U.S. patent application number 13/760540 was filed with the patent office on 2013-06-13 for methods of providing antioxidants to implantable medical devices.
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 Ni Ding.
Application Number | 20130145729 13/760540 |
Document ID | / |
Family ID | 41117593 |
Filed Date | 2013-06-13 |
United States Patent
Application |
20130145729 |
Kind Code |
A1 |
Ding; Ni |
June 13, 2013 |
Methods of Providing Antioxidants to Implantable Medical
Devices
Abstract
Methods of incorporating an antioxidant into a medical device
including a polymer are described, and methods of packaging medical
devices.
Inventors: |
Ding; Ni; (San Jose,
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: |
41117593 |
Appl. No.: |
13/760540 |
Filed: |
February 6, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12485756 |
Jun 16, 2009 |
8394446 |
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13760540 |
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11528891 |
Sep 27, 2006 |
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12485756 |
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11189216 |
Jul 25, 2005 |
7785647 |
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11528891 |
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Current U.S.
Class: |
53/431 ;
524/384 |
Current CPC
Class: |
B65B 55/00 20130101;
B65D 3/00 20130101; B65D 77/04 20130101; A61L 31/143 20130101; A61L
31/10 20130101; C08K 5/13 20130101; B65D 1/00 20130101; A61F 2/82
20130101 |
Class at
Publication: |
53/431 ;
524/384 |
International
Class: |
C08K 5/13 20060101
C08K005/13; B65B 55/00 20060101 B65B055/00 |
Claims
1. A method: providing an implantable medical device; providing a
package and an antioxidant or providing a package integrated with
an antioxidant; placing the implantable medical device and the
antioxidant in the package or placing the implantable medical
device in the package integrated with the antioxidant; and sealing
the implantable medical device and antioxidant in the package or
sealing the implantable medical device in the package integrated
with the antioxidant; wherein a fluid filling the inside of the
sealed package comprises at least 0.001 .mu.g/cm.sup.3
antioxidant.
2. The method of claim 1, further comprising providing a primary
package that is permeable to the antioxidant, and placing the
implantable medical device in the primary package before placing
the device in the package with the antioxidant or in the package
integrated with the antioxidant.
3. The method of claim 1, wherein the fluid filling the inside of
the sealed package surrounds the implantable medical device.
4. The method of claim 2, wherein the fluid filling the inside of
the sealed package surrounds the primary package.
5. The method of claim 3, wherein the fluid filling the inside of
the sealed package is argon, nitrogen, helium, or a combination
thereof.
6. The method of claim 4, wherein the fluid filling the inside of
the sealed package is argon, nitrogen, helium, or a combination
thereof.
7. The method of claim 1, wherein the implantable medical device is
a stent.
8. The method of claim 7, wherein the stent is a bioabsorbable
stent.
9. A method comprising: providing an implantable medical device
comprising a polymer, the device having a device body and an outer
surface; and exposing the device to a fluid comprising an
antioxidant such that some of the antioxidant from the fluid is
incorporated into the device; wherein the fluid is substantially
free of polymers, drugs, and materials other than
antioxidant(s).
10. The method of claim 9, wherein the fluid is in a gas phase.
11. The method of claim 10, wherein exposing the device comprises
placing the implantable medical device in contact with the gas.
12. The method of claim 9, wherein the fluid is in a supercritical
phase.
13. The method of claim 12, wherein exposing the device comprises
placing the implantable medical device in contact with the
supercritical fluid.
14. The method of claim 9, wherein the device is a stent.
15. The method of claim 14, wherein the stent is a biodegradable
stent.
16. The method of claim 15, wherein the biodegradable stent
consists essentially of poly(L-lactide),
poly(L-lactide-co-glycolide), or combinations thereof.
17. The method of claim 9, wherein the antioxidant is selected from
the group consisting of butylated hydroxytoluene ("BHT"), butylated
hydroxyanisole ("BHA"), and any combinations thereof.
18. The method of claim 9, wherein the polymer is a polymer formed
from one or more monomers selected from the group consisting of
L-lactide, D-lactide, meso-lactide, glycolide, and caprolactone,
and any combinations thereof.
19. The method of claim 9, further comprising forming a coating on
at least a portion of the outer surface of the device after the
exposure.
20. The method of claim 9, further comprising sterilizing the
device after the exposure, wherein the antioxidant reduces the
decrease in molecular weight of the polymer due to
sterilization.
21. The method of claim 9, wherein prior to sterilization the
polymer of the implantable medical device has an initial weight
average molecular weight, and after sterilization the polymer has a
weight average molecular weight of about 50% of the initial weight
average molecular weight, or greater than 50% of the initial weight
average molecular weight.
22. The method of claim 9, wherein the device exposed to the fluid
is uncoated.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 12/485,756, filed on Jun. 16, 2009, and
published on Oct. 1, 2009, as U.S. Patent Application Publication
No. 2009/0246253 A1, which is a continuation-in-part of U.S.
application Ser. No. 11/189,216, filed Jul. 25, 2005, published on
Jan. 25, 2007, as U.S. Patent Application Publication No.
2007/0020380 A1, and issued on Aug. 31, 2010, as U.S. Pat. No.
7,785,647; and U.S. application Ser. No. 12/485,756 is a
continuation-in-part of U.S. application Ser. No. 11/528,891, filed
on Sep. 27, 2006, and published on Aug. 23, 2007, as U.S. Patent
Application Publication No. 2007/0198080 A1, which is now
abandoned. U.S. application Ser. Nos. 12/485,756 and 11/189,216 are
hereby incorporated by reference herein as if fully set forth,
including any drawings.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to the fields of chemistry, chemical
engineering, and medical devices.
[0004] 2. Description of the State of the Art
[0005] The discussion that follows is intended solely as background
information to assist in the understanding of the invention herein;
nothing in this section is intended to be, nor is it to be
construed as, prior art to this invention.
[0006] Until the mid-1980s, the accepted treatment for
atherosclerosis, i.e., narrowing of the coronary artery(ies) was
coronary by-pass surgery. While effective and having evolved to a
relatively high degree of safety for such an invasive procedure,
by-pass surgery still involves serious potential complications and
in the best of cases, an extended recovery period.
[0007] With the advent of percutaneous transluminal coronary
angioplasty (PTCA) in 1977, the scene changed dramatically. Using
catheter techniques originally developed for heart exploration,
inflatable balloons were employed to re-open occluded regions in
arteries. The procedure was relatively non-invasive, took a very
short time compared to by-pass surgery and the recovery time was
minimal. However, PTCA brought with it another problem, elastic
recoil of the stretched arterial wall which could undo much of what
was accomplished and, in addition, failed to satisfactorily
ameliorate another problem, restenosis, the re-clogging of the
treated artery.
[0008] The next improvement, advanced in the mid-1980s, was use of
a stent to scaffold the vessel wall in place after PTCA. This for
all intents and purposes put an end to recoil but did not entirely
resolve the issue of restenosis. That is, prior to the introduction
of stents, restenosis occurred in from 30-50% of patients
undergoing PTCA. Stenting reduced this to about 15-20%, much
improved, but still more than desirable.
[0009] In 2003, drug-eluting stents or DESs were introduced. The
drugs initially employed with the DES were cytostatic compounds,
compounds that curtailed the proliferation of cells that resulted
in restenosis. The occurrence of restenosis was thereby reduced to
about 5-7%, a relatively acceptable figure. Today, the DES is the
default industry standard for the treatment of atherosclerosis and
is rapidly gaining favor for treatment of stenoses of blood vessels
other than coronary arteries such as peripheral angioplasty of the
superficial femoral artery.
[0010] The next generation of stents will be those designed to be
biodegradable. Although bioerodable metals may be used,
biodegradable polymers are often used for fabrication of a stent.
However, there are potential shortcomings in the use of polymers as
a material for implantable medical devices, such as stents.
Polymers that biodegrade in the body may also degrade during the
process of manufacturing, or during storage.
[0011] Methods of incorporating an antioxidant into a medical
device that includes a polymer to reduce or limit the polymer
degradation, and methods to enhance device shelf-life are needed.
The present invention provides such methods.
SUMMARY OF THE INVENTION
[0012] Various embodiments of the present invention include methods
of incorporating an antioxidant into an implantable medical device.
The methods include, but are not necessarily limited to: providing
an implantable medical device comprising a polymer, and exposing
the device to a fluid comprising an antioxidant such that some of
the antioxidant from the fluid is incorporated into the device. The
fluid may be free of or substantially free of polymers and drugs.
