U.S. patent number RE45,744 [Application Number 14/074,543] was granted by the patent office on 2015-10-13 for temperature controlled crimping.
This patent grant is currently assigned to ABBOTT CARDIOVASCULAR SYSTEMS INC.. The grantee listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Anthony Abbate, David C. Gale, Bin Huang, Stephen D. Pacetti.
United States Patent |
RE45,744 |
Gale , et al. |
October 13, 2015 |
Temperature controlled crimping
Abstract
This disclosure describes a method for crimping a polymeric
stent onto a catheter for percutaneous transluminal coronary
angioplasty or other intraluminal interventions. The method
comprises crimping the stent onto a catheter when the polymer is at
a target temperature other than ambient temperature. The polymer
can optionally comprise drug(s).
Inventors: |
Gale; David C. (Kennesaw,
GA), Huang; Bin (Pleasanton, CA), Abbate; Anthony
(Santa Clara, CA), Pacetti; Stephen D. (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: |
34620322 |
Appl.
No.: |
14/074,543 |
Filed: |
November 7, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
10725698 |
Dec 1, 2003 |
|
|
|
Reissue of: |
10957022 |
Oct 1, 2004 |
8052912 |
Nov 8, 2011 |
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F
2/958 (20130101); A61L 31/06 (20130101); A61L
31/10 (20130101); B29C 66/73117 (20130101); A61L
31/14 (20130101); B29B 13/024 (20130101); A61L
31/06 (20130101); C08L 67/04 (20130101); A61F
2/9524 (20200501); B29C 66/71 (20130101); B29K
2075/00 (20130101); B29C 66/9121 (20130101); B29K
2027/06 (20130101); B29C 2035/0822 (20130101); Y10T
428/24942 (20150115); Y10T 428/31855 (20150401); B29C
66/919 (20130101); B29C 66/91921 (20130101); B29K
2023/00 (20130101); B29L 2031/7542 (20130101); B29C
66/91641 (20130101); B29K 2033/20 (20130101); B29C
65/76 (20130101); B29K 2001/12 (20130101); B29K
2027/16 (20130101); B29K 2055/02 (20130101); B29C
66/91431 (20130101); B29K 2023/083 (20130101); B29K
2077/00 (20130101); A61F 2/9522 (20200501); B29C
65/56 (20130101); B29K 2033/08 (20130101); B29C
2071/022 (20130101); Y10T 428/31544 (20150401); A61F
2/9526 (20200501); Y10T 29/49865 (20150115); B29K
2001/00 (20130101); B29K 2023/086 (20130101); B29K
2031/00 (20130101); B29K 2027/08 (20130101); B29K
2029/00 (20130101); B29K 2083/00 (20130101); B29C
66/91941 (20130101); B29C 66/91945 (20130101); B29K
2063/00 (20130101); Y10T 428/3154 (20150401); B29C
66/71 (20130101); B29K 2083/00 (20130101); B29C
66/71 (20130101); B29K 2079/08 (20130101); B29C
66/71 (20130101); B29K 2077/00 (20130101); B29C
66/71 (20130101); B29K 2071/00 (20130101); B29C
66/71 (20130101); B29K 2069/00 (20130101); B29C
66/71 (20130101); B29K 2067/04 (20130101); B29C
66/71 (20130101); B29K 2067/00 (20130101); B29C
66/71 (20130101); B29K 2063/00 (20130101); B29C
66/71 (20130101); B29K 2059/00 (20130101); B29C
66/71 (20130101); B29K 2055/02 (20130101); B29C
66/71 (20130101); B29K 2033/20 (20130101); B29C
66/71 (20130101); B29K 2033/12 (20130101); B29C
66/71 (20130101); B29K 2033/08 (20130101); B29C
66/71 (20130101); B29K 2027/16 (20130101); B29C
66/71 (20130101); B29K 2027/08 (20130101); B29C
66/71 (20130101); B29K 2025/08 (20130101); B29C
66/71 (20130101); B29K 2023/18 (20130101); B29C
66/71 (20130101); B29K 2023/086 (20130101); B29C
66/71 (20130101); B29K 2023/083 (20130101); B29C
66/71 (20130101); B29K 2023/08 (20130101); B29C
66/71 (20130101); B29K 2023/00 (20130101) |
Current International
Class: |
A24B
5/00 (20060101); A61L 31/10 (20060101); A61L
31/14 (20060101); B29B 13/02 (20060101); B29C
65/00 (20060101); A61F 2/958 (20130101); A61F
2/95 (20130101); B29C 65/76 (20060101); B29C
65/56 (20060101); B29C 35/08 (20060101); B29C
71/02 (20060101) |
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|
Primary Examiner: McKane; Elizabeth
Attorney, Agent or Firm: Squire Patton Boggs (US) LLP
Parent Case Text
This application is a continuation-in-part of U.S. patent
application Ser. No. 10/725,698, filed on Dec. 1, 2003, the entire
disclosure of which is incorporated by reference.
Claims
What is claimed is:
1. A method of making a medical device comprising: providing a
stent cut from a tubing made of a polymer combination comprising
poly(L-lactide); positioning the stent loosely over a catheter;
.Iadd.and .Iaddend. crimping the positioned stent to secure the
stent to .[.a.]. .Iadd.the .Iaddend.catheter, wherein the crimping
reduces the diameter of the stent.[.,.]..Iadd.; .Iaddend. wherein
the temperature of the stent .[.substrate.]. during the crimping is
.[.at a temperature between 10.degree. C. below.]. .Iadd.less than
.Iaddend.the conventionally measured glass transition temperature
for poly(L-lactide) (Tg) and .[.below.]. .Iadd.greater than or
equal to 10.degree. C. less than .Iaddend.Tg.
2. The method of claim 1, wherein the method further comprises
annealing the stent at a second temperature after securing the
stent to the catheter.
3. The method of claim 1, wherein the temperature is .[.between
5.degree. C. below Tg and below.]. .Iadd.less than Tg and greater
than or equal to 5.degree. C. less than .Iaddend.Tg.
4. The method of claim 1, wherein the temperature of the stent
during crimping is adjusted by thermal contact with a heat
source.
5. The method of claim 1, wherein the crimping comprises applying
radial compression pressure to the stent to reduce the
diameter.
6. The method of claim 1, wherein the temperature is .[.between
2.degree. C. below Tg and below.]. .Iadd.less than Tg and greater
than or equal to 2.degree. C. less than .Iaddend.Tg.
.Iadd.7. The method of claim 1, wherein the polymer combination is
poly(L-lactide). .Iaddend.
.Iadd.8. The method of claim 1, wherein the polymer combination is
selected from a group consisting of: a mixture of more than one
polymer, one polymer, and a copolymerization of more than one
polymer. .Iaddend.
Description
BACKGROUND
Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A surgeon introduces a
catheter assembly having a balloon portion percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The surgeon advances the catheter assembly through the
coronary vasculature until the balloon portion crosses the
occlusive lesion. Once in position, the surgeon inflates the
balloon to radially compress the atherosclerotic plaque of the
lesion and remodel the vessel wall. The surgeon then deflates the
balloon to remove the catheter.
An advance on PTCA involved using an intravascular stent.
Mechanically, stents act as scaffoldings, physically holding open
and, if desired, expanding the vessel wall. Typically, stents
compress for insertion through small vessels and then expand to a
larger diameter once in position. U.S. Pat. No. 4,733,665, issued
to Palmaz; U.S. Pat. No. 4,800,882, issued to Gianturco; and U.S.
Pat. No. 4,886,062, issued to Wiktor disclose examples of PTCA
stents.
Before this procedure can occur, equipment for the procedure must
be manufactured. Stent crimping is a critical step in manufacturing
this equipment in that stent retention depends on it. Generally,
stent crimping is the act of affixing the stent to the delivery
catheter or delivery balloon so that it remains affixed to the
catheter or balloon until the physician desires to deliver the
stent at the treatment site. Current stent crimping technology is
sophisticated. A short time ago, one process used a roll crimper.
This damaged many polymer coatings due to its inherent shearing
action. Next came the collet crimper; in it, metal jaws are mounted
into what is essentially a drill chuck. The jaws move in a purely
radial direction. This movement was not expected to shear the
coating, because it applied forces only normal to the stent
surface. But some stent geometries require that stent struts
scissor together during crimping. In those geometries, even if the
crimper imposes only normal forces, the scissor action of the stent
struts imparts shear. Finally, the iris or sliding-wedge crimper
imparts mostly normal forces with some amount of tangential
shear.
