above studies has the
stent pattern described in U.S. application Ser. No. 12/447,758 (US
2010/0004735) to Yang & Jow, et al. Other examples of stent
patterns suitable for PLLA are found in US 2008/0275537. The
cross-section of the struts of the scaffold is 150.times.150
microns.
[0097] Above it was stated that the molecular weight and properties
of a polymeric stent can be stabilized after sterilization by aging
a stent at room temperature or a slightly higher temperature.
However, the final molecular weight after stabilizing would be a
high end value at the end of the stabilization period. The methods
of the present invention discussed above involve quenching the free
radicals during or after sterilization so that the molecular weight
is stabilized at or close to the molecular weight at the end of
radiation sterilization.
[0098] Further embodiments of the present invention include
allowing the molecular weight to increase for a period of time
after sterilization, followed by stopping the molecular weight
change through exposure of the stent to oxygen to stabilize the
polymer at a desired Mn. The stabilized Mn can be any value between
the Mn immediately after sterilization to the high end value at the
end of stabilization through room temperature stabilization
discussed above.
[0099] The method can include radiation sterilizing a stent
disposed in a package with an inert gas atmosphere. After a
selected period of time, the stent can then be exposed to an
oxygen-containing gas, preferably, a high content of oxygen content
such as air. The oxygen content may be high enough to rapidly
terminate or quench the free radicals to stop the increase in
molecular weight at a desire valued of Mn. For example, the free
radical concentration may decay to less than 5.times.10.sup.-7
DI/mg in less than 2 days, 1 day, 12 hr, 5 hr, 1 hr. The oxygen
content of the gas may be greater than 5%, 5 to 10%, greater than
10%, 10 to 20%, 20% to air concentration, or greater than air
concentration.
[0100] The method can include selecting a desired final Mn of the
polymer scaffolding of the stent. The Mn versus time relationship
post-sterilization may be determined in an inert gas atmosphere,
such as that shown in FIG. 3. The selected time required for the
scaffolding polymer to reach selected Mn may be obtained from the
relationship. A scaffolding with the selected Mn may then be
obtained by exposing a scaffolding packaged in an inert atmosphere
at the selected time post-radiation sterilization.
[0101] The above method may be achieved in a variety of ways. In
one embodiment, a radiation sterilized stent may be placed in a
pouch with two sides or enclosures. One side is made of a gas
impermeable material such as aluminum and the other side is made of
gas permeable material, Tyvek.RTM.. FIG. 10 depicts a schematic
representation of a two-sided pouch 140 having a gas impermeable
aluminum side 142 and a gas permeable Tyvek.RTM. side 144, which
has air within. The two sides are sealed from one another and are
connected by a movable sealer 146 that allows movement of a stent
148 from the aluminum side to the Tyvek.RTM. side without fluid
communication between the sides. Before sterilization, stent 148 is
placed in the aluminum side in an inert gas. The stent is
sterilized and after a certain time post-sterilization, the sealer
shifts the stent (shown in phantom) to the Tyvek.RTM. side, as
shown by arrow 150, to terminate free radicals, and therefore to
stop Mn change. After a selected stabilization time, the stent is
shifted back to the aluminum side to the inert gas environment. The
stent may then be stored in an inert gas environment by refilling
with inert gas and resealing.
[0102] Alternatively, a package can have three compartments, a
first compartment, a second compartment, and a third compartment.
The second compartment that contains the stent is separated from
the first compartment and the third compartment by a zipper or
resealable tape. The zipper or tab can be positioned to allow or
close off fluid communication between the first or third
compartments. The first compartment and the second compartment are
gas impermeable, for example, made of aluminum, and filled with
inert gas. The third compartment is gas permeable, e.g., made of
Tyvek.RTM., and filled with air. During sterilization, the stent
would remain in the second compartment and is sealed off from both
the first and third compartments. After sterilization, the zipper
or tab between the second and the third compartment is opened,
exposing stent to air. After a certain time, the same zipper or tab
is closed, and then the zipper or tab between the first and the
second compartment is opened, exposing the stent to the inert gas
environment again.
[0103] In another embodiment, both sides of a pouch may be made
from gas impermeable material such as aluminum. FIG. 11 depicts a
schematic representation of a pouch 160 with two gas impermeable
sides, a first aluminum side 162 and a second aluminum side 164.
Prior to and during sterilization the first side 162 is filled with
inert gas, while the second side 164 is filled with a mixture of an
inert gas and oxygen. Prior to and during sterilization, a stent
166 is disposed in the first side 162 and the two sides are not
fluidly connected. A selected period of time after sterilization
when the Mn of the scaffolding reaches a selected Mn, the mixture
of inert gas and oxygen may be used to terminate free radical
recombination. For example, the mixture may have at least 1%
oxygen, 1-5% oxygen, 5-15% oxygen, 15-20% oxygen, or is air. The
two sides may be connected by a valve 168 that allows the two sides
to be fluidly connected when the valve is open and sealed from one
another when the valve is closed. During sterilization and a
selected period time after sterilization valve 168 may be closed.
After the selected period of time, valve 168 may be opened to allow
the exposure of the stent to the inert gas and oxygen mixture to
terminate the free radicals and stabilize the molecular weight at
the selected Mn. After the molecular weight is stabilized valve 168
may be closed and the gas in the first side 162 may be replaced
with an inert gas atmosphere.
[0104] For the purposes of the present invention, the following
terms and definitions apply:
[0105] The "Tyvek.RTM." packaging herein refers to Tyvek.RTM.
medical packaging from Dupont of Wilmington, Del. such as
DuPont.TM. Tyvek.RTM. 1073B.
