U.S. patent application number 10/213126 was filed with the patent office on 2004-02-05 for thermoplastic fluoropolymer-coated medical devices.
Invention is credited to Chang, James W., Cleek, Robert L., Cully, Edward H., Vonesh, Michael J..
Application Number | 20040024448 10/213126 |
Document ID | / |
Family ID | 31187854 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040024448 |
Kind Code |
A1 |
Chang, James W. ; et
al. |
February 5, 2004 |
Thermoplastic fluoropolymer-coated medical devices
Abstract
A medical device provided with at least a partial surface
coating of a thermoplastic copolymer of tetrafluoroethylene and
perfluoroalkylvinylether that is free of cross-linking monomers and
curing agents. The fluoropolymer coating is preferably an amorphous
thermoplastic, is highly inert and biocompatible, has elastomeric
characteristics that provide desirable mechanical properties such
as good flexibility and durability. These characteristics allow the
coating to be considered "functionally transparent" because it
withstands mechanical deformations required for the assembly,
deployment, expansion, and placement of medical devices, without
any adverse effect on the mechanical and biological functionality
of the coated device. Further, its inertness, derived from the
perfluorocarbon structure, contributes to its functionally
transparent nature. The coating can be provided with various liquid
or solid additives, can be loaded with large quantities of
additives including a wide range of therapeutic agents, and has
excellent drug elution characteristics when elutable additives are
used. The desirable mechanical characteristics are surprising given
the absence of cross-linking monomers and curing agents that would
otherwise render such materials inadequately biocompatible. The
perfluoroalkylvinylether may be perfluoromethylvinylether,
perfluoroethylvinylether or perfluoropropylvinylether.
Inventors: |
Chang, James W.; (Flagstaff,
AZ) ; Cleek, Robert L.; (Flagstaff, AZ) ;
Cully, Edward H.; (Flagstaff, AZ) ; Vonesh, Michael
J.; (Flagstaff, AZ) |
Correspondence
Address: |
W. L. Gore & Associates, Inc.
551 Paper Mill Road
P.O. Box 9206
Newark
DE
19714-9206
US
|
Family ID: |
31187854 |
Appl. No.: |
10/213126 |
Filed: |
August 5, 2002 |
Current U.S.
Class: |
623/1.42 ;
623/1.46 |
Current CPC
Class: |
A61L 27/34 20130101;
A61L 27/34 20130101; A61L 31/10 20130101; C08L 101/04 20130101 |
Class at
Publication: |
623/1.42 ;
623/1.46 |
International
Class: |
A61F 002/06 |
Claims
The invention claimed is:
1. An implantable device comprising at least one bendable element
provided with a coating of a thermoplastic copolymer of
tetrafluoroethylene and perfluoroalkylvinylether over at least a
portion of a surface of the bendable element, wherein said
copolymer is free of cross-linking monomers and curing agents, and
said coating is substantially free of macroscopic cracks
immediately following normal bending of the bendable element.
2. An implantable device according to claim 1 wherein said bendable
element is an expandable endoluminal element, wherein said coating
is substantially free of macroscopic cracks immediately following
normal expansion of the expandable endoluminal element.
3. An implantable device according to claim 2 wherein said device
is a tubular expandable stent having a diameter prior to expansion
wherein normal expansion increases the diameter by 50 percent.
4. An implantable device according to claim 1 wherein the
perfluoroalkylvinylether is perfluoromethylvinylether.
5. An implantable device according to claim 1 wherein the
perfluoroalkylvinylether is perfluoroethylvinylether.
6. An implantable device according to claim 1 wherein the
perfluoroalkylvinylether is perfluoropropylvinylether.
7. An implantable device according to claim 1 wherein the coating
contains an additive.
8. An implantable device according to claim 7 wherein the coating
contains at least 70 weight percent weight additive.
9. An implantable device according to claim 7 wherein the coating
contains at least 50 weight percent weight additive.
10. An implantable device according to claim 7 wherein the coating
contains at least 30 weight percent weight additive.
11. An implantable device according to claim 7 wherein the coating
contains at least 20 weight percent weight additive.
12. An implantable device according to claim 7 wherein the additive
comprises a therapeutic agent.
13. An implantable device according to claim 12 wherein the amount
and rate of release of the therapeutic agent from the implantable
device is controlled by adjusting the relative types and/or
concentrations of polymers in the copolymer.
14. An implantable device according to claim 12 wherein the
therapeutic agent comprises rapamycin.
15. An implantable device according to claim 12 wherein the
therapeutic agent comprises dexamethasone.
16. An implantable device according to claim 12 wherein the
therapeutic agent comprises heparin.
17. An implantable device according to claim 12 wherein the
therapeutic agent comprises paclitaxel.
18. An implantable device according to claim 12 wherein the
therapeutic agent comprises an anti-coagulant.
19. An implantable device according to claim 12 wherein the
therapeutic agent comprises an anti-microbial.
20. An implantable device according to claim 7 wherein the additive
comprises a substance that enhances imaging of the implantable
device following implantation.
21. An implantable device according to claim 7 wherein the additive
comprises a substance that enhances visualization of the
implantable device.
22. An implantable device according to claim 1 wherein the coating
may be exposed to a temperature of 330.degree. C. for one hour with
a weight loss of less than five percent.
23. An implantable device according to claim 1 wherein the
copolymer is an amorphous thermoplastic.
24. A device comprising a medical device provided with a coating
over at least a portion of a surface of the medical device, said
coating comprising a thermoplastic copolymer of tetrafluoroethylene
and perfluoropropylvinylether, said copolymer being free of
cross-linking monomers and curing agents.
25. A device according to claim 24 wherein said medical device is
an implantable medical device.
26. A device according to claim 24 wherein said medical device
comprises an expandable stent.
27. A device according to claim 24 wherein said coating contains a
therapeutic agent.
28. A device according to claim 24 wherein the copolymer is an
amorphous thermoplastic.
29. A device according to claim 24 wherein said coating contains an
additive.
30. A device comprising a medical device provided with a coating
over at least a portion of a surface of the medical device, said
coating comprising a thermoplastic copolymer of tetrafluoroethylene
and perfluoroethylvinylether, said copolymer being free of
cross-linking monomers and curing agents.
31. A device according to claim 30 wherein said medical device is
an implantable medical device.
32. A device according to claim 30 wherein said medical device
comprises an expandable stent.
33. A device according to claim 30 wherein said coating contains a
therapeutic agent.
34. An implantable device according to claim 30 wherein the
copolymer is an amorphous thermoplastic.
35. A device according to claim 30 wherein said coating contains an
additive.
36. An implantable device comprising a first form expandable to a
second form different from the first form, said device having at
least two expandable endoluminal elements in adjacent relationship
with an open interstice between the two expandable endoluminal
elements, said expandable endoluminal elements provided with a
coating over at least a portion of a surface of the expandable
endoluminal elements such that said coating covers the open
interstice between the adjacent expandable endoluminal elements
rendering it no longer open, said coating comprising a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroalkylvinylether, wherein said coating continues to cover
the interstice between the adjacent elements immediately following
normal expansion of the expandable endoluminal elements to the
second form.
37. An implantable device according to claim 36 wherein said
copolymer is free of cross-linking monomers and curing agents.
38. An implantable device according to claim 36 wherein said
endoluminal elements comprise an expandable stent.
39. An implantable device according to claim 38 wherein during
normal expansion said stent has a diameter that is increased 50
percent.
40. An implantable device according to claim 39 wherein said stent
comprises a balloon expandable stent.
41. An implantable device according to claim 39 wherein said stent
comprises a self-expanding stent.
42. An implantable device according to claim 38 wherein said stent
comprises a stainless steel stent.
43. An implantable device according to claim 38 wherein said stent
comprises a nitinol stent.
44. An implantable device according to claim 36 wherein the
copolymer is an amorphous thermoplastic.
45. An implantable device according to claim 36 wherein the coating
contains a therapeutic agent.
46. An implantable device according to claim 36 wherein the second
form is larger than the first form.
47. An implantable device comprising a device having expandable
endoluminal elements in adjacent relationship with an open
interstice between adjacent expandable endoluminal elements, said
expandable endoluminal elements provided with a covering over at
least one open interstice rendering it no longer open, wherein at
least a portion of said covering and at least a portion of said
endoluminal elements are provided with a coating comprising a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroalkylvinylether.
48. An implantable device according to claim 47 wherein said
coating contains a therapeutic agent capable of eluting from the
coating over time following implantation in a body conduit.
49. An implantable device according to claim 47 wherein said device
is a stent-graft having a small, compacted form expandable to a
larger form.
50. An implantable device according to claim 49 wherein said
coating contains a therapeutic agent that elutes from the coating
over time following implantation in a body conduit.
51. An implantable device according to claim 49 wherein said
covering comprises polytetrafluoroethylene.
52. An implantable device according to claim 1 wherein said
covering comprises polyethylene terephthalate.
53. An implantable device according to claim 51 wherein said
coating comprises a copolymer of tetrafluoroethylene and
perfluoromethylvinylethe- r.
54. An implantable device according to claim 51 wherein said
coating contains a therapeutic agent that elutes from the coating
over time following implantation in a body conduit.
55. An implantable device according to claim 47 wherein said
coating comprises a copolymer of tetrafluoroethylene and
perfluoromethylvinylethe- r.
56. An implantable device according to claim 47 wherein said
coating comprises a copolymer of tetrafluoroethylene and
perfluoroethylvinylether- .
57. An implantable device according to claim 47 wherein said
coating comprises a copolymer of tetrafluoroethylene and
perfluoropropylvinylethe- r.
58. An implantable device according to claim 49 wherein the larger
expanded form of said stent-graft has an outside diameter 50
percent larger than said small, compacted form.
59. An implantable device according to claim 47 wherein the
copolymer is an amorphous thermoplastic.