To use a roll crimper, first the stent is slid loosely onto the
balloon portion of the catheter. This assembly is placed between
the plates of the roll crimper. With an automated roll crimper, the
plates come together and apply a specified amount of force. They
then move back and forth a set distance in a direction that is
perpendicular to the catheter. The catheter rolls back and forth
under this motion, and the diameter of the stent is reduced. The
process can be broken down into more than one step, each with its
own level of force, translational distance, and number of cycles.
With regard to a stent with a drug eluting coating, this process
imparts a great deal of shear to the stent in a direction
perpendicular to the catheter or catheter wall. Furthermore, as the
stent is crimped, there is additional relative motion between the
stent surface and the crimping plates. As a result, this crimping
process tends to damage the drug eluting stent coating.
The collet crimper is equally conceptually simple. A standard
drill-chuck collet is equipped with several pie-piece-shaped jaws.
These jaws move in a radial direction as an outer ring is turned.
To use this crimper, a stent is loosely placed onto the balloon
portion of a catheter and inserted in the center space between the
jaws. Turning the outer ring causes the jaws to move inward. An
issue with this device is determining or designing the crimping
endpoint. One scheme is to engineer the jaws so that when they
completely close, they touch and a center hole of a known diameter
remains. Using this approach, turning the collet onto the collet
stops crimps the stent to the known outer diameter. While this
seems ideal, it can lead to problems. Stent struts have a tolerance
on their thickness. Additionally, the process of folding
noncompliant balloons is not exactly reproducible. Consequently,
the collet crimper exerts a different amount of force on each stent
in order to achieve the same final dimension. Unless this force,
and the final crimped diameter, is carefully chosen, the
variability of the stent and balloon dimensions can yield stent
coating or balloon damage.
Furthermore, although the collet jaws move in a radial direction,
they move closer together as they crimp. This action, combined with
the scissoring motion of the struts, imparts tangential shear on
the coatings that can also lead to damage. Lastly, the actual
contact surfaces of the collet crimper are the jaw tips. These
surfaces are quite small, and only form a cylindrical surface at
the final point of crimping. Before that point, the load being
applied to the stent surface is discontinuous.
In the sliding wedge or iris crimper, adjacent pie-piece-shaped
sections move inward and twist, much like the leaves in a camera
aperture. This crimper can be engineered to have two different
types of endpoints. It can stop at a final diameter, or it can
apply a fixed force and allow the final diameter to float. From the
discussion on the collet crimper, there are advantages in applying
a fixed level of force as variabilities in strut and balloon
dimension will not change the crimping force. The sliding wedges
impart primarily normal forces, which are the least damaging to
stent coatings. As the wedges slide over each other, they impart
some tangential force. But the shear damage is frequently equal to
or less than that of the collet crimper. Lastly, the sliding wedge
crimper presents a nearly cylindrical inner surface to the stent,
even as it crimps. This means the crimping loads are distributed
over the entire outer surface of the stent.
All current stent crimping methods were developed for all-metal
stents. Stent metals, such as stainless steel, are durable and can
take abuse. When crimping was too severe, it usually damaged the
underlying balloon, not the stent. But polymeric coatings present
different challenges.
Moreover, as part of polymeric stent manufacture, brittle polymeric
material is laser cut. The polymer's brittle nature and the stress
induced by laser cutting often causes stress cracking in the
polymeric stent.
In the drug eluting stent arena, drugs are commonly placed on the
stent in combination with a polymer or mixed into the polymer for
polymeric stents. This placement typically coats all stent surfaces
or causes the drug to be distributed throughout the polymeric
stent. Then the stent is crimped onto the catheter. In general,
polymer coatings are softer, weaker, and less durable than the
underlying stent material. Upon crimping with a sliding wedge
crimper, and following crimp protocols for the particular stent,
coating damage is frequently seen. FIGS. 1 and 2 show an Elasteon
80A (a polyurethane) coating on poly(ethylene-co-vinyl alcohol)
(EVAL) after crimp, grip, and the wet expansion test.
Grip is a process conducted after crimping to further increase
stent retention. An outer sleeve restrains the crimped stent.
Simultaneously, pressure and heat are applied to the stent-balloon
section. Under this action, the balloon material deforms slightly,
moving in between the struts. In a wet expansion test, the final
stent-on-catheter assembly is immersed in deionized water at
37.degree. C. for 30 seconds. Then the balloon is inflated
according to the device instructions to at least a nominal pressure
(8 atmospheres). After holding this pressure for 30 seconds, the
balloon is deflated, and the stent slides off. After drying, the
stent can be examined by optical microscopy or scanning electron
microscopy for coating damage.
The primary purpose of the polymer in the stent coating is to
contain the drug and control its release at a desired rate. Other
obvious specifications for the polymer are a high level of vascular
biocompatibility and the ability to flex and elongate to
accommodate stent expansion without cracking or peeling. Meeting
all of these objectives, while also possessing a high level of
toughness and strength to withstand conventional crimping process,
can be challenging.
A crimping process that minimizes damage to the polymer coatings of
stents is needed. Moreover, a crimping process that minimizes
internal stress or strain in the polymeric substrate of a polymeric
stent is also needed.
SUMMARY
The current invention comprises several embodiments, some of which
relate to extracorporeal methods of making medical devices or
implantable medical devices. These devices can comprise portions
with coatings. In some embodiments, the coating comprises a polymer
or polymer combination or drug(s). The piece comprising the coating
is crimped onto another part of the device or onto a separate
device. In some embodiments, crimping is done at non-ambient
temperatures. Sometimes non-ambient-temperature crimping comprises
changing the temperatures of the coating, the piece comprising the
coating, the medical device, the crimping device, or any
combination of these. Likewise, medical devices made using these
methods and devices for implementing these methods are also part of
this invention. In some embodiments the medical device is or
comprise a stent.
Specific heating and cooling profiles are used in different
invention embodiments. For instance, embodiments of crimping
methods include adjusting the temperature of the coating to a
target temperature followed by a crimping step; adjusting the
temperature of the coating to a target temperature during a
crimping step; adjusting the temperature of the coating to a target
temperature and maintaining the temperature of the coating within
plus or minus 5.degree. C. of the target temperature during a
crimping step; adjusting the temperature of the coating to a target
temperature followed by crimping such that the temperature of the
coating remains within plus or minus 10.degree. C. of the target
temperature during a crimping step; and adjusting the temperature
of the coating to a temperature other than ambient towards a target
temperature and continuing to adjust the temperature of the coating
towards the target temperature during a crimping step.
Alternatively, the temperature of the coating can first be adjusted
to a target temperature with the crimper jaws then closing. After
that, the temperature can be adjusted to a second temperature,
followed by opening the crimper jaws.
Embodiments in which the target temperature takes values based on
Tg and intervals around Tg are described, with the goal of some
embodiments being to simultaneously minimize deformation- and
delamination-based failure during crimping. In some embodiments,
the target temperature ultimately depends on the predominate
failure mode of the polymer coating, Tg of the coating, shore D
hardness of the polymer coating at ambient temperature, and shore
hardness of the polymer coating at the target temperature, among
other factors.
In some embodiments, invention methods relate to making medical
devices comprising at least one piece wherein the piece can
comprise a polymer or polymer combination. In some embodiments, the
piece comprises a polymer or polymer combination and drug(s). A
typical method comprises choosing a target temperature based on the
mechanical behavior of the polymeric material, sometimes the
behavior during crimping. The method further comprises juxtaposing
the closing of the crimping jaws with adjusting the temperature of
the piece in any combination. For instance, the following heating
regimes are practical: adjusting the temperature of the piece to a
target temperature followed by a crimping step; adjusting the
temperature of the piece to a target temperature during a crimping
step; adjusting the temperature of the piece to a target
temperature and maintaining that temperature within plus or minus
5.degree. C. of the target temperature during a crimping step;
adjusting the temperature of the piece to a target temperature
followed by crimping such that the temperature of the piece remains
within plus or minus 10.degree. C. of the target temperature during
the crimping step; and adjusting the temperature of the piece to a
temperature other than ambient towards a target temperature and
continuing to adjust the temperature of the piece towards the
target temperature during a crimping step. Any of these regimes can
optionally be coupled with continued heating for a time after
crimping--either while crimping pressure is applied or after
pressure is removed.
In these embodiments or others the heating regime can comprise
closing the crimper, adjusting the temperature of the piece to a
second temperature, and opening the crimper wherein the second
temperature is greater than or less than the target temperature.
Some medical devices further comprise a catheter. In those devices,
the crimping step of invention methods can be used to attach the
piece to the catheter.