The fluid may comprise at least 10 ppm antioxidant.
[0013] Various embodiments of the present invention include methods
of fabricating a polymeric stent are provided. Such methods
include, but are not necessarily limited to: forming a polymeric
tube, or providing a polymeric tube; cutting a stent pattern into
the tube to form a polymeric stent; and exposing the polymeric
stent or the polymeric tube to a fluid including an antioxidant.
The exposure of the polymeric stent or the polymeric tube to the
fluid including the antioxidant results in incorporation of some of
the antioxidant into the polymeric stent or polymeric tube.
[0014] Various embodiments of the present invention include kits.
The kits include, but are not necessarily limited to an implantable
medical device comprising a polymer and optionally comprising an
antioxidant, the device antioxidant; and a primary package with an
interior, an interior surface and an exterior surface, the primary
package comprising a second antioxidant, which may be the same as
or different from the device antioxidant. The implantable medical
device may be sealed inside the primary package, and the fluid
filling the inside of the package and surrounding the device
contains at least 0.001 .mu.g/cm.sup.3 antioxidant.
[0015] Various embodiments of the present invention include methods
of packaging implantable medical devices. The methods include, but
are not limited to: providing an implantable medical device;
providing a package and an antioxidant or providing a package
integrated with an antioxidant; placing the implantable medical
device and the antioxidant in the package or placing the
implantable medical device in the package integrated with the
antioxidant; and sealing the implantable medical device and
antioxidant in the package or sealing the implantable medical
device in the package integrated with the antioxidant. The fluid
filling the inside of the sealed package and surrounding the device
may contain at least 0.001 .mu.g/cm.sup.3 antioxidant.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 depicts a stent.
[0017] FIG. 2 depicts the mass loss of butylated hydroxytoluene
(BHT) powder versus time for different temperatures.
[0018] FIG. 3 is a plot of the ratio of BHT remaining to the
initial mass of BHT versus time for different temperatures.
DETAILED DESCRIPTION OF THE INVENTION
[0019] Use of the singular herein includes the plural and vice
versa unless expressly stated to be otherwise. That is, "a" and
"the" refer to one or more of whatever the word modifies. For
example, "an antioxidant" includes one antioxidant, two
antioxidants, etc. Likewise, "a polymer" may refer to one, two or
more polymers, and "the polymer" may mean one polymer or a
plurality of polymers. By the same token, words such as, without
limitation, "antioxidants" and "polymers" would refer to one
antioxidant or polymer as well as to a plurality of antioxidants or
polymers unless, again, it is expressly stated or obvious from the
context that such is not intended.
[0020] As used herein, any ranges presented are inclusive of the
end-points. For example, "a temperature between 10.degree. C. and
30.degree. C." or "a temperature from 10.degree. C. to 30.degree.
C." includes 10.degree. C. and 30.degree. C., as well as any
temperature in between.
[0021] As used herein, unless specifically defined otherwise, any
words of approximation such as without limitation, "about,"
"essentially," "substantially" and the like mean that the element
so modified need not be exactly what is described but can vary from
the description by as much as .+-.15% without exceeding the scope
of this invention.
[0022] As used herein, the use of "preferred," "preferably," or
"more preferred," and the like to modify an aspect of the invention
refers to preferences as they existed at the time of filing of the
patent application.
[0023] The various embodiments of the present invention include
methods to provide antioxidants to an implantable medical device
that includes a polymer, and methods of packaging such devices. The
polymer may be a biostable polymer, a biodegradable polymer, or a
combination thereof. The antioxidants are provided to reduce
degradation of the polymer during processing, and particularly,
during sterilization, or to extend the shelf-life.
[0024] This invention relates to medical devices, and particularly
implantable medical devices. Implantable medical devices include
appliances that are totally or partly introduced, surgically or
medically, into a patient's body or by medical intervention into a
natural orifice, and which are intended to remain there after the
procedure. More particularly, this invention is directed stents, a
type of implantable medical device. Although the discussion that
follows focuses on a stent as an example of a medical device, the
embodiments described herein are easily applicable to other medical
devices, and specifically, other implantable medical devices.
Examples of implantable medical devices include, without
limitation, implantable cardiac pacemakers and defibrillators;
leads and electrodes for the preceding; implantable organ
stimulators such as nerve, bladder, sphincter and diaphragm
stimulators, cochlear implants; prostheses, vascular grafts,
self-expandable stents, balloon-expandable stents, stent-grafts,
grafts, artificial heart valves, closure devices for patent foramen
ovale, vascular closure devices, cerebrospinal fluid shunts, and
intrauterine devices.
[0025] 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. A "lumen" refers to a cavity of a tubular organ such as a
blood vessel. 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. In addition to treatment for
coronary artery disease such as atherosclerosis and restenosis,
stents may be used for the maintenance of the patency of a vessel
in a patient's body when the vessel is narrowed or closed due to
diseases or disorders including, without limitation, tumors (m, for
example, bile ducts, the esophagus, the trachea/bronchi, etc.),
benign pancreatic disease carotid artery disease, peripheral
arterial disease (PAD), and vulnerable plaque. For treatment of
PAD, stents may be used in peripheral arteries such as the
superficial femoral artery (SFA). For use of stents in the SFA
appears to be more problematic than in coronary vessels and in
other peripheral vascular beds, such as the iliac and carotid
arteries.
[0026] Stents are typically composed of scaffolding that physically
holds open and, if desired, expands the wall of a passageway. A
stent may include a pattern or network of interconnecting
structural elements or struts. FIG. 1 depicts an example of a
three-dimensional view of a stent 10. The stent may have a stent
pattern that includes a number of interconnecting elements or
struts 15. The scaffolding can be formed from wires, tubes, or
sheets of material rolled into a cylindrical shape. With respect to
a stent, the scaffolding is the device body. In general, the body
of a medical device may be the device in a functional form, but
prior to the application of a coating or other material different
from that of which the device body is formed.
[0027] 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. 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.
[0028] The stent must be able to satisfy several mechanical
requirements. First, 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 lumen. This requires a
sufficient degree of strength and rigidity or stiffness. In
addition to having adequate radial strength, the stent should be
longitudinally flexible to allow it to be maneuvered through a
tortuous path and to enable it to conform to a deployment site that
may not be linear or may be subject to flexure. The material from
which the stent is constructed must allow the stent to undergo
expansion which typically requires substantial deformation of
portions of the stent. Once expanded, the stent must maintain its
size and shape throughout its service life despite the various
forces that may come to bear thereon, such as the cyclic loading
induced by the beating heart. Therefore, a stent must be capable of
exhibiting relatively high toughness which corresponds to high
strength and rigidity, as well as flexibility. For stents used in
the SFA, the mechanical requirements are high as the SFA is
subjected to various forces, such as compression, torsion, flexion,
extension, and contraction, which place a high demand on the
mechanical performance of implants.
[0029] Although stents may be manufactured from materials such as
metals and metal alloys (see paragraph [0031] of U.S. Patent
Application Publication No. 2007/0020380 A1), stents may also be
fabricated from polymers. As noted above, it may be desirable for
implantable medical devices, such as stents, to be biodegradable.
In many treatment applications, the presence of a stent in a body
may be necessary for a limited period of time until its intended
function of, for example, maintaining vascular patency and/or drug
delivery is accomplished. Therefore, the device body, such as the
scaffolding of a stent, may be fabricated from biodegradable,
bioabsorbable, and/or bioerodable polymers can be configured to
partially or completely erode away after the clinical need for them
has ended.
[0030] Stents, whether manufactured from a polymer, from a metal,
and/or from another material, may be coated. Coatings typically
include one or more polymers, and may optionally include one or
more drugs. A coating layer refers to material described as a layer
or film "disposed over" or "formed on" a surface, and refers to
such material that is deposited directly (to the substrate) or
indirectly (applied to a previously applied material) over at least
a portion of the surface. The terms "layer" and "coating layer"
will be used interchangeably and refer to a layer, film, or coating
layer as described in this paragraph. A coating layer may be
applied by multiple applications or passes of a coating solution or
of coating material. A coating may include one or more layers. An
exemplary substrate is the outer surface of a stent, which is any
surface, however spatially oriented, that is in contact with bodily
tissue or fluids.
[0031] In addition to use in a coating or the device body, polymers
may also form another portion of a device, or be used to fill
indentations or pores in a device.