60. An article comprising a medical device provided with a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroalkylvinylether coating over at least a portion of a
surface of the medical device, said coating containing a
therapeutic agent, said therapeutic agent capable of eluting out of
said coating at a rate following implantation of said article into
a living body, wherein following puncture of said article with a
surgical tool followed by removal of said tool, said rate is
substantially increased.
61. An implantable device according to claim 60 wherein the
copolymer is an amorphous thermoplastic.
62. An article comprising a medical device provided with a coating
over at least a portion of a surface of the medical device, said
coating comprising a thermoplastic copolymer of tetrafluoroethylene
and perfluoroalkylvinylether, said coating containing a therapeutic
agent that, following implantation of the device into a body
conduit, will continue to elute out of the coating over a period of
30 days or more.
63. An article according to claim 62 wherein the therapeutic agent
will continue to elute out of the coating over a period of 45 days
or more.
64. An article according to claim 62 wherein the therapeutic agent
will continue to elute out of the coating over a period of 60 days
or more.
65. An article according to claim 62 wherein said copolymer is free
of cross-linking monomers and curing agents.
66. An article according to claim 65 wherein the therapeutic agent
will continue to elute out of the coating over a period of 24 hours
or more.
67. An article according to claim 65 wherein the therapeutic agent
will continue to elute out of the coating over a period of 3 days
or more.
68. An article according to claim 65 wherein the therapeutic agent
will continue to elute out of the coating over a period of 10 days
or more.
69. An article according to claim 65 wherein the therapeutic agent
will continue to elute out of the coating over a period of 30 days
or more.
70. An article according to claim 62 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoropropylvinylether.
71. An article according to claim 62 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroethylvinylether.
72. An article according to claim 62 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoromethylvinylether.
73. An article according to claim 62 wherein said copolymer is an
amorphous thermoplastic.
74. An article according to claim 62 comprising an expandable
stent.
75. An article according to claim 62 comprising an expandable
stent-graft.
76. A device comprising a medical device provided with a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroalkylvinylether coating over at least a portion of a
surface of the medical device, said coating being attached directly
to a portion of the surface of the medical device in the absence of
a surface treatment of the portion of the medical device.
77. A device according to claim 76 wherein the coating is applied
with the use of a primer.
78. A device according to claim 76 wherein said copolymer is free
of cross-linking monomers and curing agents.
79. An article according to claim 76 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoropropylvinylether.
80. An article according to claim 76 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoroethylvinylether.
81. An article according to claim 76 wherein said copolymer is a
thermoplastic copolymer of tetrafluoroethylene and
perfluoromethylvinylether.
82. An article according to claim 76 wherein said coating is an
amorphous thermoplastic.
83. An article according to claim 77 wherein said coating is an
amorphous thermoplastic.
84. An article according to claim 76 comprising an expandable
stent.
85. An article according to claim 76 comprising an expandable
stent-graft.
86. An article according to claim 76 wherein said coating contains
a therapeutic agent.
87. An article according to claim 76 wherein said coating contains
an additive.
88. An implantable device comprising at least one expandable
endoluminal element provided with coating of a thermoplastic
copolymer of tetrafluoroethylene and perfluoroalkylvinylether over
at least a portion of a surface of the expandable endoluminal
element, wherein said copolymer is free of cross-linking monomers
and curing agents, and said coating is substantially free of
macroscopic cracks immediately following normal expansion of the
expandable endoluminal element.
89. An implantable device according to claim 88 wherein said device
is a tubular expandable stent having a diameter prior to expansion
wherein normal expansion increases the diameter by 50 percent.
90. An implantable device according to claim 88 wherein the
perfluoroalkylvinylether is perfluoromethylvinylether.
91. An implantable device according to claim 88 wherein the
perfluoroalkylvinylether is perfluoroethylvinylether.
92. An implantable device according to claim 88 wherein the
perfluoroalkylvinylether is perfluoropropylvinylether.
93. An implantable device according to claim 88 wherein the coating
contains an additive.
94. An implantable device according to claim 93 wherein the coating
contains at least 70 weight percent weight additive.
95. An implantable device according to claim 93 wherein the coating
contains at least 50 weight percent weight additive.
96. An implantable device according to claim 93 wherein the coating
contains at least 30 weight percent weight additive.
97. An implantable device according to claim 93 wherein the coating
contains at least 20 weight percent weight additive.
98. An implantable device according to claim 93 wherein the
additive comprises a therapeutic agent.
99. An implantable device according to claim 98 wherein the
therapeutic agent comprises rapamycin.
100. An implantable device according to claim 98 wherein the
therapeutic agent comprises dexamethasone.
101. An implantable device according to claim 98 wherein the
therapeutic agent comprises heparin.
102. An implantable device according to claim 98 wherein the
therapeutic agent comprises paclitaxel.
103. An implantable device according to claim 12 wherein the
therapeutic agent comprises an anti-coagulant.
104. An implantable device according to claim 12 wherein the
therapeutic agent comprises an anti-microbial.
105. An implantable device according to claim 93 wherein the
additive comprises a substance that enhances imaging of the
implantable device following implantation.
106. An implantable device according to claim 93 wherein the
additive comprises a substance that enhances visualization of the
implantable device.
107. An implantable device according to claim 88 wherein the
coating may be exposed to a temperature of 330.degree. C. for one
hour with a weight loss of less than five percent.
108. An implantable device according to claim 88 wherein the
copolymer is an amorphous thermoplastic.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of medical
devices provided with at least a partial surface coating of
polymer.
BACKGROUND OF THE INVENTION
[0002] Surgical interventions often involve the implantation of a
medical device, typically manufactured from polymeric and/or
metallic materials, that is intended to provide a mechanical repair
of a medical malady. While providing necessary and often life
saving benefits, the implanted metal or polymer material may also
produce some type of complication. Some of the more common
complications include acute thrombosis; increased risk of infection
immediately post procedure and/or chronically; fibrous
encapsulation of the device resulting from a foreign body response
and inflammation; and vascular proliferative disease resulting in
an excessive, inflammatory, fibroproliferative response to
injury.
[0003] In some cases therapeutic agents are administered to
ameliorate complications arising from the medical implant and the
disease being treated. Most often these are administered orally or
through injection and result in systemic delivery. Ideally
therapeutic agents would be released locally in a controlled
fashion from an implant to maximize the effectiveness of the agent
at the desired site without causing severe systemic side effects. A
combination device, or product, that provides for local drug
delivery and a mechanical solution to the medical malady may result
in clinical outcomes not possible otherwise. One approach to
achieving this combination is through the use of coatings applied
to the surfaces of medical devices, implantable for short or long
terms, wherein the coating may optionally contain therapeutic
agents elutable from the coating.
[0004] Many systemic pharmacological approaches to reducing
restenosis have been proposed including the use of various agents
such as anticoagulants, antiplatelet agents, metalloprotease
inhibitors, antiproliferative agents and anti-inflammatory agents.
Many of these compounds have demonstrated some level of positive
effect in animal models of restenosis. Unfortunately, the clinical
application of these compounds has shown no positive indications.
This ineffectiveness may be largely attributed to the inability of
systemic delivery to provide effective drug concentrations at the
desired site. The dose and manner in which these compounds are
administered is suboptimal, necessitating the development of new
delivery modalities, technologies, and materials to accomplish
effective localized delivery. Furthermore, potentially useful but
toxic agents that would otherwise not be considered because of
problematic systemic concentration from injections or oral dosage
forms, could be used in combination products with an effective
localized delivery system.
[0005] While there is large potential for combination products that
provide therapeutic delivery with medical devices, development has
been slow. For example, the use of localized stent-based drug
delivery to reduce restenosis has only recently been demonstrated
in limited clinical trials. Many of the drugs being proposed for
use in these combination devices have existed for many years.
Paclitaxol is a prime example as it has long been used as a cancer
therapy, and its effects on vascular cells have been known for some
years. The slow emergence of these combination products then
appears to be due to the lack of adequate materials to combine the
drug and device into one medical embodiment that meets all the
needs for clinical applications. Each combination product requires
a suitable drug, a robust medical device, and a means to combine
these two elements together in a single entity. Most often a
polymer coating has been proposed as the material to combine the
drug and device into a single entity. Unfortunately, many of the
materials currently available have numerous shortcomings.
[0006] There is a need for biocompatible materials that can
adequately retain an efficacious dose, provide for prolonged drug
release, and be incorporated into the mechanical device, in the
simplest possible fashion, without compromising the device
functionality. Moreover, the material would truly be exemplary if
it provided more benefits to the combination product than
functioning solely as a matrix for the release of a therapeutic
agent. Preferably, this can be accomplished without the addition of
still another component, such as an adhesive material or primer
coatings, or without requiring surface modification of the medical
device, but rather with the polymer material itself serving as a
biocompatible adhesive with or without additives.
[0007] The utilization of biodegradable materials for drug delivery
such as alpha hydroxy esters is well known. These compounds have
glassy or rigid amorphous states that do not meet the flexibility
requirements of combination implantable device. These materials
have poor adhesive properties, particularly with regard to common
materials used to manufacture medical devices such as various
metals and polymers such as polytetrafluoroethylene (PTFE). The
biodegradable nature of these materials requires judicious use so
as not to create fragmentation of the material and possibly the
device as they degrade.
[0008] Silicones are among the most widely used synthetic polymers
that are intended to be non-biodegradable and are found in a
variety of medical applications. They are sometimes used as a
matrix material for elution of therapeutic agents, and as an
elastomer they offer a good degree of flexibility. See, for
example, U.S. Pat. No. 6,358,556 to Ding et al. Silicones consist
of at least three components: an elastomer, silica reinforcing
agent, and a volatile inhibitor to stop cross-linking. However,
silicones have poor bonding strengths to many medical device
substrate materials, and poor long-term in vivo tensile strength.
They are less biocompatible than most fluoropolymers. Silicones
absorb lipids and proteins over time, have a tendency to generate
particulate debris over time, and exhibit poor abrasion resistance.