Invention methods can be used on a variety of polymeric materials
including those characterized as having Tg above ambient
temperature. In some embodiments the methods act on polymeric
materials comprising ABS resins; acrylic polymers and acrylic
copolymers; acrylonitrile-styrene copolymers; alkyd resins;
biomolecules; cellulose ethers; celluloses; copoly(ether-esters);
copolymers of polycarboxylic acids and poly-hydroxycarboxylic
acids; copolymers of vinyl monomers with each other and olefins;
cyanoacrylates; epoxy resins; ethylene vinyl alcohol copolymers;
ethylene-methyl methacrylate copolymers; ethylene-vinyl acetate
copolymers; ethylene-.alpha.-olefin copolymers; poly(amino acids);
poly(anhydrides); poly(butyl methacrylates); poly(ester amides);
poly(ester-urethanes); poly(ether-urethanes); poly(imino
carbonates); poly(orthoesters); poly(silicone-urethanes);
poly(tyrosine arylates); poly(tyrosine-derived carbonates);
polyacrylates; polyacrylic acid; polyacrylic acids;
polyacrylonitrile; polyacrylonitrile; polyalkylene oxalates;
polyamides; polyamino acids; polyanhydrides; polycarbonates;
polyearboxylic acids; polycyanoacrylates; polyesters; polyethers;
poly-hydroxycarboxylic acids; polyimides; polyisobutylene and
ethylene-.alpha.-olefin copolymers; polyketones; polymethacrylates;
polyolefins; polyorthoesters; polyoxymethylenes; polyphosphazenes;
polyphosphoesters; polyphosphoester urethanes; polyphosphoesters;
polyphosphoestersurethane; polyurethanes; polyvinyl aromatics;
polyvinyl esters; polyvinyl ethers; polyvinyl ketones;
polyvinylidene halides; silicones; starches; vinyl copolymers
vinyl-olefin copolymers; and vinyl halide polymers and copolymers.
Some embodiments select the group of polymers to specifically
exclude any one of or any combination of the polymers listed
above.
Specific examples of useful polymers for some embodiments include
the following polymers: starch, sodium alginate, rayon-triacetate,
rayon, polyvinylidene fluoride, polyvinylidene chloride, polyvinyl
pyrrolidone, polyvinyl methyl ether, polyvinyl chloride, polyvinyl
acetate, polystyrene, polyisocyanate, polyisobutylene, polyethylene
glycol, polydioxanone, polycaprolactone, polycaprolactam, KYNAR
(brand poly(vinylidene fluoride) available from Atofina),
polyacrylonitrile, poly(trimethylene carbonate), poly(L-lactic
acid), poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(hydroxybutyrate-co-valerate),
poly(hydroxybutyrate-co-hydroxyvalerate), poly(hydroxybutyrate),
poly(glycolide), poly(glycolic acid),
poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide),
poly(D,L-lactide), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate), poly(3-hydroxy valerate), Nylon 66,
hyaluronic acid, fibrinogen, fibrin, elastin-collagen, collagen,
cellulose propionate, cellulose nitrate, cellulose butyrate,
cellulose acetate butyrate, cellulose acetate, cellulose,
cellophane, carboxymethyl cellulose, or poly(2-hydroxyethyl
methacrylate), Chitin, Chitosan, EVAL, poly(butyl methacrylate),
poly(D,L-lactic acid), poly(D,L-lactide), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(iminocarbonate),
poly(lactide-co-glycolide), poly(L-lactic acid),
poly(N-acetylglucosamine), poly(trimethylene carbonate), poly(vinyl
chloride), poly(vinyl fluoride), poly(vinylidene chloride),
poly(vinylidene fluoride), poly(vinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinylidene
fluoride-co-hexafluoropropene), polyanhydride, polyorthoester,
polyurethane, polyvinyl alcohol, polyvinyl chloride, rayon, SOLEF
21508 (formulation available from Solvay Solexis), and PEO/PLA.
Some embodiments select the group of polymers to specifically
exclude any one of or any combination of the polymers listed
above.
Some invention methods operate on drug-containing pieces. In some
of these embodiments, the drugs are selected from the following
types: antiproliferative, antineoplastic, antiinflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,
antibiotic, antioxidants, or their combinations.
The target temperature can be chosen in a number of ways. For
instance, the target temperature can be within or above the range
defined by definition 1, definition 2, definition 3, definition 4,
definition 5, definition 6, or definition 7 of the Tg range of the
polymer or polymer combination; above ambient temperature; above
room temperature; between ambient temperature and upper Tg of the
Tg range; between ambient temperature and lower Tg of the Tg range;
between -40.degree. C. and upper Tg of the Tg range; between
-40.degree. C. and lower Tg of the Tg range; between -40.degree. C.
and ambient temperature; at or above 60.degree. C.; between
60.degree. C. and upper Tg of the Tg range; between 60.degree. C.
and lower Tg of the Tg range; or between 60.degree. C. and ambient
temperature.
Some invention embodiments choose the target temperature to avoid
ambient temperature or a window around ambient temperature. Other
embodiments choose the target temperature such that therapeutic
agents present in the coating avoid substantial decomposition.
In some embodiments, target temperature is selected from a group
that specifically excludes any one or any combination of the
temperature range is described above.
Some invention embodiments choose the target temperature to
simultaneously minimize deformation- and delamination-based failure
during crimping. Some invention embodiments choose the target
temperature to yield an improvement in shore hardness.
The annealing temperature can be selected from any of the
temperature's described above for the target temperature. Moreover,
in some embodiments, annealing temperature is selected from a group
that specifically excludes any one or any combination of the
temperature ranges described above.
Different invention embodiments use a variety of methods for
achieving the temperature adjustment of the polymeric material. For
instance, the following ways of changing the temperature are all
within the scope of the current invention: contacting the polymeric
material or piece with a heat source. directing a heated gas at the
polymeric material or piece; placing the polymeric material or
piece near a heated surface for emitting thermal or infrared
radiation to the coating or coated piece; placing the polymeric
material or polymeric material or piece near a heated surface to
enable convection to the coating or coated piece from the surface;
heating the jaws of the crimper and thermally contacting the
polymeric material or piece with the crimper jaws; for crimper jaws
that allow the passage of infrared radiation, bathing the stent on
catheter with infrared radiation; heating the stent on catheter in
an incubator or oven to pre-equilibrate the stent on catheter to
the desired temperature before crimping.
For some invention devices useful in practicing invention methods,
the heat source is integrated with a crimping device. In some
embodiments, the piece is selected from self-expandable stents,
balloon-expandable stents, and stent-grafts.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 shows a coating as prepared in Example 1, which is an
Elasteon 80A coating on EVAL after crimp, grip, and the wet
expansion test.
FIG. 2 shows another coating as prepared in Example 1, which is
Elasteon 80A coating on EVAL after crimp, grip, and the wet
expansion test.
FIG. 3 shows a topcoat of Solef 21508 on EVAL made using the
procedures of Example 3.
FIG. 4 shows another topcoat of Solef 21508 on EVAL, also made
using the procedures of Example 3.
FIG. 5 shows the tensile stress at yield of polypropylene as a
function of temperature.
FIG. 6 shows how the stress-strain curve of a thermoplastic polymer
changes with temperature.
FIG. 7 plots heat capacity versus temperature for a typical
thermoplastic polymer.
FIG. 8 shows a stent-delivery device combination, in
cross-section.
FIG. 9 shows a polymeric stent after heat crimping.
FIG. 10 shows the polymeric stent of Ex. 3 after heat crimping.
DETAILED DESCRIPTION
This document incorporates by this reference the entire disclosure
of U.S. patent application Ser. No. 10/725,698, filed on Dec. 1,
2003.
FIGS. 1 and 2 show that the coating on the outer surface of the
stent, in one case, has been pinched or wrinkled over, while in the
other, has been smeared off. Similarly, FIGS. 3 and 4 show a
topcoat of Solef 21508 on EVAL. Solef 21508 is the softest
poly(hexafluoropropene-co-vinylidene fluoride) thermoplastic
polymer commercially available.
FIGS. 3 and 4 show dents in the high spots of the strut arms. Most
high spots of these two stents show similar damage. For these
reasons, polymer coatings made of lower durometer (80A for example)
polymers frequently fail quality assurance tests. EVAL, a hard
plastic, seems to hold up to standard crimping, but it has a
hardness of 85 shore D. For comparison, the low-density
polyethylene used in milk containers is 47-55 shore D.