[0032] Fabricating polymer stents can involve processing steps that
expose the polymer to high temperatures and other conditions such
as radiation that can result in chemical degradation. The decrease
in molecular weight can adversely affect mechanical properties and
other properties of the polymer such as biodegradation behavior,
and drug release properties.
[0033] Some of the process operations involved in fabricating a
polymeric stent may include:
[0034] (1) forming a polymeric tube using extrusion;
[0035] (2) radially deforming the formed tube by application of
heat and/or pressure;
[0036] (3) forming a stent from the deformed tube by cutting a
stent pattern in the deformed tube;
[0037] (4) coating the stent with a coating including an active
agent;
[0038] (5) crimping the stent on a support element, such as a
balloon on a delivery catheter;
[0039] (6) packaging the crimped stent/catheter assembly; and
[0040] (7) sterilizing the stent assembly.
[0041] The manufacturing process of a stent exposes the stent to
conditions such as heat, light, radiation, moisture, or other
factors that can chemically degrade the stent polymer. As a
non-limiting example, the decomposition of poly(L-lactide) (PLLA)
may occur by free radical oxidation. Once free radicals are formed
by oxidation and/or exposure to radiation or the like, the free
radicals attack the polymer chain which results in a series of
byproducts such as lactide monomers, cyclic oligomers and shorter
polymer chains. In addition, decomposition may be catalyzed by the
presence of oxygen, water, or residual metal such as from a
catalyst. More specifically the polyester poly(L-lactide) is
subject to thermal degradation at elevated temperatures, with
significant degradation (measured as weight loss) occurring at
about 150.degree. C. and higher temperatures. The polymer is
subject to random chain scission, and the degradation products also
include aldehydes, and other cyclic oligomers. It is believed that
a free radical chain process may be involved in the
degradation.
[0042] Polymer molecular weight may significantly decrease during
the processing operations used in the manufacture of a stent. A
non-limiting example is the use of a PLLA polymer to manufacture a
stent. An exemplary process including steps 1-7 results in a
decrease of the weight average molecular weight from about 550
kg/mol to about 190 kg/mol. The decrease in polymer molecular
weight results from extrusion (380 Kg/mol from the initial 550
kg/mol), radial expansion and laser cutting (280 kg/mol), and
electron beam (25 KGy) sterilization (190 Kg/mol). Decrease of
polymer molecular weight impacts the mechanical properties, such as
radial strength of the polymeric stent, as well as potentially the
drug release properties.
[0043] The decrease in the molecular weight of the polymer may have
a profound impact on a biodegradable polymer stent. For
biodegradable polymeric stents the scaffolding, which is formed
from a polymer, supports the vessel for a time period. As the
polymer biodegrades, there is a point in time at which the stent no
longer supports the vessel. It is important for the stent to
support the vessel for a time period long enough to prevent
negative remodeling of the vessel after angioplasty and excessive
recoil. For a biodegradable polymer stent, the vessel support is
provided by the radial strength of the stent. The radial strength
is largely impacted by the molecular weight of the polymer. As a
result, a decrease in the polymer molecular weight may lead to a
premature loss of radial strength and premature loss of vessel
support. In addition to the premature failure of the stent, the
decrease in polymer molecular weight may potentially result in
fracture. If the molecular weight is lower, the biodegradable stent
will biodegrade more quickly with a resultant loss in mass that is
quicker. Premature mass loss may inhibit the formation of an
endothelial layer over the stent. It is the formation of the
endothelial layer that prevents thrombosis and inflammation from
acidic by products resulting from polymer biodegradation.
[0044] As noted above, sterilization processes in particular may
degrade polymers. Ethylene oxide sterilization, or irradiation,
either gamma irradiation or electron beam (e-beam) irradiation, are
typically used for terminal sterilization of medical devices. For
ethylene oxide sterilization, the medical device is exposed to
liquid or gaseous ethylene oxide that sterilizes through an
alkalization reaction that prevents organisms from reproducing.
Ethylene oxide penetrates the device, and then the device is
aerated to assure very low residual levels of ethylene oxide
because it is highly toxic. Ethylene oxide sterilization is often
performed at elevated temperatures and with moisture to both speed
up the processes of diffusion into and out of the device and
enhance sterilization effectiveness. Polymer degradation can occur
from the combination of heat and moisture. The mechanical
properties of the stent may be changed due to prolonged exposure to
elevated temperature and/or moisture.
[0045] Alternatively, irradiation may be used for terminal
sterilization. It is known that radiation can alter the properties
of the polymers being treated by the radiation. High-energy
radiation tends to produce ionization and excitation in polymer
molecules. Resultant physical changes can include embrittlement,
discoloration, odor generation, stiffening, and softening, among
others. In particular, the deterioration of the performance of
polymers due to e-beam sterilization has been associated with free
radical formation during radiation exposure and by reaction of
these free radicals with other parts of the polymer chains. The
reaction is dependent on e-beam dose, temperature, and atmosphere
present, especially oxygen. Additionally, exposure to radiation,
such as e-beam, can cause a rise in temperature of an irradiated
polymer sample.
[0046] To prevent or reduce polymer degradation, antioxidants may
be used. Generally, a molecule that protects from free radicals is
an antioxidant, and more particularly, free radical scavengers are
antioxidants. "Free radicals" refer to atomic or molecular species
with unpaired electrons on an otherwise open shell configuration,
and can be formed by oxidation reactions. These unpaired electrons
are usually highly reactive, so radicals are likely to take part in
chemical reactions, including chain reactions. Free radical
scavengers operate through donation of an electron or hydrogen to a
free radical, thus removing the free radical from further reaction.
The free radical scavenger effectively competes with the polymer
for the free radicals, and thus removes the free radicals from the
reaction cycle.
[0047] Antioxidants may be added to the polymer to prevent,
inhibit, or reduce polymer degradation, and the associated
reduction in molecular weight. Antioxidants may be included in the
package of an implantable medical device to prevent, inhibit, or
reduce polymer degradation. The present invention is directed to
methods of incorporating an antioxidant into an implantable medical
device that includes a polymer, and methods of packaging an
implantable medical device. The embodiments discussed below are
applicable to a polymeric device, a device including a polymeric
coating, or any device including a polymer.
[0048] Antioxidants are particularly important or crucial for
biodegradable polymer stents for which the vessel wall support is
provided by the polymer. Embodiments are particularly useful for a
biodegradable polymeric stent manufactured from or including a
biodegradable polyester, and especially poly(L-lactide) (PLLA),
poly(L-lactide-co-glycolide) (PLGA), or combinations thereof.
Embodiments are particularly useful for devices, whether
biodegradable polymers, or made from other materials, that are
coated with a coating including a biodegradable polyester, and
especially poly(D,L-lactide) (PDLA).
[0049] Some embodiments of the present invention include methods of
incorporating an antioxidant into an implantable medical device
with a polymeric portion by exposing the device to a fluid
including the antioxidant. As used herein, the word "incorporate"
will be defined as the Merriam-Webster on-line dictionary defines
it that is "to unite or work into something already existent so as
to form an indistinguishable whole." The antioxidant is
incorporated within, on the surface, or both, of a polymeric
portion of the device. The polymeric portion, for example, may be a
coating and/or a scaffolding. The resulting distribution of the
antioxidant is not necessarily uniform throughout or on the
exterior of the device.
[0050] Preferred antioxidants of the present invention are volatile
antioxidants, which are those antioxidants with a vapor pressure of
at least 1 mTorr, or alternatively, those antioxidants having a
sufficient vapor pressure or that sublimate or vaporize
sufficiently such that a concentration of 1 ppm, preferably at
least 5 ppm, and more preferably, at least 10 ppm, may be obtained
where the vapor pressure or concentration is determined at the
temperature at which the device is exposed to the antioxidant.
Volatile antioxidants are preferred as these antioxidants may be
incorporated into a device as a result of exposure of the device to
a vapor or gas including, but not limited to, the antioxidant.
Although examples of antioxidants that are solid at room
temperature may be used, the scope of the present invention is not
so limited. Antioxidants that exist in the liquid or gas phase at
room temperature and one atmosphere may also be used. If the
sublimation or vaporization of the antioxidant is too low, too
little antioxidant may be incorporated into a polymeric portion of
the device. If the sublimation is too high, the antioxidant
incorporated onto or within the device may be lost from the device
prematurely. The determination of too low or too high depends upon
the particular polymer used, and subsequent processing and storage
conditions of the device after the incorporation of the
antioxidant.