Curatives in the vulcanized polymer can be problematic in that they
may react with additive. Other problems are known to include
cracking, swelling (generally due to lipid or protein absorption),
tear propagation and poor adhesion. These problems are exacerbated
by the use of additives.
[0009] Various fluoropolymer materials have been proposed as drug
delivery material; see, for example, EP 950386 to Llanos et al.
which suggests a list of materials including PTFE. While PTFE is
particularly inert and highly biocompatible, it is not elastomeric
and is limited in elution capability if not used in its porous
expanded form (ePTFE). Drugs are typically eluted from the
interconnected void spaces of ePTFE rather than by molecular
diffusion from within the polymer matrix; see, for example, U.S.
Pat. No. 5,290,271 to Jernberg. EP 1192957 to Llanos et al.,
proposes other fluoropolymer materials comprising a first monomer
chosen from the group consisting of vinylidene fluoride and a
second monomer that is different from the first monomer. These
materials are relatively non-durable according to examples that
describe cracking of the matrix during device expansion. Likewise,
these particular materials are limited in their drug loading and
drug elution capabilities. The ability to bond to a variety of
other materials without requisite primer coating or surface
treatment of the substrate, the ability to function as an integral
component of a coated medical device (without adverse effect on the
device function), and the ability to aid in the manufacturing of a
wide range of combination products has not been shown
SUMMARY OF THE INVENTION
[0010] The present invention provides a coating for a medical
device that can also act as a vehicle for delivery of therapeutic
agents. The coating comprises a fluoropolymer that is highly inert
and biocompatible, has elastomeric characteristics that provide
desirable mechanical properties such as good flexibility and
durability, can be loaded with additives (such as therapeutic
agents) either in solid or liquid form, and as such has excellent
drug elution characteristics.
[0011] The coating material is a thermoplastic copolymer of
tetrafluoroethylene (TFE) and perfluoroalkylvinylether (PAVE) that
is free of cross linking monomers and curing agents. The coating
material is preferably an amorphous thermoplastic. The
perfluoroakylvinylether may be perfluoromethylvinylether (PMVE),
perfluoroethylvinylether (PEVE) or perfluoropropylvinylether
(PPVE). The desirable mechanical characteristics are surprising
given the absence of cross-linking monomers, curing agents and
processing aids or fillers that would otherwise typically render
such materials inadequately biocompatible. The use of the coating
on a medical device results in a new, composite device that
combines the attributes of the inert, durable coating with the
utility of the device itself and, in addition, provides a vehicle
for delivery of a therapeutic agent.
[0012] The coating material is considered "functionally
transparent" for most medical device coating applications. This
means that the coating accomplishes its intended purposes without
adverse effect on the intended function of the coated medical
device. The coating material provides this unique feature in its
ability to withstand mechanical deformations required for the
assembly, deployment, expansion, and placement of medical devices,
to such an extent that the user of such devices does not realize
that the material is present. The coating is functionally
transparent to the coated medical device even while containing
additives and providing for controlled release of therapeutic
additives, if desired. The coating material has good adhesive
properties, such that it does not require a primer or other surface
treatment of the substrate to be coated, and thus, can allow for
thin coatings with or without additives that can also be used to
bond components of the device together. Because of its
perfluorocarbon nature, it has substantially no adverse effect on
the in-vivo function of the device. This inertness within a living
body contributes to its functionally transparent character. It can
be used with a wide range of additives while being able to
accommodate high levels of loading of such additives.
[0013] A medical device is hereby defined as any device used in the
cure, mitigation, treatment, or prevention of disease, in man or
other animals, or intended to affect the structure or any function
of the body of man or other animals. Medical devices are typically
used in contact with any body fluids or body tissues of man or
other animals. Implantable medical devices are those devices that
are inserted into living bodies for appreciable periods. More
specifically, long term implants are defined as items implanted for
more than 30 days while devices inserted into living bodies for
lesser periods are considered to be short term implantable
devices.
[0014] For purposes of the present invention, additives are
considered herein to be any additional materials added to the
TFE/PAVE copolymer for any reason, regardless of form. They may
therefore be in the form of liquids or solids; they may represent
solutions (including colloidal suspensions), mixtures, blends,
particulates, etc.
[0015] The term "amorphous" is used herein to define a polymer that
is substantially non-crystalline, and in which the molecular chains
exist in the random coil conformation, with little or no regularity
of structure. The copolymer has sufficient amounts of PAVE in the
molecular chains to substantially disrupt the crystallinity of the
resulting fluoropolymer. Crystallinity can be detected by
thermal/calorimetric techniques which measure the latent heat of
the melting/freezing transitions. One convenient method of
detection known to those of skill in the art is by Differential
Scanning Calorimetry (DSC). The heat of fusion calculated from any
endotherm detected in a DSC scan for the as-polymerized copolymer
is no more than about 3 J/g, and preferably no more than about 1
J/g. The scan rate should be set at 10.degree. C. per minute over a
temperature range beginning at 60.degree. C. and ending at
400.degree. C.
[0016] The term "thermoplastic" is used herein to define a polymer
that will repeatedly soften when exposed to heat and return to its
original condition when cooled to room temperature. Such a polymer
can be made to soften, flow or take on new shapes, without
significant degradation or alteration of the polymer's original
condition, by the application of heat or heat and pressure. A
thermoplastic is accordingly a polymer in which the molecular
chains are held together by the secondary van der Waals bonds; when
enough thermal energy is applied, the chains break free from one
another and the material will flow and melt.
[0017] In contrast to a thermoplastic polymer, a "thermoset"
polymer is hereby defined as a polymer that solidifies or "sets"
irreversibly when cured. Thermoset polymers have a
three-dimensional network structure which prevents chains from
being freed at higher temperatures. They will typically burn
instead of melt.
[0018] A determination of whether a polymer is a "thermoplastic"
polymer within the meaning of the present invention can be made by
slowly elevating the temperature of a slightly tensioned specimen
and watching for deformation. If the polymer can be made to
repeatedly soften, flow, or take on a new shape, without
significant degradation or alteration of the polymer's original
chemical condition, then the polymer is considered to be a
thermoplastic. If only small amounts of material are available it
may be necessary to use a hot stage microscope for this
determination.
[0019] A variety of different types of medical devices can benefit
from the inventive coatings. Stents, including both balloon
expandable and self-expanding stents, are particularly improved by
coating with the fluoropolymer. The change of overall dimensions of
the stent is accommodated by the good flexibility and durability of
the coating material. Coated stents of the present invention can be
used for applications in vascular and non-vascular body conduits
such as biliary, hepatic or esophageal. The flexibility and
adhesion of the coating substantially reduces or eliminates risk of
cracking during stent expansion. The durability of the coating
reduces risk of damage to the coating by a stent delivery catheter
or by the luminal surface of the body conduit into which it is
inserted. This is of particular utility during single balloon
procedures when the balloon is inserted into a lesion together with
a stent, wherein the balloon simultaneously expands the stent and
forcibly opens up the stenosis at the device deployment site.
[0020] Stent-grafts, that is, stents that are provided with a
covering, often of a tubular graft material, that covers some or
all of the otherwise open interstices of a deployed stent, can also
be provided with a coating over the surfaces of the stent and/or
the surfaces of the graft material with beneficial results. The
tubular graft material is most typically PTFE, PET or polyurethane.
The coating may be used as an adhesive to join the graft covering
to the stent. Likewise, it may be desirable to cover surfaces
selectively so that only some surfaces are covered, or some
surfaces are only partially covered. Further, the coating material
itself may be used in the form of a thin film as the graft covering
material. The film may be applied in the form of thin sheets, tapes
or tubes to the desired surface of a stent to create a stent-graft,
covering the stent elements and the interstices between adjacent
elements. Alternatively, a stent may be dipped into the coating to
achieve a covering that covers the stent elements and spans the
stent interstices, thereby resulting in a stent-graft
[0021] The coating may be used with or without additives. For
example, the coating may be used beneficially without an additive
by covering a less biocompatible material, in effect passivating
the less biocompatible material.
[0022] Because both stent elements and graft coverings for
stent-grafts may be beneficially covered by the inventive coating
(with or without additives) without significant adverse affect on
device profile (for thin coatings) and without adverse effects on
the coating such as cracking during device deployment, the coating
is deemed particularly useful for all bendable elements of medical
devices including both stent elements and graft coverings for
stent-grafts. Bendable elements are considered to be those elements
of a medical device that undergo bending during insertion into or
use with a body. Expandable endoluminal elements are considered to
be those portions of an expandable device such as a stent that
undergo a change of dimension during the course of the expansion of
the device, from its initial shape appropriate for insertion into a
body and transfer to a desired site, to its deployed size at the
desired site.
[0023] There may be multiple such elements within a single device
that, while integral to the device, undergo appreciably more change
than adjacent portions of the device. Conversely, the entire device
may constitute a single such element if the change of shape is
accomplished relatively uniformly over virtually the entire device,
as, for example, with many self-expanding stents.
[0024] Devices such as vascular grafts, venous valves, heart valves
and heart valve leaflets, left ventricular assist devices, ocular
implants including lenses and corneal implants, device introducers,
access ports, topically-applied devices (e.g., wound dressings and
transdermal patches), embolic filters, embolic particles,
catheters, device delivery components, catheter balloons,
guidewires, occluders, implantable electrical leads and devices,
implantable patches including vascular and hernia patches, sutures
and other surgical fasteners, and orthopedic implants can be
beneficially coated. Catheter balloons for stent delivery can be
beneficially coated to improve their ability to retain a stent
during insertion of a stent delivery system into a body conduit,
substantially reducing any risk of loss or misplacement of a stent
during the insertion process due to the stent having inadvertently
moved with respect to the balloon surface. This risk can be
considerable when it is attempted to insert a catheter balloon and
stent into a restrictive vascular lesion. Vascular grafts can be
provided as tubular grafts or as sheet grafts for the repair of
only a portion of the circumference of a blood vessel. This list is
intended only to be representative of the types of medical devices
that may be improved by the present invention, and consequently is
not limiting. Further, the coating (with or without an additive)
may be used as an adhesive between different components of a
medical device.