Some embodiments of this invention are directed at stents
containing a substrate material that is polymeric in nature and
methods of manufacturing those stents. Some methods pertain to
crimping the stent to the delivery device or balloon.
In some embodiments, crimping is done at a temperature greater than
Tg; in some embodiments, crimping is done at a temperature greater
than ambient but not necessarily greater than Tg. A device for
crimping the polymeric stent onto the delivery device is also
contemplated as an invention embodiment. The device can resemble
any crimping device as is known in the art or in this document.
Additionally, the device is especially modified so that it can heat
the stent during crimping. In some embodiments, the device can
apply pressure and heat simultaneously. In these or other
embodiments, after crimping, the crimping device can hold the stent
at an elevated temperature, which may be selected such that it is
greater than, equal to, or less than the target temperature or may
be selected to specifically exclude temperatures greater than,
equal to, or less than the target temperature. In some embodiments,
the device crimps the polymeric stent while the stent is heated by
other means.
In some embodiments, the crimping method comprises: placing the
stent in the crimping device; heating the stent to a target
temperature long enough that the stent substantially reaches the
target temperature; applying pressure (radial compression pressure)
to the stent to attach it to a delivery device; holding the stent
at a radial compression pressure adequate to affix it to the
delivery device and holding the stent at an annealing temperature
for a time sufficient to set the crimp state into the polymeric
stent or coating; removing the stent-delivery-device
combination.
The stent can be heated for up to one hour, 30 seconds to one hour,
or for 30 seconds. In some embodiments, the stent is heated long
enough that the material becomes ductile enough to adequately lower
the brittleness of the stent. Adequate means having a value for the
parameter in question such that one of ordinary skill in the art
would expect the invention to function in the particular
application. For example, "adequately lower the brittleness of the
stent" means that the brittleness of the stent is reduced enough to
warrant the extra heating step and the extra cost and complication
of the heating step, as viewed by one of ordinary skill in the
art.
In some embodiments the radial compression pressure is chosen so
that no damage to the stent or coating occurs. In some embodiments,
the radial compression pressure is chosen so that any damage or
deformation that occurs is insufficient to cause one of ordinary
skill in the art to reject the stent for use.
In the forgoing embodiments or others, variable temperature means a
temperature above ambient. In these or other embodiments, it means
a temperature equal to, above or below Tg of the material. In some
embodiments, variable temperature means a temperature equal to or
below ambient. In some embodiments, the stent is cooled to ambient
temperature or below before the radial compression pressure is
removed.
In the forgoing embodiments or others, a time sufficient to set the
crimp state is any time long enough that the polymeric stent or
coating has substantially assumed the new shape induced by crimping
such that it substantially retain this shape until the stent is
implanted. In these or other embodiments, this time is 1 second to
2 hours, 2 seconds to 1 hour, 3 seconds to 30 minutes, 4 sec to 5
minutes; 1 second to 5 minutes, 2 seconds to 5 minutes, or 3
seconds to 5 minutes.
This procedure is believed to provide the polymer chains with
increased mobility and such that they relax into a lower energy
(less stressed) configuration. Using this procedure results in
polymeric stents with significantly fewer cracks.
In a separate production step, polymeric stents are sometimes
sterilized with e-beam radiation. E-beam sterilization frequently
exhibits higher polymer degradation rates at high stress regions in
the polymer (stent). But after the heat crimping of this invention,
which relieves extrusion and laser-cutting-induced stress and
strain, e-beam sterilization of treated stents results in
significantly fewer cracks and exhibits less pronounced polymer
degradation rates at high stress regions in the polymer.
A crimp process in which the coated stent or polymeric stent is
held at a target temperature, which may be different from ambient,
is disclosed. Temperatures above ambient can be used in cases where
the Tg is above ambient or room temperature and greater ductility
is desired. For purposes of this disclosure, ambient temperature is
the temperature of the crimper or polymer when the crimper or
polymer has not been purposely heated or cooled. Typically, this
temperature will be close to room temperature or the temperature
surrounding the crimping equipment or the polymer. Similarly, for
purposes of this disclosure, a target temperature is a temperature
numerically different from ambient temperature brought about by
purposely heating or cooling the crimper, stent, balloon, polymer,
or any combination of these. For purposes of this disclosure,
"polymer", "polymer combination" and "polymer mixture" are
synonymous, meaning a composition of one polymer or, when more than
one polymer, a mixture of, a blend of, a copolymerization of, or
any other combination of more than one polymer. The combination can
occur after the polymers are polymerized or can occur during the
polymerization of monomer into one or more polymers.
TABLE-US-00001 Durometer Temperature Temperature Hardness Range for
Range Polymer Tg .degree. C. Shore D Greater Hardness for Ductility
Solef 21508 -29 60 -62 to 10 Ambient to 60 Elasteon 80A -100, 0
30-35 -110 to -10 Ambient to 60 Elasteon 55D -100, 0 55 -110 to -10
Ambient to 60 EVAL-E151 55 85 Zero to Ambient 50 to 100 Kynar-Flex
-30 65-70 -62 to 10 Ambient to 60 2800 Butvar B-90 72-78 85-90 Zero
to Ambient Ambient to 100 Kynar 710 -30 76-80 -62 to 10 Ambient to
60 Poly(n-butyl 20 NA -30 to 15 Ambient to 60 methacrylate)
A representative method includes heating a polymer on a medical
device to or towards a target temperature. Next, either after the
target temperature has been reached or while the polymer is
changing temperature towards the target temperature, the portion of
the medial device containing the polymer is crimped onto another
portion of the medical device or onto another medical device.
Crimping is done in a temperature region designed to minimize both
cohesive and adhesive failure (or deformation- and
delamination-based failure) caused by local pressure from the jaws
or surfaces of the crimping device, and deformation of the stent
caused by reducing its diameter. For instance, a stent can be
heated with a stream of air and crimped onto a delivery catheter
with an iris crimper. Moreover, in some embodiments, the
temperature region is chosen so that internal stress in the
polymeric stent or polymer coating diminishes over time after
crimping.
Heating is generically discussed as "adjusting" the temperature of
the polymer, the crimper, or the medical device. Adjusting the
temperature comprises placing the object that is to have its
temperature adjusted into thermal contact with a heat source. For
purposes of this disclosure, thermal contact with a heat source
means heat source arrangement vis-a-vis the object so that energy
would flow or be carried from the heat source to the object.
Thermal contact is a generic term at least encompassing an
arrangement of the object such that radiation, conduction, or
convection from the heat source would transfer energy. In some
embodiments, thermal contact is defined to exclude any of
radiation, conduction, convection, or any combination of these.
Different invention embodiments employ different heating profiles.
For instance, when the heating profile calls for softening the
polymer by choosing a target temperature above some temperature
value, the polymer is adjusted to the target temperature before
crimping and then crimping occurs (with or without some amount of
temperature decrease before crimping); alternatively, the polymer
is adjusted to the target temperature before crimping and
maintained at or near the target temperature during crimping;
alternatively, crimping is started, the polymer is adjusted to the
target temperature, and crimping is completed. For purposes of this
disclosure, "maintained near the target temperature" means that the
temperature of the polymer at the instant of contact with the
crimper is the target temperature plus or minus 20.degree. C.,
15.degree. C., 10.degree. C., 5.degree. C., 2.degree. C. or
1.degree. C. In some embodiments, "maintained near the target
temperature" means that the temperature of the polymer at the
instant of contact with the crimper is the target temperature plus
or minus 10.degree. C.
Polymers on crimped stents or crimped polymeric stents exhibit
adhesive and cohesive failure as two main failure modes. In
adhesive failure, polymer is sheared off the stent due to poor
adhesion to the metal stent or between the polymer molecules in a
polymeric stent. This is a failure of the polymer due to poor
interaction between polymer molecules. Since at higher
temperatures, particularly those above Tg, polymeric materials are
softer, a higher temperature crimp process should assist in
preventing adhesive failure. Adhesive failure is sometimes referred
to as an adhesive-based failure or delamination-based failure. When
a polymer exhibits adhesive failure, that polymer becomes a
candidate for crimping above Tg of the polymer. Adhesive failure is
also caused by a build-up of stress. Heating the polymer above its
Tg lowers its modulus and decreases the internal stress within the
polymer. When stents are crimped, whether polymer coated or
substantially polymeric, certain portions of the stent undergo
elongation. If too much elongation occurs, the polymer will crack.