[0051] Presently preferred antioxidants are butylated
hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). The
toxicological concerns with BHA and BHT are minimal as BHA and BHT
are commonly used in the food industry. BHA is a relatively
volatile solid with a melting temperature of 45 to 63.degree. C.
BHT can be sublimated at temperatures under its melting point
(70.degree. C.). Other antioxidants may also be used in the methods
of the present invention.
[0052] The fluid including the antioxidant may be a gas, vapor,
supercritical fluid, a liquid, or any combination thereof. The
methods of the present invention differ from adding the antioxidant
to a formulation or materials that are used in manufacturing the
device. In other words, disposing a coating over a device wherein
the coating includes an antioxidant differs because the antioxidant
is added to the device at the same time that part of the device is
formed or manufactured. Therefore, in some embodiments, the fluid
is free of or substantially free of polymer, drug, and/or other
materials (as used herein substantially free is about 10 ppm or
less).
[0053] As used herein, exposure of the device to a gas including an
antioxidant encompasses exposure to a gas, a vapor, a supercritical
fluid, or any combination thereof, that includes an
antioxidant.
[0054] Exposure may occur by placing the device in a chamber or
other enclosed container filled with the gas, or the device may be
placed in a chamber with a continuous flow or semi-continuous flow
of gas through the chamber. For those embodiments using an enclosed
chamber, the gas may be stagnant, or substantially stagnant, or
alternatively a fan or other apparatus may be used to assure that
there is some gas flow or convection.
[0055] Exposure may occur as a result of placing the device in an
environment with a solid that sublimates or a liquid that
evaporates. In some embodiments, the device is placed in a chamber
or container along with the antioxidant, and then subsequently the
entire chamber is heated, for example to 50.degree. C., 60.degree.
C., or 70.degree. C., resulting in sublimation or vaporization of
the antioxidant. The antioxidant concentration in the environment
increases and as a result, the antioxidant is incorporated into the
polymeric portion of the device. The antioxidant that is placed
into the chamber or container may be in a permeable container or
package, in an open dish, or may be provided in any other manner
that allows for sublimation or evaporation of the antioxidant. The
device is exposed for a sufficient time and at sufficient
concentration that the antioxidant is incorporated onto the
device.
[0056] The concentration of antioxidant in the gas may be high
enough to that there is a thermodynamic driving force resulting in
diffusion of the antioxidant into the polymeric portion of the
device and/or adsorption onto the surface of the device. The gas
typically has at least 0.1 ppm of antioxidant and no more than 20%
by volume antioxidant. Embodiments encompass the use of a gas
having an antioxidant concentration of at least 1 ppm, at least 5
ppm, or at least 10 ppm, where the ppm is on a mass basis. Other
embodiments encompass the use of a gas having an antioxidant
concentration of at least 20 ppm, at least 50 ppm, at least 100
ppm, or at least 500 ppm. The concentration of antioxidant may be
determined on a volume basis, and may be not more than 20% by
volume as an upper limit, preferably not more than 15%, and more
preferably not more than 10%. Embodiments of the invention
encompass lower limits of not less than 0.005%, not less than
0.01%, not less than 0.05%, not less than 0.1%, not less than 0.5%,
not less than 1.0%, and not less than 2.0% by volume of antioxidant
in the gas used. In some embodiments, the antioxidant is not less
than 0.001 .mu.g/cm.sup.3, preferably not less than 0.1
.mu.g/cm.sup.3, and more preferably, not less than 1
.mu.g/cm.sup.3.
[0057] The gaseous antioxidant can be absorbed on the surface of
the device through polar-polar interaction to protect the device
from oxidation. It can also acts as a scavenger of the residual
oxygen in the package or container, and block the penetration of
small oxygen molecules into the device. The antioxidant level may
need to be higher if the device already includes the same
antioxidant that is included in the gas to assure that there is a
chemical potential gradient favoring diffusion into the polymeric
portion of the device and/or adsorption onto the surface, rather
than out of the device or desorption.
[0058] Because antioxidants are free radical scavengers, exposure
of the antioxidant to an environment with free radicals may result
in a premature reaction during the incorporation process, thus
reducing the efficiency of the antioxidant incorporated. Therefore,
in some embodiments, the gas may be free of, or substantially free
of, oxygen which may be a factor in free radical formation. As used
herein, substantially free of oxygen refers to not more than 0.01%
by volume oxygen. However, a gas completely free of oxygen may not
be possible. Likewise, the medical device as manufactured in the
atmospheric environment contains surface absorbed oxygen.
Therefore, in some embodiments, some oxygen such as up to about 2%
by volume may be present. The other protective gas present with
oxygen and antioxidant may be nitrogen, helium, argon, or other
gases or fluids that do not assist oxidation.
[0059] In other embodiments, the exposure is to a liquid including
the antioxidant. The liquid chosen should not dissolve the polymer
of the polymeric portion of the device. If the device includes a
drug, the liquid may or may not dissolve the drug. The antioxidant
may be dissolved or dispersed in the liquid, although in preferred
embodiments, the antioxidant is dissolved in the liquid. The liquid
may be an organic liquid, one the chemical composition of which
includes carbon atom(s). In one embodiment, the liquid may not
swell the polymer at all. For PLLA, non-limiting examples of such
liquids are hexane, pentane, cyclohexane, and any combination of
these. In another embodiment, the liquids are those that swell but
do not dissolve the polymer. Liquids for use with PLLA include
isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran and
combinations of these with a solvent in which the PLLA is soluble,
such as without limitation, chloroform and hexafluoroisopropanol
(HFIP). Other representative examples of liquids that may be used
include, but are not limited to isopropanol, methanol, acetone,
1,4-dioxane, tetrahydrofuran (THF), dichloromethane acetonitrile,
dimethyl sulfoxide (DMSO), and dimethylformamide (DMF),
cyclohexane, toluene, xylene, ethyl acetate or combination of these
non-solvents with a solvent in which the PLLA is soluble, such as,
without limitation, chloroform, and hexafluoroisopropanol.
Similarly, if the antioxidant is itself a liquid, it may be applied
to the device without being either dissolved or dispersed in a
liquid or vaporized, provided that the antioxidant does not
dissolve or excessively swell the polymeric portion of the
device.
[0060] In choosing a liquid, the solubility parameter may be used.
The solubility parameter is provided in units of
(cal/cm.sup.3).sup.1/2. Solubility parameters of selected fluids
are shown in Table 1.
TABLE-US-00001 TABLE 1 Solubility parameters of fluids at
25.degree. C. Liquid Solubility Parameter (cal/cm.sup.3).sup.1/2
Chloroform 9.3 Acetone 10.0 Chlorobenzene 9.5 Ethyl acetate 9.1
Ethylene dichloride 9.8 2-ethyhexanol 9.5 1,4-dioxane 9.9
If the solubility parameter of the liquid is equal to that of the
polymer, the polymer will likely swell or dissolve in the liquid.
Dissolution is also a function of the polymer molecular weight. As
the difference between the solubility parameters of the liquid and
the polymer increases, the tendency of the polymer to swell in the
liquid decreases.
[0061] The level of antioxidant in the liquid is not critical, but
needs to be sufficient to at least partially cover the device. If a
solvent that swells the polymer is chosen to dissolve the
antioxidant, the antioxidant may diffuse into the polymeric portion
of the device during the application of antioxidant. The coverage
of the antioxidant on the device surface should be more than 1% of
the surface area. The antioxidant deposition layer should be thin
(<1 .mu.m). In the subsequent drug-coating solution applications
for forming a coating on at least a portion of the outer surface of
the device, the sandwiched antioxidant can diffuse into the polymer
layers in both directions, that is into the polymer of the device
body and into the polymer of the coating.
[0062] The device may be exposed to the liquid by immersing the
device, partially or completely, in the liquid, spraying the liquid
onto the device, brushing or wiping the liquid on the device, or
any combination thereof. The device may be immersed by dipping the
device in a container of the liquid, or placing the device in a
flow through apparatus. The liquid may be agitated in some manner,
or may be stagnant, or substantially stagnant. If the liquid is
sprayed onto the device the liquid may be allowed to evaporate, it
may be wiped off, or liquid removal may use a flow of a gas,
particularly a gas at a temperature above room temperature, over
the surface of the device.