[0025] The medical devices can be coated by a variety of known
processes including spraying, dip-coating, powder coating,
dispersion coating, lamination to other substrates, extrusion,
molding, compression molding, or any other suitable means. It can
be applied as very thin coatings, even when loaded with additive
materials, and as such it enables medical devices to be made with
minimal effect on the thickness and profile of the devices. The
coating material adheres well to a variety of substrates including
various metals (e.g., stainless steels and nitinols) and to various
polymers (e.g., ePTFE). It does not require special preparation of
the substrate surface, additional bonding agents, or high
temperature processing.
[0026] Because the coating material adheres well and because it has
an elastomeric character, it is effective for use on stents and
stent-grafts. The coating is not adversely affected by the stent
deployment process involving expansion of the stent diameter from
its small, compacted diameter at which it was inserted into the
vasculature, up to its larger diameter following deployment and
expansion. The coating does not crack or otherwise disrupt during
this expansion process, which may involve plastic deformation of
the metallic stent elements. Any elutable therapeutic agent
contained in the coating can thus be expected to follow its
intended release rate because of the robust and durable character
of the coating, minimizing risk of cracking or loss of adhesion.
The coating may be employed in the manufacture of medical devices
as a drug-eluting adhesive. The coating material is self-adhesive,
meaning that additional layers of the coating will adhere well to
previously applied layers.
[0027] When used with solvents such as FC-75 fluorinated solvent
(3M Fluorinert, 3M Specialty Chemicals Division, St. Paul, Minn.),
the inventive coating material can be a practical, low temperature
adhesive. It is generally preferable to use solvents of this type
that typically do not dissolve or chemically react with most
additives. A uniform coating of a heterogeneous mixture of a drug
and the copolymer is possible with the present invention. This
allows for coexistence of drug-loaded regions adjacent to drug-free
regions in a pattern design that most efficiently delivers a drug
(or other therapeutic agent) in a localized, strategic fashion.
Thus, one common solvent and polymer are used to easily create
polymer-drug regions in contact with polymer-coated regions that do
not contain drugs.
[0028] The coating may be applied over any or all surfaces of a
medical device. The coating can be provided over the entire surface
area of a medical device in a fully continuous fashion whereby none
of the original surface of the device remains exposed.
Alternatively, only some surfaces may be covered or some surfaces
may only be partially covered. The coating may be provided in
discontinuous fashion such that it is interrupted at desired
portions of a surface, for example, the coating may be provided as
a dot-matrix pattern on a desired surface.
[0029] The coating can be provided as a film, in the form of thin
sheets or tubes, in which form it can be used for numerous
applications. For example, the film can be used as the covering
material over various devices (including, as previously mentioned,
a stent to create a stent-graft). It may be used as a stand-alone
biological barrier material, for example, to separate different
types of living tissues during healing. It can be applied over
other substrates and subsequently bonded to the substrate by the
use of heat or by the use of more of the coating polymer in a
liquid form as an adhesive. Films can be made with conventional
methods including extrusion and solvent casting. They can be
separately made for subsequent application to the surface of a
device, or alternatively can be provided by techniques such as
dip-coating directly over the surfaces of various devices (such as,
for example, guidewires and stents).
[0030] The coating can be provided over porous substrates in order
to reduce their porosity and/or permeability, including to an
extent that the porous substrate is rendered non-porous across
opposing surfaces of a device made from the porous substrate.
[0031] Likewise, the coating can be provided in porous forms. The
copolymer material may be rendered porous by methods such as the
inclusion of foaming agents, dissolving impregnated particles or by
forcing gasses or supercritical fluids through the thermoplastic
coating.
[0032] The coating material can be provided with a wide variety of
additives including a variety of therapeutic agents. Depending on
the type of additive used (particularly with regard to the
inertness of the additive), the additive can remain stable and
resident with the coating material (e.g., radiopaque additives), or
alternatively an additive can be provided to allow for its elution
over a specific period. Solid or liquid additives may be used with
the coating material at the time of coating the medical device
surface. While smaller particle sizes are preferred for particulate
additives, the coating material can accommodate larger particle
sizes with minimal effect on the mechanical properties of the
coating.
[0033] Additives, including those that are intended to elute, may
be provided in relatively high weight percent amounts, such as
about 1, 2, 5, 10, 20, 30, 40, 50, 60, or 70 weight percent, or
more. Elutable additives may be provided with an additional capping
layer of the coating polymer in order to reduce the rate of elution
and extend the time of elution. The capping layer may be provided
over another filled layer of the coating, or alternatively may be
applied directly over a layer of the additive material itself in
some instances. Likewise, a capping layer may contain an additive
which is different from an additive contained beneath the capping
layer. The release kinetics may be varied in other ways, such as,
for example for particulate additives, by controlling the particle
size as well as the weight percent loading. Various layers of the
coating may be applied, each containing different agents wherein
the different agents may have different elution kinetics. The
different layers may vary in thickness. It is apparent that layers
such as capping layers can be used to control directionality of
drug elution. Additives may be used that are thermally activated,
or that enhance in vivo imaging during, for example, fluoroscopic
or magnetic resonance imaging. These latter additives are referred
to herein as imaging opaque substances. Radioactive additives may
be used to locally deliver radiation therapy.
[0034] While various bioactive therapeutic agents such as
antithrombotic drugs including heparin, paclitaxol, dexamethasone
and rapamycin are most commonly proposed to aid the performance of
stents, many others can also be used beneficially, either alone or
in various combinations.
[0035] Therapeutic agents for a wide variety of applications can be
used as additives with the coating for use with various devices.
These agents include, but are not limited to, antithrombotic
agents, anticoagulants, antiplatelet agents, thrombolytics,
antiproliferatives, antiinflammatories, hyperplasia and restenosis
inhibitors, smooth muscle cell inhibitors, antibiotics,
antimicrobials, analgesics, anesthetics, growth factors, growth
factor inhibitors, cell adhesion inhibitors, cell adhesion
promoters and drugs that may enhance neointimal formation such as
the growth of endothelial cells. Again, these therapeutic agents
may be used alone or in various combinations, and may be in
coatings that cover all surfaces of a device or only portions of a
device.
[0036] Additives that are not bioactive and not elutable can be
used, for example, various pigments, MRI-opaque additives or
radiopaque additives (e.g., tantalum or gold) that are used to
enhance imaging of an implanted device. Encapsulated void spaces
may be used for enhanced echogenicity during procedures such as
ultrasound. Pigments may be beneficially added to enhance direct
visualization, for example, to provide a contrast against the blood
of a surgical field. Pigments may also be used for printed indicia
for various labeling or instructional purposes. Specialty pigments
(e.g., luminescent) may be used for particular applications, such
as enhancing visibility of devices (e.g., guidewires) in darkened
catheter labs.
[0037] Mechanically induced release of an additive is possible. For
example, pockets or layers of an additive may be captured within
the coating. These pockets or layers may then be exposed to body
fluids by penetrating the coating with a sharp surgical device or
tool.
[0038] The term elution as described herein pertains to diffusion
of an additive that occurs within a solvent, where the solvent may
be any suitable fluid including body fluids. When the additive is
contained within a copolymer, such as for controlled release within
the body, the copolymer must wet in order for elution to take
place.
[0039] The term diffusion is defined to mean the transport of
matter by random molecular motion from one region in space to
another. It is one of the processes that govern the elution of
additives from a copolymer-additive formulation.
[0040] The coating material of the present invention can be exposed
to high temperatures without degradation. For example, the coating
material can be exposed to 330.degree. C. for one hour with a
resultant weight loss of less than five percent, preferably less
than one percent, and more preferably less than 0.5 percent.
Because of the high temperature capability and the inert character
of the coating material, it lends itself to high temperature
sterilization. Because it is not hydrolyzable, it is not adversely
affected by conventional steam sterilization. Further,
sterilization does not adversely affect elution profiles as long as
the sterilization process does not affect any additive contained in
the coating.
[0041] The coating is mechanically durable and tough. It is
unaffected by exposure to body fluids because of its highly inert
character. Coatings containing elutable additives retain good
durability following elution of additives including particulate
additives. The coating has good abrasion resistance for
applications that may expose it to some degree of frictional wear.
Further, the coating shows good resistance to tear propagation,
even with high loading of additives.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1A is a transverse cross section of an elongate article
of round cross section such as a metal wire (for example, as from a
self-expanding stent or an electrical conductor), or a polymeric
suture, provided with a coating of the present invention.
[0043] FIG. 1B is a transverse cross section of an article of
rectangular cross section such as a stent element from a laser-cut
balloon expandable stent, provided with a coating of the present
invention.
[0044] FIG. 1C is a transverse cross section of the same article
shown by FIG. 1B except that a partial coating of the present
invention is provided, on only one surface of the article.
[0045] FIG. 1D is a transverse cross section of the same article
shown by FIG. 1B except that first coating layer of the present
invention is used that is provided with an additive, and then a
second layer of the coating material is provided which does not
contain an additive.
[0046] FIG. 1E is a transverse cross section of the same article
shown by FIG. 1B except that two opposing sides of the article are
provided with differently-filled coating layers.
[0047] FIG. 1F is a transverse cross section of the same article
shown by FIG. 1B except that one surface of the article is provided
with a first continuous layer of the inventive coating containing a
first additive, and a second discontinuous layer of the coating
material is provided containing a second additive different from
the first additive. FIG. 1G is a transverse cross section of the
same article shown by FIG. 1B except that discontinuous layers of
the coating material are provided on both surfaces of the article,
leaving portions of the article surface exposed between the
discontinuous segments of the coating.
[0048] FIG. 1H is a transverse cross section of the same article
shown by FIG. 1B except that the article is provided with pockets
that are filled with a first coating of the inventive material with
a continuous second layer of the material being used as a cap over
the first layer contained by the pockets in the article.