The ultimate elongation of polymers depends on the temperature, and
heating the polymer above its Tg can increase the ultimate
elongation, thereby preventing failure. If the polymer exhibits a
cohesive failure due to insufficient elongation, it is also a
candidate for crimping above the Tg of the polymer.
In some embodiments, after crimping, the polymer is then heated to
set, anneal or otherwise remove internal stresses caused by
mechanically stressing the polymer during assembly of the medical
device. In some embodiments, the polymer is heated to an annealing
temperature.
FIG. 5 shows tensile stress at yield of polypropylene as a function
of temperature. This property is not the same as hardness, but
correlates with it. Both involve the stress needed to permanently
deform the polymer. For thermoplastics in general, a lower
temperature leads to greater hardness. FIG. 6 shows how a
thermoplastic's stress-strain curve changes with temperature.
For some embodiments of this invention, the target temperature is
selected in relation to Tg of the polymer. Tg is the temperature at
which the amorphous domains of a polymer change from a brittle
vitreous state to a plastic state at atmospheric pressure. In other
words, Tg corresponds to the temperature where the onset of
segmental motion in the chains of the polymer occurs, and it is
discernible in a heat-capacity-versus-temperature graph for a
polymer, as is depicted in FIG. 7. When an amorphous or
semicrystalline polymer is heated, its coefficient of expansion and
heat capacity both increase as the temperature rises, indicating
increased molecular motion. As the temperature rises, the sample's
actual molecular volume remains constant. Therefore, a higher
coefficient of expansion points to a free volume increase of the
system and increased freedom of movement for the molecules. The
increasing heat capacity corresponds to increasing 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. Furthermore,
polymer chemical structure heavily influences Tg by affecting
polymer mobility. Generally, flexible main-chain components lower
Tg and bulky side groups raise Tg. Similarly, increasing
flexible-side-group length lowers Tg and increasing main-chain
polarity increases Tg. Additionally, the presence of crosslinks can
increase the observed Tg for a given polymer, and the presence of a
drug or therapeutic agent can alter the Tg of a polymer due to
plasticization effects. The magnitude of these plasticization
effects depends on the miscibility and compatibility of the drug
and polymer and the loading of drug in the polymer.
By way of illustration, when a semicrystalline polymer is heated,
the polymer crystallinity begins to increase as temperature reaches
Tg. At or above Tg, the increased molecular motion allows the
polymer chains to adopt a more thermodynamically stable
relationship, and thereby increases polymer crystallinity. In FIG.
7, Tg is shown on the first curve, 60, which is the temperature at
which half of the increase in heat capacity has occurred. The
crystallinity then increases rapidly after Tg and reaches a maximum
at Tc (the apex of second curve, 62).
As can be seen in FIG. 7, Tg is somewhat arbitrarily placed on the
temperature versus heat capacity curve. For purposes of this
disclosure, the Tg range is defined in several different ways for a
polymer or polymer combination. Some invention embodiments can be
predicated on any one of these Tg range definitions.
Tg Range Definition 1
For this definition, Tg range is greater than or equal to the
initial point on the polymer's (or polymer combination's)
temperature-versus-heat-capacity curve showing a drop in heat
capacity, indicated as Tg1 (100) on FIG. 7 (this point is defined
as lower Tg for definition 1). Tg range is less than or equal to Tc
(110) on the curve in FIG. 7 (this point is defined as upper Tg for
definition 1). This Tg range is referred to in this disclosure as
Tg range definition 1. Those of ordinary skill in the art recognize
that the specific curvature and temperature points in FIG. 7 depend
upon the nature of the polymer or polymer combination. Therefore,
the indication of a point on FIG. 7 is meant to communicate a point
corresponding to the FIG. 7 point on a similar graph for the
particular polymer or polymer combination being used.
A target temperature is within Tg range definition 1 if it is above
or equal to Tg1 and below or equal to Tg2. A target temperature is
below Tg range definition 1 if it is below or equal to Tg2. A
target temperature is above Tg range definition 1 if it is above or
equal to Tg1. A target temperature is between a higher temperature
and a lower temperature if it is above or equal to the lower
temperature and below or equal to the higher temperature. These
concepts hold for all temperatures and ranges throughout this
disclosure.
Tg Range Definition 2
For this definition, the Tg range is greater than or equal to the
point Tg1 (100) on FIG. 7 (lower Tg for definition 2) and less than
or equal to point 140 on FIG. 7 (upper Tg for definition 2). This
range is referred to in this disclosure as Tg range definition 2.
Point 140 corresponds to the onset of the crystallization phase
transition for the material.
Tg Range Definitions 3, 4, 5, and 6
For definition 3, the Tg range is the conventionally measured Tg
(180) for the polymer (or combination) plus 40.degree. C. (upper Tg
for definition 3) and minus 40.degree. C. (lower Tg for definition
3).
For definition 4, the Tg range is the conventionally measured Tg
for the polymer (or combination) plus 20.degree. C. (upper Tg for
definition 4) and -20.degree. C. (lower Tg for definition 4).
For definition 5, the Tg range is the conventionally measured Tg
for the polymer (or combination) plus 10.degree. C. (upper Tg for
definition 5) and minus 10.degree. C. (lower Tg for definition
5).
For definition 6, the Tg range is the conventionally measured Tg
for the polymer (or combination) plus 5.degree. C. (upper Tg for
definition 6) and minus 5.degree. C. (lower Tg for definition
6).
Tg Range Definition 7
For this definition, the Tg range is greater than or equal to the
point Tg1 (100) on FIG. 7 (lower Tg for definition 7) and less than
or equal to point 160 on FIG. 7 (upper Tg for definition 7). This
range is referred to in this disclosure as Tg range definition 7.
Point 160 corresponds to the tail off or end of the glass phase
transition for the material.
These embodiments also include embodiments in which the Tg range
specifically excludes ambient temperature, ambient temperature + or
-1.degree. C. or ambient temperature + or -5.degree. C. Also, in
some embodiments the target temperature has a maximum at or below
the temperature at which any included therapeutic agents
substantially decompose. For purposes of this disclosure,
"substantially decompose" means decomposition to the extent that
one of ordinary skill in the art would conclude that the
decomposition would reduce the efficacy of the therapeutic
substance too much. In other words, decomposition would reduce the
efficacy enough that one of ordinary skill in the art would reject
the heated or cooled, crimped composition for use in vivo.
Based on the shore hardness of the polymer or the failure mode of
the coating or polymer, several embodiments can be described. For
polymers that are too soft, that exhibit cohesive or deformation
failures, that have Tg below ambient or room temperature, or that
have a shore hardness of shore 60A to 80D (alternatively, shore 80A
to 60D), the polymer can be improved by causing the polymer to be
harder during crimping. This can be accomplished by choosing a
target temperature less than upper Tg. (When this disclosure speaks
of upper Tg or lower Tg, but does not specify which definition of
Tg range is being used, this disclosure is intended to cover upper
and lower Tg for each range definition). Alternatively, the polymer
can be hardened during crimping by choosing a target temperature
below lower Tg. Alternatively, choosing a target temperature below
ambient temperature can harden the polymer. Alternatively, choosing
a target temperature below -30.degree. C., -40.degree. C.,
-50.degree. C., or -60.degree. C. can harden the polymer. In some
embodiments, the target temperature is between ambient temperature
and upper Tg; ambient temperature and lower Tg; or -30.degree. C.,
-40.degree. C., -50.degree. C., or -60.degree. C. and upper Tg;
-30.degree. C., -40.degree. C., 50.degree. C., or -60.degree. C.
and lower Tg; or -30.degree. C., -40.degree. C., -50.degree. C., or
-60.degree. C. and ambient temperature.
In addition to choosing the target temperature based on the Tg
range definitions discussed above, various embodiments can be
described otherwise. For polymers that are too soft, that exhibit
cohesive or deformation failures, that have Tg below ambient or
room temperature, or that have a shore hardness of shore 60A to 80D
(alternatively, shore 80A to 60D), the polymer can be improved by
causing the polymer to be harder during crimping. Therefore, an
improvement in cohesive or deformation failures can be achieved by
choosing a target temperature that yields a 50% increase in shore
hardness, alternatively, a 40%, 30%, 20%, or 10% increase in shore
hardness.
Medical devices that use polymers with shore hardness of shore 60A
to 60D frequently experience cohesive failure during crimping.
Invention medical devices prepared with invention crimping methods
allow the use of polymers with shore D hardness as low as 30 to 80,
or 35 to 60. Alternatively, invention medical devices prepared with
invention crimping methods allow the use of polymers with shore D
hardness less than or equal to 45, 40, 35, or 30.