[0063] The exposure may occur at supercritical pressures if a
supercritical fluid is used. The exposure to a gas, not including a
supercritical fluid, or a liquid may occur at or about normal
atmospheric pressure (760 mm Hg), or at pressures below normal
atmospheric pressure.
[0064] The exposure of the device to the fluid may occur at room
temperature, that is about 20.degree. C. to about 25.degree. C., or
at an elevated temperature such as a temperature of at least
30.degree. C., at least 40.degree. C., or at least 50.degree. C. It
is believed that exposure to an elevated temperature will increase
the rate of diffusion of the antioxidant into the polymeric portion
of the device. When exposure is to a gas, elevated temperatures are
preferable as the increased temperature is expected to increase the
diffusion of the antioxidant into the polymeric portion of the
device.
[0065] The exposure to the fluid may range from 1 second to 12
hours or more in duration. In some embodiments, the exposure may be
from about 1 second to about 1 hour, about 30 seconds to about 5
minutes, from about 1 minute to about 15 minutes, from about 10
minutes to about an hour, or about 45 minutes to about 3 hours or
more.
[0066] The exposure may be intermittent. In particular, if the
antioxidant is included in a liquid that is sprayed onto the
device, the liquid may be sprayed onto the device at room
temperature or slightly higher such as 30.degree. C. to 35.degree.
C., and then exposed to flow of gas to remove the liquid which is
at a higher temperature, such as about 40.degree. C. to about
50.degree. C., or even higher. Evaporation of the liquid may leave
some solid antioxidant at the surface of the device. Although some
of the antioxidant may sublime, the increased temperature may
enhance diffusion of the solid antioxidant into the device.
[0067] A liquid may be chosen that plasticizes the polymer. It is
also believed that if the liquid plasticizes the polymer and
decreases the glass transition temperature of the polymer,
diffusion of the antioxidant into the polymer may be enhanced. In
general, diffusion of a substance through a polymer is
significantly higher above the glass transition temperature where
the polymer chains may move more freely as compared to below the
glass transition temperature. However, even below the glass
transition temperature, and particularly within about 10.degree. C.
or about 5.degree. C. of the glass transition temperature, the
diffusion coefficient of a substance should be higher as compared
to temperatures that are much lower, such as 20.degree. C. below
the glass transition temperature. Without being bound by theory, it
is believed that exposing the polymeric portion of the device to a
liquid which is also a plasticizer for the polymer may not only
increase diffusion of antioxidant into the polymeric portion of the
device, but also may help reduce loss of the antioxidant once it
has diffused into the device. If the liquid chosen is one for which
the diffusion is higher than of the antioxidant, the antioxidant
may be effectively "frozen" into the polymer. As the liquid
diffuses out, the plasticizing effect is lost with the result that
the glass transition temperature is increased. The increase in the
glass transition temperature results in a lower diffusion
coefficient for the antioxidant, and thus the antioxidant may be
"frozen" into the polymer.
[0068] For exposure to a gas, or a liquid, the device may be placed
in contact with the gas or liquid including the antioxidant, and
then the temperature of the environment and/or the device is
subsequently raised. In some embodiments, the temperature of the
gas, liquid, and/or device is raised prior to the exposure.
[0069] The antioxidant may be incorporated into the device
nonuniformly. The antioxidant concentration may be higher at or
near the surface if the time frame of exposure is not sufficient to
allow the antioxidant to diffuse throughout the entire polymeric
portion of the device. Thus, in some embodiments, the concentration
of the antioxidant decreases as the distance from the surface
increases. In some embodiments, the antioxidant incorporated into
the device is not present throughout the entire polymeric portion
of the device, such as throughout the thickness of the scaffolding,
or the entire thickness of the coating. In other embodiments, the
antioxidant is incorporated on and/or near the surface, such as
without limitation, the first 5000 .ANG. from the surface. If the
polymeric portion of the device is a coating, the antioxidant may
be incorporated throughout the coating at essentially a uniform
level. It is believed that incorporation of the antioxidant in this
manner, which is with more near and/or at the surface, will reduce
degradation as oxygen is a major factor in degradation, and oxygen
must diffuse into the polymeric portion of the device.
[0070] In some embodiments, the exposure results in a level of at
least 1 .mu.g antioxidant/g of polymer, at least 5 .mu.g
antioxidant/g of polymer, or at least 10 .mu.g antioxidant/g of
polymer. In other embodiments, the exposure results in
incorporation of at least 1 .mu.g antioxidant/g of coating, at
least 5 .mu.g antioxidant/g of coating, or at least 10 .mu.g
antioxidant/g of coating. The level of antioxidant provided may be
sufficient to prevent degradation of the polymer. If the level is
too high, the antioxidant may impact the mechanical properties of
the polymer and or drug release. Also, the level should be within
the range that is toxicologically acceptable, or within the levels
set by regulatory authorities.
[0071] A non-limiting example of exposure to a fluid including an
antioxidant is placing a device in a chamber, removing the air from
the chamber, and filling the chamber with a gas including an
antioxidant. Alternatively, as mentioned above, an antioxidant such
as, without limitation, solid BHT or BHA, may be placed in the
chamber in an open dish or permeable container, the device placed
in the chamber, air or other gasses removed to form a vacuum and
allowing the antioxidant to sublime or evaporate. The temperature
in the chamber may be raised after the device has been placed
inside the chamber, or prior to placing the device and/or
antioxidant into the chamber.
[0072] As used herein, the exposure to a fluid encompassing an
antioxidant refers to an exposure of the device by placing the
device in contact with a fluid including an antioxidant that is
more than an incidental exposure. An incidental exposure is
unlikely to result in incorporation of the antioxidant into the
device, and particularly unlikely to incorporate antioxidant at a
sufficient level to inhibit or limit degradation of the
polymer.
[0073] The methods of the present invention may be integrated into
a manufacturing process for a polymeric stent. The exposure may
occur at any point, or multiple points, in the manufacture. In some
embodiments, the manufacturing scheme involves more than one
exposure to a fluid including an antioxidant, and each exposure may
be to the same, or to a different fluid, and to the same or to a
different antioxidant than previously used. In some cases, the
exposure may be used to replace antioxidant lost in processing as a
result of sublimation or other processes.
[0074] In some embodiments, a polymer tube formed by extrusion may
be exposed to a fluid prior to radial and/or axial expansion and
cutting a stent pattern into the tube such as with a laser to form
a polymeric stent. The exposure may replace antioxidant lost during
the extrusion process and reduce degradation during the subsequent
processes. In another embodiment, the exposure may be after
cutting, but prior to coating. This exposure may occur in addition
to the exposure prior to radial expansion and laser cutting. The
advantage of the exposure prior to coating, and particularly after
cutting a stent pattern and prior to coating is to assure that
antioxidant is incorporated into the polymeric scaffolding to limit
the degradation of the polymer due to sterilization. The subsequent
formation of a coating on the device may increase the time and
difficulty of incorporating antioxidant into the scaffolding of the
device. The device may be additionally exposed to a fluid to
incorporate an antioxidant after the coating has been applied.
[0075] In some manufacturing schema, after cutting, the stent is
washed with an organic fluid that does not dissolve the polymer.
For example, a PLLA stent can be rinsed or washed with isopropanol.
Thus, in some embodiments, the two processing operations may be
combined by adding antioxidant to the isopropanol used in the
washing or rinsing operation. Exposure at these points in the
manufacturing process results in incorporation of the antioxidant
into the polymeric scaffolding, or the device body.
[0076] The exposure may occur after forming a coating on the
polymeric stent, and result in incorporation of the antioxidant
into the coating. In some embodiments, antioxidant may also be
incorporated into the polymeric device body in addition to the
coating. The antioxidant may also incidentally migrate from the
coating into the polymeric device body. The fluid may be the same
as or different from the fluid used in the coating operation.
[0077] As noted above, for the non-limiting example of a PLLA
biodegradable stent, the molecular weight decreased from 400 to
about 300 kg/mol during radial expansion and laser cutting with a
further decrease to 200 kg/mol after sterilization. Exposure prior
to radial expansion and laser cutting, and optionally before and/or
after a coating is formed on the device, may reduce the decrease in
molecular weight in both the device body and the coating that is
due to subsequent processing. In particular, polymer degradation
resulting from sterilization may be reduced. Alternatively and/or
additionally, sterilization may be performed at room temperature,
about 20.degree. C. to about 25.degree. C., rather than
temperatures below room temperature because the antioxidant reduces
or inhibits polymer degradation. As the molecular weight is
critical to the radial strength of the biodegradable stent, any
reduction in molecular weight decrease is likely to improve the
stent performance. The molecular weight of a polymer in the coating
impacts both drug release and biodegradation rates, and therefore,
a reduction in the decrease of the molecular weight of the polymer
in the coating also improves stent performance.