[0049] FIG. 1J is a cross section of multiple metallic stent
elements provided with a continuous coating of the present
invention that fully covers the stent elements and spans the
interstices between the stent elements.
[0050] FIG. 2A is a perspective view of a laser-cut balloon
expandable stent.
[0051] FIG. 2B is a top view of a section of the stent of FIG. 2A
prior to deployment.
[0052] FIG. 2C is a top view of a section of the stent of FIG. 2A
following deployment involving expansion of stent elements.
[0053] FIGS. 3A and 3B are perspective views of stent-grafts having
a coating of the present invention.
[0054] FIG. 4A is a perspective view of a vascular graft provided
with a coating of the present invention.
[0055] FIGS. 4B and 4C are transverse cross sections of coated
vascular grafts of the present invention.
[0056] FIG. 4D is a perspective view of a helically-wrapped
vascular graft of the present invention.
[0057] FIG. 5 is a longitudinal cross section of a catheter
guidewire device or alternatively a helically wound electrical
conductor provided with a coating of the present invention.
[0058] FIGS. 6A and 6B are isometric and cross sectional views of a
keratoprosthesis using the coating material of the present
invention.
[0059] FIG. 7A is a cross-sectional view of a composite two-layered
device containing a dot-matrix pattern of a therapeutic agent
applied between the two layers, shown as punctured by a needle.
[0060] FIG. 7B is a top view of the two-layered device of FIG. 7A,
shown following removal of the puncturing needle.
[0061] FIG. 7C is a graph describing the release of drug from the
device of FIGS. 7A and 7B, indicating a substantial, abrupt
increase in the release rate following puncture with a needle.
[0062] FIG. 8A is a graph of normalized cumulative mass of
dexamethasone released from three samples of wires provided with
different polymer-drug coating formulations demonstrating a range
of possible release kinetics. The open circles depict the emulsion
plus dispersion formulation, filled circles the single emulsion and
filled triangles the powder coating formulation.
[0063] FIG. 8B is a scanning electron photomicrograph (SEM; about
20.times.) of a straight, 0.5 mm diameter wire provided with the
coating of the present invention, and subsequently bent.
[0064] FIG. 9 is a scanning electron photomicrograph (about
260.times.) of a stent element provided with the coating of the
present invention following a scrape test with a scalpel blade.
[0065] FIGS. 10A and 10B are scanning electron photomicrograph
(about 100.times. and 200.times., respectively) of two adjacent,
curved expandable stent elements from balloon expandable stents,
both provided with a coating of the present invention, steam
sterilized and subsequently fully expanded.
[0066] FIGS. 11A and 11B are light micrographs (about 15.times.) a
stent coated with three layers of drug/polymer, and subjected to
ethylene oxide (EtO) sterilization at 67.7.degree. C., before and
after expansion with a balloon.
[0067] FIGS. 12A and 12B are light micrographs (about 15X and 30X,
respectively) of a TFE/PPVE polymer-coated stent that has been
subjected to EtO sterilization at 67.7.degree. C., before and after
balloon expansion.
[0068] FIGS. 13A and 13B are light micrographs (about 15.times. and
30.times., respectively) of a drug-TFE/PPVE polymer-coated stent
that has been subjected to EtO sterilization at 67.7.degree. C.,
before and after balloon expansion.
[0069] FIG. 14 is a light micrograph (about 10.times.) of a
self-expanding stent-graft having a graft covering of the TFE/PMVE
coating of the present invention.
[0070] FIGS. 15A and 15B are light micrographs (about 30.times.) of
a TFE/PMVE polymer coated stent-graft, unsterilized, before and
after balloon expansion.
[0071] FIGS. 16A and 16B are light micrographs (about 30.times. and
15.times., respectively) of TFE/PMVE polymer coated stent-graft,
unsterilized, before and after balloon expansion.
[0072] FIG. 17 is a graph of the cumulative mass of drug released
as a function time and capping mass ratio for Example 14.
[0073] FIG. 18 is a graph of the cumulative mass of drug released
as a function time for Example 15, where control device is filled
triangles and test is open and filled circles.
[0074] FIGS. 19A and 19B are light micrographs (about 15.times. and
20.times., respectively) of an EtO sterilized, TFE/PPVE-polymer
coated stent-graft before and after balloon expansion.
[0075] FIGS. 20A and 20B are light micrographs (about 25.times. and
30.times., respectively) of a TFE/PPVE-polymer coated stent-graft
including a TFE/PMVE drug-containing layer, shown before and after
expansion.
DETAILED DESCRIPTION OF THE INVENTION
[0076] The present invention comprises a medical device in
combination with a thermoplastic fluoropolymer, which is preferably
an amorphous fluoropolymer. The fluoropolymer may optionally
contain various additives. The thermoplastic fluoropolymer is a
copolymer of tetrafluoroethylene (TFE) and perfluoroalkylvinylether
(PAVE) that is free of cross-linking monomers and curing agents.
The perfluoroakylvinylether may be perfluoromethylvinylether
(PMVE), perfluoroethylvinylether (PEVE) or
perfluoropropylvinylether (PPVE). The desirable mechanical
characteristics, particularly tensile strength and toughness, are
surprising given the absence of cross-linking monomers, curing
agents, and process aids and fillers that would otherwise render
such materials inadequately biocompatible.
[0077] The copolymer of TFE and PMVE is generally preferred, and
may be made by emulsion polymerization techniques. The PMVE content
ranges from 40 to 80% by weight, while the complemental TFE content
ranges from 60 to 20% by weight. These materials have a secant
modulus at 100% elongation of between 1 and 7 MPa (per ASTM
D412-98, using 1/2 scale type IV dogbone with 250 mm/minute
crosshead speed and 40 mm grip separation). The material has a
durometer in the range of 50-90 Shore A.
[0078] Durometer measurements are made at room temperature (about
23.degree. C.) by the method of ASTM D2240-91 using a Shore
Durometer Type O with a Shore model CV-71200 Conveloader (Shore
Instrument Co., Freeport, N.Y.). The durometer uses a hemispherical
indenter of 1.2 mm radius. Samples tested by this method should be
at least 6 mm thick; two or more samples may be stacked if
necessary to achieve the minimum 6 mm thickness. Five durometer
readings should be taken at five different points on each sample;
these five readings are then averaged with the resulting mean value
taken as the representative hardness value of the sample. Thickness
measurements are the average of three or more measurements with a
set of measuring calipers.
[0079] The PAVE component of the present invention is of the
form
F.sub.2C=FCOC.sub.nF.sub.2n+1
[0080] where n, the number of carbon atoms in the side chain,
equals 1 to 3. For n=1, the PAVE is PMVE; for n=2 the PAVE is PEVE
and for n=3 the PAVE is PPVE.
[0081] Copolymers of TFE/PAVE can be analyzed for copolymer
composition with various characterization techniques known to those
of skill in the art, including both nuclear magnetic resonance
(NMR) spectroscopy and Fourier transform infrared (FTIR)
spectroscopy, with NMR as the primary method, complemented and
confirmed by FTIR.
[0082] Various TFE/PAVE copolymer samples were analyzed by DSC
using instruments such as a Perkin Elmer DSC7 equipped with Pyris
for Windows.TM. software version 3.72. When scanned as described
previously, it was determined that the materials were
amorphous.
[0083] FIG. 1A is a transverse cross section of an elongate article
14 of round cross section such as a metal wire (for example, as
from a self-expanding stent or an electrical conductor), or a
polymeric suture, provided with a coating 12 of the present
invention. Coating 12 covers the entire surface of the article 14
to create a coated article 10 which may be of any shape. Article 14
may be of any material other than the TFE/PAVE material of the
coating. Typical metallic materials for article 14 may be metals
such as stainless steels, nitinol alloys, platinum, gold, silver,
etc. Alternatively, polymeric materials useful as article 14
include PTFE or ePTFE, polyethylene terephthalate (PET),
polydimethylsiloxane (silicone), polyurethane (PU), or various
other polymers known for use as medical devices. While the figure
indicates that the entire outer surface of article 14 is provided
with coating 12, it is apparent that only selected portions of the
surface of article 14 may be covered as desired.
[0084] As coating 12 covers the entire surface (i.e., all surfaces)
of article 14, it is referred to as a continuous coating, that is,
an uninterrupted coating that fully covers the article 14. Partial
coatings that are interrupted in any of a variety of possible ways
(e.g., covering some surfaces while other surfaces remain
uncovered, or dot-matrix pattern coatings, etc.) are considered to
be discontinuous coatings.
[0085] Coatings may be in single or multiple layers. Any layer can
contain one or more additives such as therapeutic agents. Any of
the layers may be provided in porous (e.g., containing void spaces)
forms or non-porous forms.
[0086] FIG. 1B is a transverse cross section of an article 16 of
rectangular cross section such as a stent element from a laser-cut
balloon expandable stent, provided with a coating 12 of the present
invention. Again, the article 16 may be made from a variety of
materials and the coating 12 may be full or partial.
[0087] FIG. 1C is a transverse cross section of the same article 16
shown by FIG. 1B except that a partial coating 12 of the present
invention is provided, on only one surface of the article.
[0088] FIG. 1D is a transverse cross section of the same article 16
shown by FIG. 1B except that first coating layer 12a of the present
invention is used that is provided with an additive, and then a
second layer 12b of the coating material is provided as a capping
layer which does not contain an additive.
[0089] FIG. 1E is a transverse cross section of the same article 16
shown by FIG. 1B except that two opposing sides of the article are
provided with differently-filled coating layers 12c and 12d.
[0090] FIG. 1F is a transverse cross section of the same article 16
shown by FIG. 1B except that one surface of the article is provided
with a first continuous layer of the inventive coating 12a
containing a first additive, and a second discontinuous layer 12e
of the coating material is provided containing a second additive
different from the first additive. It is apparent that
discontinuous layer 12e may be applied in any desired pattern, to
any or all surfaces, etc. so that any desired pattern that is less
than fully covering (i.e., continuous) may be produced.