For polymers that are too hard, that exhibit adhesive failures,
have insufficient elongation, or that have Tg above ambient or room
temperature, or that have a shore hardness of 60D to 95D
(alternatively, 65D to 90D), the polymer can be improved by causing
the polymer to be softer during crimping or by maintaining an
increased temperature in the polymer after crimping to relieve any
stress. This can be accomplished by choosing a target temperature
greater than upper Tg. Alternatively, the target temperature is
above lower Tg. Alternatively, the target temperature is above
ambient temperature. Alternatively, the target temperature is above
70.degree. C., 80.degree. C., 90.degree. C., or 100.degree. C. In
some embodiments, the target temperature is between ambient
temperature and upper Tg; ambient temperature and lower Tg; between
70.degree. C., 80.degree. C., 90.degree. C., or 100.degree. C. and
upper Tg; between 70.degree. C., 80.degree. C., 90.degree. C., or
100.degree. C. and lower Tg; or between 70.degree. C., 80.degree.
C., 90.degree. C., or 100.degree. C. and ambient temperature.
In addition to choosing the target temperature based on the Tg
range definitions discussed above, various embodiments can be
described otherwise. For polymers that are too hard, that exhibit
adhesive failures, that have Tg above ambient or room temperature,
or that have a shore hardness of 60D to 95D (alternatively, 65D to
90D), the polymer can be improved by causing the polymer to be
softer during crimping. Therefore, an improvement in adhesive
failure can be achieved by choosing a target temperature that
yields a 50% decrease in shore hardness, alternatively, a 40%, 30%,
20%, or 10% decrease in shore hardness.
Medical devices that use polymers with shore hardness of shore 60D
to shore 90D frequently experience adhesive, or elongational
failure during crimping. Invention medical devices prepared with
invention crimping methods allow the use of polymers with shore
hardness as high as 60D to 90D, or 65D to 85D. Alternatively,
invention medical devices prepared with invention crimping methods
allow the use of polymers with shore hardness greater than or equal
to 60D, 70D, 80D, or 90D.
When EVAL is crimped at ambient temperature, it is in a glassy
state (FIG. 6, curve A). By crimping at a temperature above its
glass transition temperature (Tg) (55.degree. C.), the ultimate
elongation becomes higher (FIG. 6, curve B). This should reduce
cracking in the tensile regions on the outside of stent junctions.
For PBMA, Tg of 20.degree. C., crimping at a low temperature of
0.degree. or less should reduce crimping damage from shear and
compression. Similarly, for KYNAR (a polymer consisting of
poly(vinylidene fluoride) and available from Atofina of
Philadelphia, Pa.), Tg of -30.degree. C., crimping at a temperature
of -40.degree. C. should also reduce denting and shearing
damage.
In some embodiments, a polymeric stent is crimped onto a delivery
device, such as a catheter, after being heated to a target
temperature. The target temperature is greater than Tg range for
definitions 1-7, any of definitions 1-7, any combination of
definitions 1-7, or any combination of definitions 1-7 that also
excludes any one or any combination of definitions 1-7.
In some embodiments, a polymeric stent is crimped onto a delivery
device, such as a catheter, while being heated to a target
temperature. The target temperature is greater than Tg range for
definitions 1-7, any of definitions 1-7, any combination of
definitions 1-7, or any combination of definitions 1-7 that also
excludes any one or any combination of definitions 1-7.
Devices for crimping medical devices are well known in the art. In
some embodiments, the device is designed to crimp the
polymer-coated stent onto the balloon portion of a catheter for
PTCA. For crimpers such as the sliding wedge design, the
temperature may be controlled by passage of a stream of dry air, or
inert gas through the bore. This air can be heated or cooled by
first passing it through a tube heater or chilled heat exchanger.
The stent is loosely placed onto the catheter, and then the
assembly is inserted into the bore of the crimper. The passage of
air would rapidly equilibrate the stent delivery system (SDS) to
the crimp temperature. Continuously heated or cooled airflow would
bring the crimping jaws to the desired temperature.
Alternative ways include heating or cooling the jaws of the crimper
itself. Electrical heating elements can be installed into the
crimper jaws. By appropriate placement of thermocouples and
feedback controls, an elevated temperature can be maintained.
Cooling of the crimper jaws can be accomplished by rendering them
with passageways through which a cooling medium is pumped. This may
also be used to heat the crimping jaws. If the jaws were composed
of an electrically conductive material, application of an
oscillating electric field can heat them via eddy currents. If the
jaws were made of an IR transparent material, the stent on catheter
can be thermostated by infrared radiation.
If the crimper is at ambient temperature, but the jaws themselves
are of a material with low thermal conductivity, then processes can
be considered where the stent loosely applied to the catheter is
pre-equilibrated to a non-ambient temperature before crimping. As
the stent is small, with a high surface area to volume ratio, it
would have to be rapidly moved from the controlled temperature
environment to the crimper to maintain the desired temperature.
Heating in an incubator or oven, or cooling in a refrigerator can
pre-equilibrate the stent to the desired temperature before
crimping.
Processes of the current invention provide medical devices. These
medical devices contain a piece or portion that is coated with or
constructed of, in some embodiments, polymer(s). In some
embodiments, the crimping device used in invention crimping steps
can be heated or cooled before it is used to crimp the piece or
portion onto the remainder of the medical device or onto another
medical device. This heating or cooling causes the temperature of
the material to change so that the crimping effectively occurs at a
target temperature other than ambient temperature. Other ways of
modifying the temperature of the polymer include heating or cooling
the substrate of the medical device or heating or cooling the
material directly with forced air, among other methods.
Some invention embodiments select medical devices to be those
adapted for placement in arterial, venous, neurovascular, urethral,
biliary, prostate, intravascular, ureteral, bronchial, esophageal,
fallopial, tracheal, laryngeal, gastrointestinal, lymphatic,
eustachiaic, pancreatic, cerebral, other genitourinary, other
gastrointestinal, or other respiratory lumens or passages.
Invention methods can be used on a variety of polymeric materials
including those characterized as having Tg above ambient
temperature. In some embodiments the methods act on polymeric
materials comprising ABS resins; acrylic polymers and acrylic
copolymers; acrylonitrile-styrene copolymers; alkyd resins;
biomolecules; cellulose ethers; celluloses; copoly(ether-esters);
copolymers of polycarboxylic acids and poly-hydroxycarboxylic
acids; copolymers of vinyl monomers with each other and olefins;
cyanoacrylates; epoxy resins; ethylene vinyl alcohol copolymers;
ethylene-methyl methacrylate copolymers; ethylene-vinyl acetate
copolymers; ethylene-.alpha.-olefin copolymers; poly(amino acids);
poly(anhydrides); poly(butyl methacrylates); poly(ester amides);
poly(ester-urethanes); poly(ether-urethanes); poly(imino
carbonates); poly(orthoesters); poly(silicone-urethanes);
poly(tyrosine arylates); poly(tyrosine-derived carbonates);
polyacrylates; polyacrylic acid; polyacrylic acids;
polyacrylonitrile; polyacrylonitrile; polyalkylene oxalates;
polyamides; polyamino acids; polyanhydrides; polycarbonates;
polycarboxylic acids; polycyanoacrylates; polyesters; polyethers;
poly-hydroxycarboxylic acids; polyimides; polyisobutylene and
ethylene-.alpha.-olefin copolymers; polyketones; polymethacrylates;
polyolefins; polyorthoesters; polyoxymethylenes; polyphosphazenes;
polyphosphoesters; polyphosphoester urethanes; polyphosphoesters;
polyphosphoesters-urethane; polyurethanes; polyvinyl aromatics;
polyvinyl esters; polyvinyl ethers; polyvinyl ketones;
polyvinylidene halides; silicones; starches; vinyl copolymers
vinyl-olefin copolymers; and vinyl halide polymers and copolymers.
Some embodiments select the group of polymers to specifically
exclude any one of or any combination of the polymers listed
above.