[0078] The polymeric portion of the device that is exposed may
already include an antioxidant. As a non-limiting example, the
polymer used to extrude the tube from which the stent is
manufactured may have antioxidant added during, or prior to, the
extrusion process. Another example, without limitation, is
inclusion of an antioxidant in a coating formulation that is
disposed over at least a portion of the device's outer surface to
form a coating on the device. The antioxidant in the fluid may be
the same as or different from the one already included in the
polymeric portion of the device.
[0079] Antioxidants may be added directly to the polymer forming
the body of the stent, to the coating formulation, and/or to other
polymer used to form a portion of the device. However, addition of
the antioxidant by exposure to a fluid avoids potential changes
that may occur as a result of adding the antioxidant to a
formulation. Non-limiting potential changes include any impact that
the antioxidant may have on polymer crystallization or the
distribution of the drug in the coating. The presence of the
antioxidant may limit the temperatures that may be used in a
process, or may limit the humidity conditions under which a process
may occur. The distribution of solid antioxidant that is added to
solid polymer resin prior to or during extrusion may be
non-uniform. Further, adsorption at the surface of the device
through polar-polar interaction of antioxidants such as BHT may
protect the device from oxidation.
[0080] Although one alternative to the methods of the present
invention is using higher molecular weight polymers as starting
materials, processing with the higher molecular weight materials is
more difficult, and in some cases, not possible.
[0081] In some embodiments, exposure of the device to a fluid
including an antioxidant results in the polymer of the device, as
measured at the end of the manufacturing process, having a weight
average molecular weight that is at least 2%, at least 5%, at least
10%, at least 15%, or at least 20% greater than that of a polymer
of a device body that has not been exposed to such a fluid. In some
embodiments, the result of the exposure is the polymer of the
device body has a weight average molecular weight that is at least
5%, at least 10%, or at least 15% greater after one or more
processing operations such as radial expansion, stent pattern
cutting, or coating. Incorporation of antioxidant by exposure to a
fluid reduces the molecular weight decrease occurring due to
sterilization. In some embodiments, at least 5%, at least 10%, at
least 20% reduction in molecular weight decrease resulting from
sterilization is obtained, as measured by comparing the weight
average molecular weight before and after sterilization.
[0082] Some medical devices also includes drug, either in the body
of the device, distributed in a coating on the device, or in
another polymer forming a portion of the device. Degradation of the
polymer may therefore impact drug release rate. In some
embodiments, the exposure of a device including a drug to a fluid
including an antioxidant assures that the drug release profile is
essentially unchanged by sterilization. In some embodiments, the
release profiles before and after sterilization are similar as
measured by the FDA similarity factor f2 (typically used for
dissolution profiles).
[0083] In the methods described above, although the antioxidant is
added to reduce or inhibit polymer degradation, it may also reduce
or inhibit degradation of other components of the device, such as a
drug, that are subject to degradation by oxidation.
[0084] Other aspects of the present invention are methods of
packaging medical devices, particularly implantable medical
devices, to extend the shelf-life of the packaged device, and kits
of the devices so packaged. Methods of extending shelf-life of
packaged medical device are described in paragraphs [0017]-[0020]
of U.S. Patent Application Publication No. 2007/0020380 A1.
Although these methods are discussed in terms of preventing drug
degradation, these methods may also be used to extend the
shelf-life by reducing the molecular weight degradation of polymers
included in the device. The methods may also be used to prevent or
inhibit polymer degradation during sterilization. The level of
antioxidant required to prevent polymer degradation and to prevent
drug degradation may differ, or may be the same, or may overlap.
Based on the disclosure of U.S. Patent Application Publication No.
2007/0020380 A1 in conjunction with the disclosure herein, one of
skill in the art would be able to determine the appropriate levels
without undue experimentation.
[0085] The device may be placed into a package with a permeable or
porous container including an antioxidant that sublimes to fill the
package. The package may be a Tyvek pouch or the like. The device
may be crimped onto a catheter to form an assembly. The device may
be sterilized before or after placement in the package. With regard
to the packaging methods herein, reference to a device also
encompasses an assembly of a device on a catheter, or other
delivery apparatus.
[0086] In other embodiments, the device may be packaged in a
primary package that is permeable and then placed in a second
impermeable, or substantially impermeable package, with the
antioxidant in the secondary package. As used herein, a
substantially impermeable package refers to one for which the
antioxidant permeation rate is not more than 1 .mu.g/min/m.sup.2.
As used herein, secondary package does not refer to boxes or other
containers in which packaged medical devices are placed for
shipment. Antioxidant may be present in the primary or secondary
package as a solid, gas, or fluid form. Preferably pure solid or
liquid antioxidant is not inserted directly "as is" into the
primary package as it may stick or attach to the device. The
primary and/or secondary package interior may be filled with a gas
or fluid including the antioxidant. The interior of the primary or
secondary package may include antioxidant as a result of placing
antioxidant, whether in solid form or otherwise, into the secondary
package, coating the interior surfaces of the primary and/or
secondary package, and/or the exterior surface of the primary
package with a material including the antioxidant. Antioxidant in
the second package may diffuse through the primary package to
increase the antioxidant level in the primary package. The interior
of the primary package refers to the space inside the primary
package, and the interior of the secondary package refers to the
space within the secondary package, and when the primary package is
placed inside the secondary package, the space between the primary
and secondary package.
[0087] A carrier material including the antioxidant may be placed
in the primary and/or secondary package. A non-limiting example of
such a carrier is a permeable or porous container including the
antioxidant. The carrier may be a porous bead, or a woven material
or absorbent fiber that includes the antioxidant. The carrier may
in the form of a tablet, powder, or granular material which
includes the antioxidant and optionally inert materials. The
carrier may be placed in a permeable container or pouch. A
non-limiting example is a strip of a woven material with
antioxidant adsorbed on the surface, or absorbed within the fibers.
Preferably, the carrier has a high surface area to allow the
antioxidant to sublime. A carrier that is a container may be a
plastic permeable container, or another type of container such as a
sealed permeable pouch.
[0088] In some embodiments, the antioxidant may be part of the
packaging itself, or integrated with or into the packaging, as a
result of absorption or diffusion into the walls or the film or
other material forming the package. In other embodiments, the
antioxidant is integrated with the package as a result of the
inclusion of an inner liner or one or more laminates of a
multi-laminate film having a high level of antioxidant that forms
part of either the primary or the secondary package or both. The
material forming the primary and/or secondary package may be
integrated with an antioxidant because the material itself has a
higher level of antioxidant. In such embodiments, the quantity of
antioxidant present is greater than the amount that is added to
polymer packaging films to inhibit or prevent degradation of the
polymer of the packaging material. The antioxidant level is higher
than the "as received" level typically present in such packaging
material. The higher level may result from specifying a package
with a higher level of antioxidant in the material forming the
package, or the addition of or formation of a liner or layer
including antioxidant at a higher level in the package. The higher
level of antioxidant that is added or integrated with the package
material is a sufficient quantity or level to allow for sublimation
and/or evaporation of the antioxidant into the interior of the
package. Likewise, as used herein with respect to the coating of
the packaging, a "coating" is not a polymer or film of the
packaging that incidentally includes antioxidant to prevent or
inhibit degradation of the polymer of the packaging.
[0089] In those embodiments in which the antioxidant is included in
a coating on the interior or exterior of the package, included in a
liner or laminate of the package, or including in the material
forming the package, the antioxidant may be present at a level of 2
.mu.g/cm.sup.2 to 10 mg mg/cm.sup.2, preferably 10 .mu.g/cm.sup.2
to 5 mg/cm.sup.2, and more preferably 50 .mu.g/cm.sup.2 to 10
mg/cm.sup.2.