[0091] FIG. 1G is a transverse cross section of the same article 16
shown by FIG. 1B except that a discontinuous layer 12e of the
coating material is provided on both surfaces of the article 16,
leaving portions of the article surface exposed between the
discontinuous segments of the coating.
[0092] FIG. 1H is a transverse cross section of the same article 16
shown by FIG. 1B except that the article is provided with pockets
18 that are filled with a first coating 12e containing an additive
with a continuous second layer 12b of the material being used as a
cap over the first layer contained by the pockets in the
article.
[0093] FIG. 1J is a cross section of multiple metallic stent
elements of the present invention provided with a continuous
coating that fully covers the stent elements and spans the
interstices between the stent elements.
[0094] FIG. 2A is a perspective view of a laser-cut balloon
expandable stent, intended as representative of stents generally.
Stent 22 is provided with a coating of the thermoplastic
fluoropolymer. As stated previously, the coating may be continuous
or discontinuous, and may be provided with a variety of additives.
The stent 22 is made from a suitable material such as any of
various polymers or various metals including stainless steels or
nitinols. While the stent shown is a balloon expandable stent, it
is apparent that other types of stents including self-expanding
stents may be coated as well. Stent 22 is provided with a series of
apices 24 that are plastically deformable during diametrical
expansion of the stent.
[0095] FIG. 2B is an enlarged top view of a flattened section 22a
of the stent 22 of FIG. 2A prior to deployment. Apices 24 have a
relatively small radius prior to expansion. FIG. 2C is an enlarged
top view of the flattened section 22a of FIG. 2B following
deployment involving expansion of stent elements. The previous
relatively small radius of apices 24 is now increased due to
plastic deformation resulting from stress applied during expansion.
This deformation of stent apices 24 is problematic for many prior
stent coatings in that they often crack or otherwise disrupt, with
the result that the intended elution rate of any therapeutic agent
contained in the coating can be significantly compromised.
Macroscopic cracking of the coating may be ascertained by expanding
an endoluminal device under ambient conditions in an amount of 50
percent (measured as change in the outside diameter of the device)
in accordance with the instructions for use for the particular
device (if applicable), followed immediately by visual examination
(aided if necessary by 10.times. magnification). The coating is
typically unaffected by such a normal stent expansion, even when
the coating is provided with a high additive content. A device that
is substantially free of such macroscopic cracks will have at most
only a few minor cracks.
[0096] The capability of the coating of the present invention to be
unaffected by deformation of stent components resulting from
typical expansion (generally in the form of bending) can be
demonstrated by providing a coating onto the surface of a wire. The
coating should be applied in a desired amount, loaded with the
desired additive in the desired amount. A straight length of wire
having a round cross section of about 0.5 mm diameter should be
used, with the wire being made of the same metal as a desired
stent. After the coating has adequately dried, the wire is
subjected to any sterilization procedure intended for the similarly
coated stent. Following sterilization, the wire is bent at least 90
degrees at about the middle of its length, to a bend radius of 1.5
mm (i.e., to a bend radius of three times the wire diameter). The
radius is measured to the inner meridian of the bent wire so that
the wire can be bent around a form having a radius of 1.5 mm. With
the present invention, typically no cracking or other similar
disruption of the coating will occur.
[0097] FIG. 3A describes a stent-graft 32 of the present invention
wherein stent 22 is provided with a graft covering 34. The graft
covering may be provided over the inner surface of the stent as
described by FIG. 3A, or over the outer surface of the stent, or
both the outer and inner surfaces of the stent. Stent 22 may be any
type of stent, including balloon expandable or self-expanding. The
stent 22 described by FIG. 3A is intended only to be representative
of stent forms generally and as such is not intended as limiting.
The graft material may be made from a variety of materials
including any known graft materials, for example, polyethylene
terephthalate, silicone, polyurethane or ePTFE. Stent-graft 32 is
beneficially provided with a coating of the present invention that
may optionally contain any of a variety of additives as described
previously.
[0098] A stent-graft such as described by FIG. 3A may be provided
with a continuous coating of the coating material, wherein the
TFE/PAVE coating covers the stent elements and the graft covering
material. The entire graft covering may be coated including inner
and outer surfaces. If the graft covering extends over only the
inner or the outer surface of the stent (or any portion of those
surfaces), the remaining surfaces of the stent that are not covered
by the graft material may also be provided, or alternatively not
provided, with the coating. Likewise, if desired, only the exposed
portions of the stent 22 may be provided with the coating, leaving
the graft material uncoated.
[0099] Because the coating adheres tenaciously to many types of
surfaces, the coating may, for many inventive combinations of stent
and graft materials, optionally be used as an adhesive to attach
stent surfaces to the portions of the graft surfaces.
Alternatively, as shown by FIG. 3B, the stent-graft may be provided
with a discontinuous coating 12e according to the present
invention. This discontinuous coating can take a variety of forms
as suggested by FIG. 3B. As shown, a dot-matrix coating 12e is
applied over portions of the outer surface of the graft material
covering the stent. As noted previously, the dot-matrix coating may
be provided with any of various additives in desired amounts.
Different dots within the dot-matrix pattern may be provided with
different therapeutic agents if desired.
[0100] It is also apparent that different coatings may be used on
different surfaces of a stent-graft. For example, a coating
containing a first therapeutic agent may be provided to the luminal
surface while another coating containing a second therapeutic agent
different from the first may be applied to the exterior
surface.
[0101] FIG. 4A describes a tubular vascular graft 42 provided with
a coating of the present invention. The coating may be continuous
or discontinuous (including, for example, dot-matrix patterns) as
described previously. Additives may be added to the coating as
desired for any of a variety of purposes, also as described
previously. The vascular graft substrate material may be, for
example, any known graft material such as ePTFE, PET or PU. As
shown by the transverse cross section of FIG. 4B, the coating 12
may be provided on the luminal surface of the graft substrate 44.
Alternatively, as shown by the transverse cross section of FIG. 4C,
the coating 12 may be provided as a middle layer between inner and
outer layers of vascular graft substrate 44. In another
alternative, the coating may be provided on the abluminal surface
of the graft.
[0102] If a porous vascular graft substrate is used, the coating
may be impregnated into a portion or the entirety of the void space
within the porous substrate.
[0103] In another embodiment, the perspective view of FIG. 4D shows
an ePTFE vascular graft substrate 44 provided with a helical wrap
46 of ePTFE film that has been provided as a narrow tape. ePTFE
films are made generally as taught by U.S. Pat. Nos. 3,953,566 and
4,187,390 to Gore. The void space of the ePTFE film 46 may be
impregnated with the coating described, or alternatively, the graft
or the helically wrapped film may be coated as desired on any
surface with the coating. In another alternative, because the
coating may be provided in the form of a film, the helical wrap 46
may be in the form of the coating material.
[0104] In still another embodiment, the entire tubular vascular
graft may be made from the coating material. Such a vascular graft
may be provided with a variety of additives as noted previously.
Such a graft may be formed with external mechanical support, such
as molded in ridges, rings or struts. It is thus apparent that the
coating may be applied in thicknesses as desired, to enhance the
mechanical integrity or to provide other improved mechanical
behavior to various medical devices in various ways. Coatings such
as these may also incorporate additives.
[0105] FIG. 5 is a longitudinal, partial cross-section of a
catheter guidewire device 52 or alternatively a helically wound
electrical conductor 52 provided with a coating 12. Coating 12 may
be provided continuously as shown or alternatively in a
discontinuous form if desired; likewise the coating may be provided
with one or more additives if desired. The coating 12 may also be
provided as a helical wrap of a tape made from the coating
material.
[0106] FIG. 6A is an isometric view of an implantable cornea
prosthesis or keratoprosthesis. Keratoprosthesis 60, preferably
having an ePTFE peripheral skirts or skirts 63 and 64, is attached
to a fluoropolymer cornea substitute 66. The skirts have a porosity
that can be tailored to promote rapid ingrowth and attachment into
surrounding native tissue. FIG. 6B is a cross-sectional view of an
implantable keratoprosthesis 60, taken along section lines 62,
showing a first ePTFE skirt layer 63, a second ePTFE skirt layer 64
and an polymeric cornea substitute layer 66. The cornea substitute
layer 66 can be shaped to conform to surrounding native tissue and
have a thickness, flexibility and creep resistance suitable for
long term ocular implantation. In addition, the ePTFE skirts can be
pre-treated with a wetting agent such as poly(vinyl alcohol) to
promote rapid post implant wetting, which enhances to initial
anchoring to surrounding tissue. Keratoprosthesis 60 can be
produced, for example, by a lamination process in which one or more
layers of ePTFE 63, 64 are aligned onto a polymeric corneal layer
66 and compression molded to form a laminate.
[0107] The material of polymeric corneal layer 66 can also be used
to form an implantable lens or other light-transmitting device.
Additives such as ultraviolet absorbers, pigments or therapeutic
agents can also be incorporated into the polymeric layer 66, or
into other optical devices such as lenses or transparent
coatings.
[0108] The following examples are intended to describe various
embodiments possible with the scope of the present invention. As
such, they are not intended to be limiting with regard to variables
such as stent type, choice of PAVE polymer, coating thickness,
surface on which a coating is placed, coated vs. uncoated portions
of devices, therapeutic agent contained in one or more layers of
the coating, type of therapeutic agent incorporated, etc.
EXAMPLE 1
[0109] TFE/PMVE Film Evaluation of Thermal Stability of the
Material.
[0110] A sample of TFE/PMVE copolymer was made by emulsion
polymerization resulting in average emulsion particle size of 32
nanometers (particle size estimated using light scattering
methods), exhibiting the following properties: mean tensile
strength of 15.2 MPa, mean 100% secant modulus of 2.37 MPa, average
tensile set of 0%, and PMVE content of about 66% by weight. This
copolymer sample was compression molded to produce a thin film of
0.18 mm thickness. Approximately 15 micrograms of the thin film in
the form of a square sample of about 0.2 mm length per side was
utilized for determination of the copolymer degradation temperature
by themogravimetric analysis. The high-resolution scan covered the
temperature range of 0-800.degree. C. at heating rate of 20.degree.