Specific examples of useful polymers for some embodiments include
the following polymers: starch, sodium alginate, rayon-triacetate,
rayon, polyvinylidene fluoride, polyvinylidene chloride, polyvinyl
pyrrolidone, polyvinyl methyl ether, polyvinyl chloride, polyvinyl
acetate, polystyrene, polyisocyanate, polyisobutylene, polyethylene
glycol, polydioxanone, polycaprolactone, polycaprolactam, KYNAR
(brand poly(vinylidene fluoride) available from Atofina),
polyacrylonitrile, poly(trimethylene carbonate), poly(L-lactic
acid), poly(lactide-co-glycolide), poly(hydroxyvalerate),
poly(hydroxybutyrate-co-valerate),
poly(hydroxybutyrate-co-hydroxyvalerate), poly(hydroxybutyrate),
poly(glycolide), poly(glycolic acid),
poly(D,L-lactide-co-L-lactide), poly(D,L-lactide-co-glycolide),
poly(D,L-lactide), poly(4-hydroxybutyrate),
poly(3-hydroxybutyrate), poly(3-hydroxy valerate), Nylon 66,
hyaluronic acid, fibrinogen, fibrin, elastin-collagen, collagen,
cellulose propionate, cellulose nitrate, cellulose butyrate,
cellulose acetate butyrate, cellulose acetate, cellulose,
cellophane, carboxymethyl cellulose, or poly(2-hydroxyethyl
methacrylate), Chitin, Chitosan, EVAL, poly(butyl methacrylate),
poly(D,L-lactic acid), poly(D,L-lactide), poly(glycolic
acid-co-trimethylene carbonate), poly(hydroxybutyrate-co-valerate),
poly(hydroxyvalerate), poly(iminocarbonate),
poly(lactide-co-glycolide), poly(L-lactic acid),
poly(N-acetylglucosamine), poly(trimethylene carbonate), poly(vinyl
chloride), poly(vinyl fluoride), poly(vinylidene chloride),
poly(vinylidene fluoride), poly(yinylidene
fluoride-co-chlorotrifluoroethylene), poly(vinylidene
fluoride-co-hexafluoropropene), polyanhydride, polyorthoester,
polyurethane, polyvinyl alcohol, polyvinyl chloride, rayon, SOLEF
21508 (formulation available from Solvay Solexis), and PEO/PLA.
Some embodiments select the group of polymers to specifically
exclude any one of or any combination of the polymers listed
above.
The polymer for use with this invention can comprise a mixture of
polymers, such as an intimate mixture of polymer molecules, or can
use a combination of polymers arranged in a layered structure. One
of ordinary skill in the art will recognize that the optimal target
temperature can be chosen based on the overall thermal behavior of
the polymers or combination of polymers.
Some embodiments add conventional drugs, such as small, hydrophobic
drugs, to invention polymers (as discussed in any of the
embodiments, above), making them biostable, drug systems. Some
embodiments graft-on conventional drugs or mix conventional drugs
with invention polymers. Invention polymers can serve as base or
topcoat layers for biobeneficial polymer layers.
The selected drugs can inhibit vascular, smooth muscle cell
activity. More specifically, the drug activity can aim at
inhibiting abnormal or inappropriate migration or proliferation of
smooth muscle cells to prevent, inhibit, reduce, or treat
restenosis. The drug can also include any substance capable of
exerting a therapeutic or prophylactic effect in the practice of
the present invention. Examples of such active agents include
antiproliferative, antineoplastic, antiinflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
and antioxidant substances, as well as their combinations, and any
prodrugs, metabolites, analogs, congeners, derivatives, salts and
their combinations.
An example of an antiproliferative substance is actinomycin D, or
derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001
West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN
available from Merck). Synonyms of actinomycin D include
dactinomycin, actinomycin IV, actinomycin II, actinomycin X1, and
actinomycin C1. Examples of antineoplastics include paclitaxel and
docetaxel. Examples of antiplatelets, anticoagulants, antifibrins,
and antithrombins include aspirin, sodium heparin, low molecular
weight heparin, hirudin, argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogs, dextran,
D-pheproarg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist, recombinant hirudin, thrombin inhibitor (available from
Biogen), and 7E-3B.RTM. (an antiplatelet drug from Centocor).
Examples of antimitotic agents include methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, adriamycin, and mutamycin.
Examples of cytostatic or anti-proliferative agents include
angiopeptin (a somatostatin analog from Ibsen), angiotensin
converting enzyme inhibitors such as CAPTOPRIL (available from
Squibb), CILAZAPRIL (available from Hoffman-LaRoche), or LISINOPRIL
(available from Merck & Co., Whitehouse Station, N.J.), calcium
channel blockers (such as Nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, histamine antagonist, LOVASTATIN
(an inhibitor of HMG-CoA reductase, a cholesterol lowering drug
from Merck &Co.), monoclonal antibodies (such as PDGF
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitor (available from Glazo), Seramin (a PDGF
antagonist), serotonin blockers, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), and nitric oxide. Other
useful drugs may include alpha-interferon, genetically engineered
epithelial cells, dexamethasone, estradiol, clobetasol propionate,
cisplatin, insulin sensitizers, receptor tyrosine kinase
inhibitors, and carboplatin. Exposure of the composition to the
drug should not adversely alter the drug's composition or
characteristic. Accordingly, drug containing embodiments choose
drugs that are compatible with the composition. Rapamycin is a
suitable drug. Additionally, methyl rapamycin (ABT-578),
everolimus, 40-O-(2-hydroxy)ethyl-rapamycin, or functional analogs
or structural derivatives thereof, is suitable, as well. Examples
of analogs or derivatives of 40-O-(2-hydroxy)ethyl-rapamycin
include, among others, 40-O-(3-hydroxy)propyl-rapamycin and
40-O-2-(2-hydroxy)ethoxyethylrapamycin. Those of ordinary skill in
the art know of various methods and coatings for advantageously
controlling the release rate of drugs, such as
40-O-(2-hydroxy)ethyl-rapamycin.
Some embodiments choose the drug such that it does not contain at
least one of or any combination of antiproliferative,
antineoplastic, antiinflammatory, antiplatelet, anticoagulant,
antifibrin, antithrombin, antimitotic, antibiotic, or antioxidant
substances, or any prodrugs, metabolites, analogs, congeners,
derivatives, salts or their combinations.
Some invention embodiments choose the drug such that it does not
contain at least one of or any combination of actinomycin D,
derivatives and analogs of Actinomycin D, dactinomycin, actinomycin
IV, actinomycin II, actinomycin X1, actinomycin C1, paclitaxel,
docetaxel, aspirin, sodium heparin, low molecular weight heparin,
hirudin, argatroban, forskolin, vapiprost, prostacyclin,
prostacyclin analogs, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist, recombinant hirudin,
thrombin inhibitor and 7E-3B, methotrexate, azathioprine,
vincristine, vinblastine, fluorouracil, adriamycin, mutamycin,
angiopeptin, angiotensin converting enzyme inhibitors, CAPTOPRIL,
CILAZAPRIL, or LISINOPRIL, calcium channel blockers, Nifedipine,
colchicine, fibroblast growth factor (FGF) antagonists, histamine
antagonist, LOVASTATIN, monoclonal antibodies, PDGF receptors,
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitor, Seramin, PDGF antagonists, serotonin blockers,
thioprotease inhibitors, triazolopyrimidine, nitric oxide,
alpha-interferon, genetically engineered epithelial cells,
dexamethasone, estradiol, clobetasol propionate, cisplatin, insulin
sensitizers, receptor tyrosine kinase inhibitors, carboplatin,
Rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, or a functional analogs
of 40-O-(2-hydroxy)ethyl-rapamycin, structural derivative of
40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin,
and 40-O-2-(2-hydroxy)ethoxyethyl-rapamycin, or any prodrugs,
metabolites, analogs, congeners, derivatives, salts or their
combinations.
Some invention embodiments comprise a drug or drug combination, and
some require a drug or combination of drugs. Of the drugs
specifically listed above, some invention embodiments exclude a
single or any combination of these drugs.
Some embodiments comprise polymers combined with other polymers in
multilayer arrangements. For example, one polymer can under- or
over-lay another polymer such as a polymer coated on a device, a
medical device, an implantable medical device, or a stent. The
polymer can be used neat in this regard, or it can first be mixed
with another polymer.
Examples of implantable devices useful in the present invention
include self-expandable stents, balloon-expandable stents, and
stent-grafts. The underlying structure of the device can be of
virtually any design. The device can comprise a metallic material
or an alloy such as, but not limited to, cobalt chromium alloy
(ELGILOY), stainless steel (316 L), high nitrogen stainless steel,
e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N," "MP20N,"
ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,
platinum-iridium alloy, gold, magnesium, or combinations thereof.
"MP35N" and "MP20N" are trade names for alloys of cobalt, nickel,
chromium, and molybdenum available from Standard Press Steel Co.,
Jenkintown, Pa. "MP35N" consists of 35% cobalt, 35% nickel, 20%
chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20%
nickel, 20% chromium, and 10% molybdenum. Of course, one of
ordinary skill in the art recognizes that the invention method is
only useful for medical devices that use a crimping step in their
production.