[0090] As noted in paragraph [0018] of U.S. Patent Application
Publication No. 2007/0020380 A1, to increase the rate of
sublimation, one may optionally heat the entire packaged device to
a temperature from about 20.degree. C. and, 70.degree. C. for a
short period of time (e.g., about 10 seconds, about 20 seconds,
about 30 seconds, about 40 seconds, about 50 seconds, about 60
seconds, about 90 seconds, or about 120 seconds). Embodiments
encompass temperatures between 20.degree. C. and, 70.degree. C.,
such as without limitation, from about 20.degree. C. to about
30.degree. C., from about 25.degree. C. to about 40.degree. C.,
from about 30.degree. C. to about 50.degree. C., and from about
40.degree. C. about 60.degree. C. The increased temperature for a
short time period allows the antioxidant gas (e.g., BHT gas) to
fill the space of the primary and/or secondary package. A preferred
temperature for a biodegradable polymeric stent and/or coating is a
temperature that is in the neighborhood of the glass transition
temperature of the polymer (e.g. 55.degree. C. for PLLA) but also
high enough that sublimation of the solid occurs at a rate that at
least 10% of antioxidant can be sublimated in 24 hrs.
[0091] A sufficient amount of antioxidant is added to obtain at
least 0.001 ppm of antioxidant and no more than 99% by volume
antioxidant in the interior of the primary and/or secondary package
that is for the fluid of the interior of the primary and/or
secondary package that surrounds the device and/or the primary
package. Embodiments encompass antioxidant concentrations of at
least 0.01 ppm, at least 0.1 ppm, at least 1 ppm, at least 5 ppm,
or at least 10 ppm, where the ppm is on a mass basis in the
interior of the primary and/or secondary package. Embodiments
encompass antioxidant concentrations of at least 0.001
.mu.g/cm.sup.3, at least 0.01 .mu.g/cm.sup.3, at least 0.1
.mu.g/cm.sup.3, at least 1 .mu.g/cm.sup.3, at least 5
.mu.g/cm.sup.3, or at least 10 .mu.g/cm.sup.3 in the interior of
the primary and/or secondary package. The concentration of
antioxidant may be determined on a volume basis, and may be not
more than 30% by volume as an upper limit, preferably not more than
25%, and more preferably not more than 20%. Embodiments of the
invention encompass lower limits of not less than 0.0005%, not less
than 0.001%, not less than 0.005%, not less than 0.01%, not less
than 0.05%, not less than 0.1%, and not less than 0.5% by volume.
The measurement of antioxidant concentration may be made after
exposure to an elevated temperature, or about 30 minutes to about
24 hours after packaging.
[0092] The fluid (such as a gas) filling the packaging,
particularly the primary package, is free of, or essentially free
of, oxygen since oxygen is a known factor increasing the rate of
degradation for many polymers and drugs. Preferably the fluid
filling the primary and secondary packages is an inert gas, such as
without limitation, argon, nitrogen, and/or helium.
[0093] The packaging methods of the present invention may be used
for packaging a device either before or after sterilization. If
packaged prior to sterilization, the polymer of the device so
packaged may have a weight average molecular weight that is at
least 5%, at least 10%, at least 15%, or at least 20% greater than
the polymer sterilized after packaging without the addition of
antioxidant. In some embodiments, the drug release profiles before
and after sterilization for a device packaged with antioxidant are
similar as measured by the FDA similarity factor f2.
[0094] By packaging the device with antioxidant in the package, it
is believed that the antioxidant will react with oxygen that
incidentally permeates or seeps into the package. It will also
react with residual oxygen in the interior of the package, or
absorb on the surface of the device. Thus, the packaging methods of
the present invention extend the shelf-life of the packaged device.
In some embodiments, the shelf-life is increased by at least 1
month, at least 2 months, at least 3 months, or at least 6 months.
In some embodiments, the shelf-life is increased by at least 10%,
at least 25%, or at least 50%. In some embodiments, the polymer of
the device packaged according to the methods of the invention may
have a higher weight average molecular weight at 3 months, at 6
months, at 12 months, or at 24 months, than the polymer of a device
that is not so packaged.
[0095] In some embodiments, packaging a device including a polymer
with an antioxidant in the packaging environment leads to some
incorporation of the antioxidant in the device and/or a polymer of
the device. If the device does not include this particular
antioxidant, diffusion of antioxidant into a polymer of the device
may occur over time. If the device includes the same antioxidant
included in the package, diffusion will occur only if the chemical
potential gradient is sufficient, or that is if the concentration
of the antioxidant in the package is sufficient. Incorporation of
an antioxidant in a device as described above may be accomplished
by placing the device in a sealed container, such as a package,
with antioxidant that sublimates into the gas phase in the
container.
[0096] In other embodiments, packaging the device with antioxidant
is to prevent potential degradation. The antioxidant present in the
package may act as an oxygen scavenger, and thus reduce the
potential degradation resulting from oxygen that does penetrate the
package over time. Thus, in some embodiments, the level of
antioxidant included for methods of packaging may be lower than
those levels used for purposes of incorporating antioxidant into
the device. In some embodiments, the packaging methods may be used
both to protect the device from oxygen that seeps into the package,
or is absorbed on the surface of the device as well as for
incorporation of antioxidant into a polymeric portion of the
device.
[0097] Some embodiments of the present invention include kits
containing an implantable medical device, either as is or crimped
onto a catheter or onto another apparatus for delivery, in any of
the above packaging configurations. The fluid in the interior of
the primary and/or secondary package of the kit may have
antioxidant present at the levels described above.
Antioxidants and Free Radical Scavengers
[0098] As noted above antioxidants are a type of free radical
scavengers. Some representative examples of free radical scavengers
that may be used in the methods of the present invention include,
without limitation, oligomeric or polymeric proanthocyanidins,
polyphenols, polyphosphates, polyazomethine, high sulfate agar
oligomers, chitooligosaccharides obtained by partial chitosan
hydrolysis, polyfunctional oligomeric thioethers with sterically
hindered phenols, hindered amines such as, without limitation,
p-phenylene diamine, trimethyl dihydroquinolones, and alkylated
diphenyl amines, substituted phenolic compounds with one or more
bulky functional groups (hindered phenols) such as tertiary butyl,
arylamines, phosphites, hydroxylamines, and benzofuranones. Also,
aromatic amines such as p-phenylenediamine, diphenylamine, and N,N'
disubstituted p-phenylene diamines may be utilized as free radical
scavengers. Other examples include, without limitation, butylated
hydroxytoluene ("BHT"), butylated hydroxyanisole ("BHA"),
L-ascorbate (Vitamin C), Vitamin E, herbal rosemary, sage extracts,
glutathione, melatonin, carotenes, resveratrol, ethoxyquin,
rosmanol, isorosmanol, rosmaridiphenol, propyl gallate, gallic
acid, caffeic acid, p-coumeric acid, p-hydroxy benzoic acid,
astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid,
ellagic acid, propyl paraben, sinapic acid, daidzin, glycitin,
genistin, daidzein, glycitein, genistein, isoflavones, and
tertbutylhydroquinone. Examples of some phosphites include
di(stearyl)pentaerythritol diphosphite, tris(2,4-di-tert-butyl
phenyl)phosphite, dilauryl thiodipropionate and
bis(2,4-di-tert-butyl phenyl)pentaerythritol diphosphite. Some
examples, without limitation, of hindered phenols include
octadecyl-3,5,di-tert-butyl-4-hydroxy cinnamate,
tetrakis-methylene-3-(3',5'-di-tert-butyl-4-hydroxyphenyl)propionate
methane 2,5-di-tert-butylhydroquinone, ionol, pyrogallol, retinol,
and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate.
Polymers
[0099] The embodiments of the various methods and kits described
herein are applicable to medical devices including any polymer(s).
However, preferred polymers for use with a device include, without
limitation: biodegradable polymers, biodegradable polyanhydrides,
poly(ether-esters), or polyesters such as poly(L-lactide), poly
(D,L-lactide), poly(L-lactide-co-D,L-lactide),
poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(D,L-lactide-co-caprolactone), polyethylene glycol,
polyethylene oxide, other polymers formed from one or more of
L-lactide, D-lactide, meso-lactide, glycolide, and caprolactone,
and combinations thereof, and blends of the aforementioned
polymers. Preferred polymers for a biodegradable scaffolding
include, without limitation, poly(L-lactide) (PLLA), and
poly(L-lactide-co-glycolide) (PLGA) where the mol % lactide varies
from 0 to 100%, such as, without limitation, PLGA with 85% lactide
and 15% glycolide. When reference is made to a polymer having X mol
% of a particular monomer such refers to the mole percent of the
monomer used to form the polymer.