C. per minute. Test results indicated that material degradation
initiated at approximately 400.degree. C., with a weight loss of
less than about 0.5% at 400.degree. C.
[0111] In an isothermal sweep, in which temperature was held at
330.degree. C. for 1 hr, the same copolymer experienced a total
weight loss of less than about 0.5%. The exceedingly low weight
loss associated with these severe thermal conditions demonstrates
the high thermal stability of this thermoplastic material.
[0112] A similar procedure can be used to demonstrate the thermal
stability of a drug-containing TFE/PMVE material. The drug is first
eluted from the material, and then the thermogravimetric analysis
is performed as described above.
EXAMPLE 2
[0113] TFE/PMVE Film Having Pockets Loaded With Chlorhexidine
Dihydrochloride.
[0114] Thin films of TFE/PMVE copolymer described by Example 1,
were produced via melt extrusion at temperatures exceeding
200.degree. C. A film possessing a thickness of approximately 0.2
mm was used to construct a laminate with pockets of chlorhexidine
dihydrochloride, an antimicrobial agent. A polypropylene template
with 0.7 mm diameter holes arranged in a rectangle pattern was made
to facilitate manufacturing of the device. The holes were evenly
spaced approximately 2 mm apart, from edge to edge. This template
was placed on top of one of the TFE/PMVE extruded sheets, then
dusted with chlorhexidine dihydrochloride. The template was
removed, leaving a dot-matrix pattern of the drug on the surface of
the extruded film. A second sheet of extruded polymer was gently
placed on top of the first sheet. The composite of polymer sheets
and drug was wrapped in aluminum foil, placed between two metal
plates, heated in an oven set at 115.degree. C. for 15 minutes,
removed from the oven, immediately pressed between the two hot
metal plates for 15 minutes, and then removed from the metal plates
and aluminum foil. This process created encapsulated drug pockets
between the polymer films.
[0115] The composite exhibited excellent bond characteristics. The
bond strength was so high that all attempts to delaminate the
polymer films resulted in destruction of the composite.
[0116] A cross-sectional view of the composite device 70 is shown
in FIG. 7A. First film layer 72 is provided as a cap over second
film layer 74, with film layer 74 being provided with a dot-matrix
pattern 76 of a desired drug. The device 70 is shown as it would
appear when punctured with a needle 78. FIG. 7B illustrates device
function following removal of the puncturing needle, allowing
immediate release of drug from dots 76 that are affected by the
needle puncture 79.
[0117] An approximately 1 cm by 1 cm square of finished material
was placed into phosphate buffered saline (PBS) at 37.degree. C.,
periodically sampled for antimicrobial content, and punctured with
a 16-gauge needle. The release of the chlorhexidine dihydrochloride
as a function of puncturing the composite and time in solution is
shown in FIG. 7C. It is important to note that chlorhexidine
dihydrochloride was continuously released at a minimal level until
the composite was punctured with the needle. Thus, an additional
dose of the drug can be delivered on demand as a consequence of
puncturing drug pockets.
EXAMPLE 3
[0118] Vascular Graft Coated With TFE/PMVE Containing
Dexamethasone.
[0119] The copolymer of Example 1 was obtained in a 4 wt % solution
of FC-75. The working drug formulation was a mixture of 2 ml of 4
wt % polymer, 8 ml of FC-75, and 150 mg of dexamethasone (52 wt %
drug based on total weight of coating solids; dexamethasone
obtained from Pharmacia & UpJohn, Kalamazoo Mich.). The
formulation was made by weighing dexamethasone into a test tube,
adding FC-75, vortexing vigorously to complete mixing, adding the
polymer, and ensuring complete mixing with additional
vortexing.
[0120] A 10 cm length of Gore-Tex Vascular Graft (part number
UT05070L, WL Gore & Associates, Flagstaff Ariz.) was used to
demonstrate the drug release coating. The 5 mm inside diameter
graft was mounted onto a mandrel for coating. The mandrel was
rotated by hand as an airbrush (Badger standard set model 350
airbrush set at 220 KPa gauge air pressure, Badger Air Brush Co.,
Franklin Park, Ill.), held at a constant distance of approximately
3.8 cm from the graft surface, was moved back and forth across the
graft while spraying a coating of the above-described polymer-drug
formulation. The vascular graft was continuously spray-coated for
approximately 10 minutes, after which time the graft was
transferred to an oven set at 60.degree. C. for 2 minutes.
Microscopic examination of cross sections of such a coated graft
indicated that the coating penetrated into the void spaces of the
microstructure of the porous ePTFE vascular graft. Physical
examination of these coated graft samples indicated that the
coating was well adherent.
[0121] After the drug layer was applied, the vascular graft was
divided into two sections, 5 and 4 cm in length. A slight
contraction of the graft in the longitudinal direction was noted
after the coating was applied, as the total length measured about 9
cm after coating. This contraction was believed to be the result of
drying of the relatively heavy coating. The 5 cm section was coated
with a capping layer that did not contain any drug. The capping
formulation consisted of 2 ml of 4 wt % polymer mixed with 8 ml of
FC-75. The solution was sprayed in a similar manner as above in
five 30 second spray intervals. Spraying intervals were separated
by a 15 second interval of not spraying. The 4 cm section was
sprayed in eight 30 second intervals, alternating with 15 second
intervals of not spraying. The 5 cm long section was taken for
determination of total drug loading. Loading determinations were
performed by placing the sample in 5 ml of ethanol in a glass test
tube for 15 hours at 55.degree. C. After ethanol extraction, the
solution was analyzed for dexamethasone content using a UV
spectrophotometer (dexamethasone wavelength: 244 nanometers). The
loading was determined to be 7.5.+-.1.0 mg/cm graft length.
[0122] It is apparent that there are many different possible
applications of the coating polymer, with or without a therapeutic
agent, to vascular grafts made of virtually any known graft
materials. For example, TFE/PMVE not containing any drugs (e.g.,
the capping material) could also have been spray coated directly
onto the vascular graft surface. The coating may be applied between
layers of the vascular graft, or may be applied to the luminal
surface of a vascular graft.
EXAMPLE 4
[0123] Wires Coated With TFE/PMVE Containing Dexamethasone.
[0124] A sample of the same TFE/PMVE copolymer of Example 1 was
prepared. The polymer was dissolved in FC-75 to obtain a 4 wt %
solution.
[0125] A spray formulation was consisting of a dexamethasone
emulsion plus dispersion was investigated first. Two ml of this 4
wt % polymer solution was diluted with 8 ml of FC-75 and mixed in a
15 ml plastic test tube, with periodic vortexing. 12.5 mg of
dexamethasone as a powder and 200 microliters of a saturated
ethanol solution containing dexamethasone (approximately 15 mg/ml
of dexamethasone) were added to the solution. The system was
vortexed for 1 minute to ensure complete mixing. It contained 10 wt
% drug based on total weight of coatings solids, with wt % drug
content calculated as drug mass/(drug+polymer mass), multiplied by
100.
[0126] The system was then coated onto a straight length of 0.51 mm
diameter silver-plated copper wire. This wire was intended to serve
as a model of a structural element used in various medical devices,
such as stents. The wire was spray-coated with the polymer using a
Badger standard set model 350 airbrush, for 1 minute, at an air
pressure of 220 KPa, and placed in an air forced furnace for 5
minutes at 60.degree. C. Ethanol extraction of such a coated wire
segment followed by UV spectrophotometric analysis yielded 6.4
micrograms of drug per cm of wire length. After the drug layer was
applied, a capping layer that did not contain any drug was sprayed
onto the wire. The capping formulation consisted of 2 ml of 4 wt %
polymer mixed with 8 ml of FC-75. The solution was sprayed in a
similar manner as described above. The total coating on the wire
was approximately 10 microns thick.
[0127] A spray formulation consisting of a single emulsion of
dexamethasone was also investigated. The working formulation was
made by combining 2 ml of the 4 wt % polymer solution with 8 ml of
FC-75 and allowing the system to mix in a 15 ml plastic test tube,
with periodic vortexing. 400 microliters of a saturated ethanol
solution containing dexamethasone (approximately 15 mg/ml of
dexamethasone) was added to the copolymer solution. The system was
vortexed for 1 minute before coating to ensure complete mixing. The
coating on this wire was approximately 5 microns thick. The coating
contained 4.1 wt % drug based on total weight of coating solids.
Ethanol extraction of wire segment followed by UV
spectrophotometric analysis yielded 17.5 micrograms per cm of wire
length.
[0128] A powder coating formulation was also investigated. Two ml
of the 4 wt % polymer solution was combined with 8 ml of FC-75,
then mixed in a 15 ml plastic test tube, with periodic vortexing. A
polymer base coat was applied to the wire for 2 min. While still
wet, the wire was suspended in a blender that had been pulsed
briefly to air suspend dexamethasone. A capping layer that did not
contain any drug was sprayed on the wire. The capping formulation
consisted of 2 ml of 4 wt % polymer mixed with 8 ml of FC-75. The
solution was sprayed in a similar manner as described above. The
coating on this wire was approximately 5 microns thick. No
theoretical loading was calculated. Ethanol extraction of wire
segment followed by UV spectrophotometric analysis yielded 63.5
micrograms per cm wire length. Samples of the coated wires were
taken for SEM analysis and the determination of drug release. The
graph of FIG. 8A demonstrates the extended elution times possible
with the different emulsion spray formulations, based on three
samples made as described above (open circles depict the emulsion
plus dispersion formulation, filled circles depict the single
emulsion and filled triangles depict the powder coating
formulation). Each of the three types of coating resulted in smooth
and uniform surfaces before and after drug release as evidenced by
SEM analysis. These findings suggest that drug elution occurred on
a molecular level. FIG. 8B is an SEM (about 20.times.
magnification) showing the crack-free mechanical integrity of the
single emulsion coating of the different emulsion spray formulation
process when the coated wire was bent in excess of a 90 degree
angle, at a radius of about 1.1 mm as measured to the inside
meridian of the bent wire.