Various, specialized tests are used to assay the integrity of a
drug eluting stent coating. In all of them, completed units are
tested which have been though all stent-catheter assembly
processes, including crimping and any heat-pressure processes. One
test is inspection of the coated stents by scanning electron
microscopy. This can be done on the completed units by cutting the
stent-balloon section from the catheter, or the stent can be
removed from the catheter by dry expansion in air or wet expansion
in aqueous solution. Under SEM, the fraction of compromised coating
surface area can be estimated. Compromised coating is coating that
has been deformed, torn, or removed. When this fraction of surface
area exceeds 5-10%, the drug-release rate properties, and total
drug content can be affected. Another measure of coating integrity,
which is tied to crimping damage, is the number and size of
particles shed when the stent is expanded in aqueous solution. The
stent is deployed in a solution of previously filtered water and
the particles shed are counted by one of several available
particle-counting instruments. Example instruments would be those
produced by Malvern that work by light scattering, instruments that
work by light obscuration, such as the Hiac-Royco, or the Coulter
counter which works by electrical conductivity. Elevated numbers,
and sizes, of particles shed are indicative of coating failure,
which is affected by crimping damage either in the form of coating
pieces that are completely shorn off, or cracks in the coating
which propagated during stent expansion to liberate particles. Yet
another approach to measuring the effects of coating crimping
damage is by acute thrombogenicity testing, one example of which is
that detailed by Sukavaneshvar et al. ASIAO Journal, Aug. 11, 2000,
p 301 and ASIAO Journal, Jul. 5, 2000, p M393, which approach
subjected stents deployed in tubing to a flow of bovine blood in
which the platelets have been radiolabeled. Accumulation of
platelets and thrombus is a measure of the acute thrombogenicity.
The effect of coating cracks and defect can be compared to uncoated
stents, or to stents where the coatings have fewer, or no cracks
and coating defects.
EXAMPLES
Example 1
Used to Make Stents for FIGS. 1&2
A first composition was prepared by mixing the following
components: (a) 2.0 mass % of poly(ethylene-co-vinyl alcohol)
(EVAL) EC-151A and (b) the balance, dimethylacetamide
The first composition was applied onto the surface of bare 13 mm
TETRA stents (available from Guidant Corporation), which were first
pre-expanded by passing them over a 0.071 inch, tapered mandrel.
Coating was sprayed and dried to form a primer layer. A spray
coater was used having a 0.046 fan nozzle maintained at about 60 C
with a feed pressure 2.5 psi (0.17 atm) and an atomization pressure
of about 15 psi (1.02 atm). Coating was applied at 10 .mu.g per
pass, in between which the stent was dried for 10 seconds in a
flowing air stream at 60 C. Approximately 70 .mu.g of wet coating
was applied. The stents were baked at 140 C for one hour, yielding
a primer layer composed of approximately 50 .mu.g of EVAL.
A simulated reservoir layer was applied onto the primer layer,
using the same spraying technique, equipment, and formulation used
for the applying the primer. In this case, approximately 340 .mu.g
of wet coating is applied, followed by drying, e.g., baking at 50 C
for about two hours, yielding about 300 .mu.g of simulated
drug-polymer reservoir layer.
A second composition can be prepared by mixing the following
components: (a) 2.0 mass % of Elast-Eon 80A and (b) the balance
dimethylacetamide.
The second composition can be applied onto the dried simulated drug
reservoir layer to form a topcoat layer. Using the same spraying
technique and equipment used for applying the simulated drug
reservoir layer. Approximately 340 .mu.g of wet topcoat is applied
followed by baking at 80 C for two hours, yielding a 300 .mu.g
Elast-Eon 80A topcoat layer.
Using a sliding wedge crimper, the stents were crimped onto 13 mm
Tetra catheters (available from Guidant Corporation). The stents
were expanded in deionized water at 37 C with a balloon deployment
pressure of 12 atm. Examination by SEM yielded FIGS. 1 &2.
Example 2
Used to Make Stents for FIG. 3
A first composition was prepared by mixing the following component
(a) 4.0 mass % of poly(ethylene-co-vinyl alcohol) (EVAL) EC-151A
and (b) the balance, an 80/20 weight blend of dimethylacetamide and
pentane.
The first composition was applied onto the surface of bare 13 mm
TETRA stents (available from Guidant Corporation), which were first
pre-expanded by passing them over a 0.071 inch, tapered mandrel.
Coating was sprayed and dried to form a primer layer. A spray
coater was having a 0.046 fan nozzle maintained at about 60 C with
a feed pressure 2.5 psi (0.17 atm) and an atomization pressure of
about 15 psi (1.02 atm). Coating was applied at 10 .mu.g per pass,
in between which the stent was dried for 10 seconds in a flowing
air stream at 60 C. Approximately 65 .mu.g of wet coating was
applied. The stents were baked at 140 C for one hour, yielding a
primer layer composed of approximately 60 .mu.g of EVAL.
A simulated reservoir layer was applied onto the primer layer,
using the same spraying technique, equipment, and formulation used
for the applying the primer. In this case approximately 340 .mu.g
of wet coating is applied, followed by drying, e.g., baking at 80 C
for about two hours, yielding about 315 .mu.g of a simulated
drug-polymer reservoir layer.
A second composition can be prepared by mixing the following
components: (a) 2.0 mass % of Solef 21508 and (b) the balance a
50/25/25, by weight, blend of acetone, cyclohexanone, and AMS
Defluxer.
AMS Defluxer is a blend of dichloropentafluoropropanes and methanol
available from Tech Spray Inc. of Amarillo Tex.
The second composition can be applied onto the dried simulated drug
reservoir layer to form a topcoat layer. Using the same spraying
technique and equipment used for applying the simulated drug
reservoir layer. Approximately 345 .mu.g of wet topcoat is applied
followed by baking at 50 C for two hours, yielding a 325 .mu.g
Solef 21508 topcoat layer.
Using a sliding wedge crimper, the stents were crimped onto 13 mm
Tetra catheters (available from Guidant Corporation). After this,
they were subjected to a heat and pressure process wherein the
balloon was restrained by a sheath, air pressure was applied to the
catheter, and heat was applied to the balloon. Units were packaged
and sterilized by electron beam radiation at a dose of 35 KGy. The
stent coating performance was evaluated in an apparatus where a
guiding catheter was connected to flexible silicone tubing embedded
in a block with three gradual 90-degree bends. Deionized water at
37 C was recirculated through the guiding catheter. The stents were
passed through a rotating hemostatic valve attached to the guiding
catheter, through the guiding catheter, through the tortuous
silicone tubing, and deployed at a pressure of 12 atmospheres.
After the stents were removed from the tubing, examination by SEM
yielded FIGS. 3 & 4.
Example 3
Used to make the Stent Shown in FIG. 10
Stents are laser cut from polymer tubing, then crimped to the
desired diameter. A sliding wedge style heated crimper is used. The
stents are supported on a wire mandrel during the crimping
process.
TABLE-US-00002 Parameters: Tubing material: 100% poly(L-lactide)
Tubing OD: 0.084'' Tubing ID: 0.070'' Pre-heat temp: 30 C. Pre-heat
time: 30 seconds Crimp temperature: 30 C. Descent time: 3-5 seconds
Mandrel diameter: 0.031'' Post crimp dwell time: 99.9 seconds
Number of crimp cycles: 1
Appropriate standards for the measurement of durometer hardness are
ASTM D2240 or ISO868.
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. Additionally,
various embodiments have been described above. For convenience's
sake, combinations of aspects composing invention embodiments have
been listed in such a way that one of ordinary skill in the art may
read them exclusive of each other when they are not necessarily
intended to be exclusive. But a recitation of an aspect for one
embodiment is meant to disclose its use in all embodiments in which
that aspect can be incorporated without undue experimentation. In
like manner, a recitation of an aspect as composing part of an
embodiment is a tacit recognition that a supplementary embodiment
exists that specifically excludes that aspect. All patents, test
procedures, and other documents cited in this specification are
fully incorporated by reference to the extent that this material is
consistent with this specification and for all jurisdictions in
which such incorporation is permitted.
Moreover, some embodiments recite ranges. When this is done, it is
meant to disclose the ranges as a range, and to disclose each and
every point within the range, including end points. For those
embodiments that disclose a specific value or condition for an
aspect, supplementary embodiments exist that are otherwise
identical, but that specifically exclude the value or the
conditions for the aspect.
* * * * *
References