[0106] The term "molecular weight" can refer to one or more
definitions of molecular weight. "Molecular weight" can refer to
the molecular weight of individual segments, blocks, or polymer
chains. "Molecular weight" can also refer to weight average
molecular weight or number average molecular weight of types of
segments, blocks, or polymer chains. The number average molecular
weight (Mn) is the common, mean, average of the molecular weights
of the individual segments, blocks, or polymer chains. Molecular
weight is typical expressed in grams/mole which is referred to as
"Daltons." It is determined by measuring the molecular weight of N
polymer molecules, summing the weights, and dividing by N:
M _ n = i N i M i i N i ##EQU00001##
where Ni is the number of polymer molecules with molecular weight
Mi. The weight average molecular weight is given by
M _ w = i N i M i 2 i N i M i ##EQU00002##
where Ni is the number of molecules of molecular weight Mi Unless
otherwise specified, "molecular weight" will refer to number
average molecular weight (Mn).
[0107] "Semi-crystalline polymer" refers to a polymer that has or
can have regions of crystalline molecular structure and amorphous
regions. The crystalline regions may be referred to as crystallites
or spherulites which can be dispersed or embedded within amorphous
regions.
[0108] The "glass transition temperature," Tg, is the temperature
at which the amorphous domains of a polymer change from a brittle
vitreous state to a solid deformable or ductile state at
atmospheric pressure. In other words, the Tg corresponds to the
temperature where the onset of segmental motion in the chains of
the polymer occurs. When an amorphous or semi-crystalline polymer
is exposed to an increasing temperature, the coefficient of
expansion and the heat capacity of the polymer both increase as the
temperature is raised, indicating increased molecular motion. As
the temperature is increased, the heat capacity increases. The
increasing heat capacity corresponds to an increase in heat
dissipation through movement. Tg of a given polymer can be
dependent on the heating rate and can be influenced by the thermal
history of the polymer as well as its degree of crystallinity.
Furthermore, the chemical structure of the polymer heavily
influences the glass transition by affecting mobility.
[0109] The Tg can be determined as the approximate midpoint of a
temperature range over which the glass transition takes place.
[ASTM D883-90]. The most frequently used definition of Tg uses the
energy release on heating in differential scanning calorimetry
(DSC). As used herein, the Tg refers to a glass transition
temperature as measured by differential scanning calorimetry (DSC)
at a 20.degree. C./min heating rate.
[0110] "Stress" refers to force per unit area, as in the force
acting through a small area within a plane. Stress can be divided
into components, normal and parallel to the plane, called normal
stress and shear stress, respectively. Tensile stress, for example,
is a normal component of stress applied that leads to expansion
(increase in length). In addition, compressive stress is a normal
component of stress applied to materials resulting in their
compaction (decrease in length). Stress may result in deformation
of a material, which refers to a change in length. "Expansion" or
"compression" may be defined as the increase or decrease in length
of a sample of material when the sample is subjected to stress.
[0111] "Strain" refers to the amount of expansion or compression
that occurs in a material at a given stress or load. Strain may be
expressed as a fraction or percentage of the original length, i.e.,
the change in length divided by the original length. Strain,
therefore, is positive for expansion and negative for
compression.
[0112] "Strength" refers to the maximum stress along an axis which
a material will withstand prior to fracture. The ultimate strength
is calculated from the maximum load applied during the test divided
by the original cross-sectional area.
[0113] "Modulus" may be defined as the ratio of a component of
stress or force per unit area applied to a material divided by the
strain along an axis of applied force that results from the applied
force. The modulus typically is the initial slope of a
stress-strain curve at low strain in the linear region. For
example, a material has both a tensile and a compressive
modulus.
[0114] The tensile stress on a material may be increased until it
reaches a "tensile strength" which refers to the maximum tensile
stress which a material will withstand prior to fracture. The
ultimate tensile strength is calculated from the maximum load
applied during a test divided by the original cross-sectional area.
Similarly, "compressive strength" is the capacity of a material to
withstand axially directed pushing forces. When the limit of
compressive strength is reached, a material is crushed.
[0115] "Toughness" is the amount of energy absorbed prior to
fracture, or equivalently, the amount of work required to fracture
a material. One measure of toughness is the area under a
stress-strain curve from zero strain to the strain at fracture. The
units of toughness in this case are in energy per unit volume of
material. See, e.g., L. H. Van Vlack, "Elements of Materials
Science and Engineering," pp. 270-271, Addison-Wesley (Reading,
Pa., 1989).
[0116] The underlying structure or substrate of an implantable
medical device, such as a stent can be completely or at least in
part made from a biodegradable polymer or combination of
biodegradable polymers, a biostable polymer or combination of
biostable polymers, or a combination of biodegradable and biostable
polymers. Additionally, a polymer-based coating for a surface of a
device can be a biodegradable polymer or combination of
biodegradable polymers, a biostable polymer or combination of
biostable polymers, or a combination of biodegradable and biostable
polymers.
[0117] It is understood that after the process of degradation,
erosion, absorption, and/or resorption has been completed, no part
of the stent will remain or in the case of coating applications on
a biostable scaffolding, no polymer will remain on the device. In
some embodiments, very negligible traces or residue may be left
behind. For stents made from a biodegradable polymer, the stent is
intended to remain in the body for a duration of time until its
intended function of, for example, maintaining vascular patency
and/or drug delivery is accomplished.
[0118] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
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