[0100] Representative examples of polymers that may be included in
an implantable medical device, such as without limitation the
device body and/or a coating, include, but are not limited to:
poly(N-acetylglucosamine) (Chitin), Chitosan, polyesters,
biodegradable polyesters, poly(hydroxyvalerate),
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polyorthoesters, polyanhydrides,
poly(glycolic acid), poly(glycolide),
poly(glycolide-co-trimethylene carbonate), poly(caprolactone),
poly(trimethylene carbonate), polyethylene amide, polyethylene
acrylate, poly(glycolic acid-co-trimethylene carbonate),
co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes,
biomolecules (such as fibrin, fibrinogen, cellulose, starch,
collagen and hyaluronic acid), polyurethanes, silicones,
polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin
copolymers, acrylic polymers and copolymers other than
polyacrylates, vinyl halide polymers and copolymers (such as
polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl
ether), polyvinylidene halides (such as polyvinylidene chloride),
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as
polystyrene), polyvinyl esters (such as polyvinyl acetate),
acrylonitrile-styrene copolymers, ABS resins, polyamides (such as
Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes,
polyimides, polyethers, rayon, rayon-triacetate, cellulose,
cellulose acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, carboxymethyl cellulose, and any blends and any copolymers
thereof.
[0101] As used herein, the terms poly(D,L-lactide),
poly(L-lactide), poly(D,L-lactide-co-glycolide), and
poly(L-lactide-co-glycolide) are used interchangeably with the
terms poly(D,L-lactic acid), poly(L-lactic acid), poly(D,L-lactic
acid-co-glycolic acid), and poly(L-lactic acid-co-glycolic acid),
respectively.
Active Agents
[0102] Active agents, or drugs, may optionally be included in the
device. The active agent may be either in the body of the
implantable medical device such as a stent, and/or in a coating on
the device, or in another part of the device. These active agents
can be any agent which is a therapeutic, prophylactic, or a
diagnostic agent, or any agent that is used to treat a disease or
condition. Preferred active agents include, without limitation:
everolimus, sirolimus, biolimus, paclitaxel, or zotarolimus. Other
active agents that may be included in the implantable medical
devices are listed in paragraphs [0029] and [0030] U.S. Patent
Application Publication No. 2007/0020380 A1.
DEFINITIONS
[0103] As used herein, "therapeutic agent," "drug," "active agent,"
"bioactive agent," or "pharmaceutically active agent," which will
be used interchangeably, refers to any substance that, when
administered in a therapeutically effective amount to a patient
suffering from a disease or condition, has a therapeutic beneficial
effect on the health and well-being of the patient. A therapeutic
beneficial effect on the health and well-being of a patient
includes, but is not limited to: (1) curing the disease or
condition; (2) slowing the progress of the disease or condition;
(3) causing the disease or condition to retrogress; or, (4)
alleviating one or more symptoms of the disease or condition.
[0104] As used herein, a drug also includes any substance that when
administered to a patient, known or suspected of being particularly
susceptible to a disease, in a prophylactically effective amount,
has a prophylactic beneficial effect on the health and well-being
of the patient. A prophylactic beneficial effect on the health and
well-being of a patient includes, but is not limited to: (1)
preventing or delaying on-set of the disease or condition in the
first place; (2) maintaining a disease or condition at a
retrogressed level once such level has been achieved by a
therapeutically effective amount of a substance, which may be the
same as or different from the substance used in a prophylactically
effective amount; or, (3) preventing or delaying recurrence of the
disease or condition after a course of treatment with a
therapeutically effective amount of a substance, which may be the
same as or different from the substance used in a prophylactically
effective amount, has concluded.
[0105] As used herein, "therapeutic agent," "drug," "active agent,"
"bioactive agent," or "pharmaceutically active agent," also refers
to pharmaceutically acceptable, pharmacologically active
derivatives of those drugs specifically mentioned herein,
including, but not limited to, salts, esters, amides, prodrugs,
active metabolites, analogs, and the like.
[0106] As used herein when an implantable medical device, such as a
stent, is said to be fabricated from a polymer (polymeric stent or
polymeric device), or the device or device body is composed of a
polymer, or is referred to as a "polymeric stent" or "polymer
stent," it means the body of the device is made from a polymer or a
polymer formulation. Thus, for a "polymeric stent" the body of the
stent may be completely, or substantially completely, a polymer, or
made from a composition including a polymer and other materials
such that the polymer is the continuous phase. The body of the
stent may be at least 50% by weight polymer. In other embodiments,
polymer may be at least 50% by volume of the composition forming
the stent body. Similarly, a tube referred to as a polymeric tube
or a polymer tube may be formed from a polymer or a polymer
formulation, may be completely or substantially completely polymer,
may have a continuous phase of polymer, or may have at least 50% by
weight or at least 50% by volume polymer. Only one criterion needs
to be satisfied.
[0107] As used herein, the terms "biologically degradable" (or
"biodegradable"), "biologically erodable" (or "bioerodable"),
"biologically absorbable" (or "bioabsorbable"), and "biologically
resorbable" (or "bioresorbable"), are used interchangeably, and
refer to polymers, coatings, and materials that are capable of
being completely or substantially completely, degraded, dissolved,
and/or eroded over time when exposed to physiological conditions,
and can be gradually resorbed, absorbed and/or eliminated by the
body, or that can be degraded into fragments that can pass through
the kidney membrane of an animal (e.g., a human). Conversely, a
"biostable" refers to a material that is not biodegradable.
[0108] As used herein, "degradation" of a polymer refers to at
least a decrease in the molecular weight of the polymer, and also
encompasses other undesirable changes such as cross-linking,
discoloration and oxidation, and/or the appearance of other
chemical species. Degradation of the polymer is the result of
physical and chemical processes and is distinguished from
biodegradation that occurs once implanted in the body. Thus, a
biodegradable polymer may "degrade" during polymer processing, and
"biodegrade" when the polymer is implanted in the body. The
mechanisms of degradation in the body, "biodegradation" (hydrolysis
etc.) may be different than the mechanisms of processing
degradation.
EXAMPLES
[0109] The following example is provided to aid in understanding
the invention, but it is to be understood that the invention is not
limited to the particular materials or procedures of the
example.
Example 1
Sublimation of BHT
[0110] A study was performed that demonstrated the sublimation of
BHT. In the first experiment, 100 mg of BHT was weighed in an
aluminum pan and heated in a convection oven at 55.degree. C. At 1
hour and 16 hours after placement in the oven, the pan was removed
and weighed. At the next time point, after leaving the pan in the
oven overnight, no solids were present. A subsequent experiment was
carried out utilizing a temperature of 70.degree. C., and weighted
at time-points of 30 minutes and 1 hr. The melting point of BHT is
70.degree. C. so this temperature was the highest temperature in
the experiments. Additional data was obtained from measurements at
40.degree. C. and 50.degree. C. with weight measurements at
time-points of 1, 4, 7 and 24 hours. The results are illustrated in
FIG. 2 which shows a plot of BHT weight loss vs. time for the
different temperatures. As shown in FIG. 2, it is clear that BHT
sublimation occurred at temperatures under 70.degree. C.
[0111] FIG. 3 is a plot of Ln (BHT/BHT.sub.0) vs. time. A
log-linear profile was observed at 40.degree. C. and 50.degree. C.,
indicating first order sublimation kinetics. No curve fitting was
performed for the data at 55.degree. C. and 70.degree. C. because
there were an insufficient number of data points. Equation 1
represents 1.sup.st order kinetics,
Ln BHT BHT 0 = - kt ( 1 ) ##EQU00001##
where BHT/BHT.sub.0 is the ratio of BHT remained in the pan at time
t and k is the sublimation rate constant at the experimental
temperature. Using equation 1, the half-lives for BHT sublimation
are .about.13 hr at 40.degree. C. and .about.5 hr at 50.degree.
C.
[0112] Based on the curve fitting in FIG. 5, k.sub.40C=0.048 and
k.sub.50C=0.1331. Using the Arrhenius equation shown in Equation
2,
Ln k 2 k 1 = E a R [ T 2 - T 1 T 1 T 2 ] ( 2 ) ##EQU00002##
where R is the gas constant (1.987) and E.sub.a is the sublimation
activation energy, the activation energy for BHT sublimation is
20.5 kcal/mol. The rate constant at other temperatures can be
readily calculated from equations 1 and 2.
[0113] 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 the embodiments of this invention in its broader
aspects and, therefore, the appended claims are to encompass within
their scope all such changes and modifications as fall within the
true spirit and scope of the embodiments of this invention.
* * * * *