[0129] In all of these embodiments, the TFE/PMVE coating remained
intact after complete elution of the drug.
EXAMPLE 5
[0130] Balloon-Expandable Stent Coated With TFE/PMVE Made With
Standard Emulsion, No Drug.
[0131] A sample of TFE/PMVE copolymer, made from emulsion
polymerization resulting in an average emulsion particle size of
about 120 nanometers, was prepared having the following properties:
mean tensile strength of 26.7 MPa, mean 100% secant modulus of 2.7
MPa, mean tensile set of 12%, and PMVE content of about 60% by
weight. Neither this TFE/PMVE copolymer nor any TFE/PMVE copolymer
used in any the examples contained any cross-linking monomers or
curing agents or system. The copolymer was added to FC-75
fluorinated solvent, to make a 4 wt % solution. The FC-75
fluorinated solvent, 3M Fluorinert, was obtained from 3M Specialty
Chemicals Division, St. Paul, Minn. 55144. The working formulation
was made by diluting 2 ml of the 4 wt % polymer solution with 8 ml
of FC-75 and allowing the system to mix in a 15 ml plastic test
tube, with periodic vortexing.
[0132] Stents made in accordance with the teachings of U.S. Pat.
No. 5,925,061 to Ogi, et al. were laser cut and polished by
Laserage Technology Corp., Waukegan, Ill. 60087. All stents were
cut from 316H stainless steel tubing possessing a wall thickness of
0.127 mm. The outside diameter of the stents was 1.57 mm while the
length was 21 mm.
[0133] Each stent was temporarily placed onto a small wire for
handling during the coating process. The wire was curved at one end
to prevent the stent from slipping off. Once secured on the wire,
the stent was dipped into the polymer solution, sprayed with
compressed air to minimize any bridging of the coating between
adjacent stent elements, and placed in an air forced furnace for 5
minutes at 60.degree. C. The dipping procedure may be repeated if
multiple coatings are desired. For this example the dipping
procedure was repeated 4 times. Scanning electron photomicrographs
of uncoated and coated stents were taken before and after
diametrically expanding up to 4.5 mm inner diameter with an
angioplasty balloon. The expansion ratio was approximately 3.
Scanning electron micrographs of the coated stent surfaces after
balloon expansion show complete and uniform coverage of the metal
surface by the polymer coating, regardless of stent shape or
geometry. Subsequent to balloon expansion a portion of the stent
surface was scraped with a surgical blade to test for coating
integrity. This was done by positioning the blade perpendicular to
the surface of the stent element, applying a downward force and
dragging the blade a short distance.
[0134] FIG. 9 is a scanning electron photomicrograph (about
260.times. magnification) of the surface after the scrape test. The
coating was only removed from the regions of blade contact. There
appeared to be no gross delamination or shrink-back of the coating
from the scraped region, indicating good adhesion of the
coating.
EXAMPLE 6
[0135] Balloon-Expandable Stent Coated With TFE/PMVE, No Drug.
[0136] Other stents were coated with a polymer solution, which
included the copolymer of TFE/PMVE described by Example 1. The
polymer was dissolved in FC-75 to obtain 4 wt % solution. The
working formulation was made by diluting 2 ml of the 4 wt % polymer
solution with 8 ml of FC-75 and allowing the system to mix in a 15
ml plastic test tube, with periodic vortexing.
[0137] Coated stents were made and tested as described above for
Example 5, yielding the same results regarding complete and uniform
metal surface coverage and smoothness of the coating surface. No
gross delamination of the coating was observed.
[0138] Coated stents made in this manner were steam sterilized
(134.degree. C. at 216 KPa for 12 minutes followed by a 30 minute
drying cycle), balloon expanded to 3 mm diameter, and subjected to
SEM analysis for determination of coating stability. The scanning
electron photomicrographs of FIG. 10A (about 100.times.
magnification) and FIG. 10B (about 200.times. magnification) show
that after processing and expansion, the polymer coating was still
adherent to irregular shapes, without any evidence of delamination
or tearing, demonstrating coating integrity even after steam
sterilization and subsequent expansion.
EXAMPLE 7
[0139] Balloon-Expandable Stent Coated With TFE/PMVE Containing
Dexamethasone.
[0140] A copolymer-drug coating, where the TFE/PMVE copolymer is
described by Example 1, was applied to balloon expandable stents of
the same type as used in Example 5. The amount of dexamethasone was
approximately 400 micrograms per stent, applied by single emulsion
spray coating as was done previously with the wire coating in
Example 4. The stent was balloon expanded to a diameter of 3.5 mm
prior to initiating drug release studies. SEM analysis of the
device surface subsequent to balloon expansion evidenced no
delamination or separation of the coating from the metal. Release
studies performed on another of these coated balloon expanded
stents demonstrated that the drug was released in a controlled
fashion. After completion of release studies, the sample underwent
SEM analysis. The coating showed no delamination or separation from
the metal. The polymer-drug coating thickness was estimated to be
approximately 3 microns.
EXAMPLE 8
[0141] Balloon-Expandable Stent Coated With TFE/PMVE Containing 60
wt % Dexamethasone.
[0142] A sample of the same TFE/PMVE copolymer, made as described
for Example 1, was prepared. The polymer was dissolved in FC-75 to
obtain a 4 wt % solution. One hundred and twenty mg of
dexamethasone as a powder was weighed into a 15 ml plastic test
tube, 6 ml of FC-75 was added, and the system was mixed vigorously
to ensure complete mixing. Two grams of the 4 wt % TFE/PMVE polymer
solution was added and the mixture was vortexed. This formulation
is 60 wt % dexamethasone on a total solids basis. The formulation
was applied to balloon expandable stents of the same type used in
Example 5. These stents were coated with the copolymer-drug
solution through a dip coating processes in which the stents were
suspended from a thin wire, immersed in the formulation, sprayed
with compressed air at 1.7 KPa air pressure, and placed in a
convection oven set at 60.degree. C. briefly for compete drying.
One group of stents received 1 dip coating and another group 3 dip
coatings. Stents from each group were distended with the use of 3.5
mm PTFE balloons before and after sterilization with EtO at a total
cycle time of 15 hours, including an EtO sterilization time of 1.3
hours at 67.7.degree. C. Stents were examined with the use of a
light microscope at magnification of up to 90.times.. Microscopic
examination of samples before and after expansion with or without
EtO sterilization showed the coating to be tough, and well adhered,
and without evidence of cracking.
[0143] FIG. 11A is a light micrograph (about 15.times.
magnification) of a drug/polymer coated stent according to this
example that has been subjected to EtO sterilization at
67.7.degree. C., before expansion. Three drug-polymer coat layers
were applied to this stent as described above. FIG. 11B (about
15.times. magnification) describes the same stent after balloon
expansion using a 3.5 mm diameter ePTFE/elastomer composite balloon
(made generally as taught by example 7 of U.S. Pat. No. 6,120,477
to Campbell et al.). It is anticipated that virtually any suitable
commercially available catheter balloon of suitable size would
provide the same stent expansion results.
[0144] EXAMPLE 9
[0145] Balloon-Expandable Stent Coated With TFE/PPVE, No Drug.
[0146] A sample of TFE/PPVE copolymer was obtained, which was
synthesized by emulsion polymerization, resulting in average
emulsion particle size of 83 nanometers, exhibiting the following
properties: mean tensile strength of about 12.2 MPa, mean 100%
secant modulus of 4.30 MPa, average tensile set of 31%, and PPVE
content of about 56% by weight. The polymer was dissolved in FC-75
to obtain a 20 wt % solution. The working formulation was made by
diluting 2 ml of the 20 wt % polymer solution with 8 ml of FC-75
and allowing the system to mix in a 15 ml plastic test tube, with
periodic vortexing.
[0147] Balloon expandable stents of the same type used in Example 5
were utilized. Each stent had a small wire temporarily looped
through one end for handling during the subsequent dip-coating
process. Once secured on the wire, the stent was dipped into the
polymer solution, sprayed with compressed air, and placed in an air
forced furnace for 5 minutes at 60.degree. C. The dipping procedure
was repeated to bring the total number of layers to 2. A portion of
the TFE/PPVE coated stents were then expanded without being EtO
sterilized using a balloon as described for Example 8, and examined
with the use of a light microscope. Additional coated stents
underwent EtO sterilization with a total cycle time of 15 hours,
including an EtO sterilization time of 1.3 hours at 67.7.degree. C.
After sterilization the stents were expanded using a balloon of the
type described for Example 8, and examined with a light microscope
at magnification of up to 90.times.. Microscopic examination of
samples before and after expansion with or without EtO
sterilization showed the coating to be tough, well adherent, and
without evidence of cracking.
[0148] FIG. 12A is a light micrograph (about 15.times.
magnification) of a TFE/PPVE polymer coated stent according to this
example that has been subjected to EtO sterilization at
67.7.degree. C. before balloon expansion. FIG. 12B is a light
micrograph (about 30.times. magnification) of the same stent
following balloon expansion using a balloon as described in Example
8.
EXAMPLE 10
[0149] Balloon-Expandable Stent Coated With TFE/PPVE Containing 60
wt % Dexamethasone.
[0150] Approximately 60 mg of dexamethasone powder was weighed into
a 15 ml plastic test tube, 6 ml of FC-75 was added, and the system
was mixed vigorously to ensure complete mixing. Two hundred mg of
20 wt % TFE/PPVE polymer solution (made per Example 9) was added
and the mixture was vortexed. This formulation is 60 wt %
dexamethasone on a total solids basis. Balloon expandable stents of
the same type used in Example 5 were utilized. Each stent had a
small wire temporarily looped through one end for handling during
the subsequent dip-coating process. Once secured on the wire, the
stent was dipped into the polymer solution, sprayed with compressed
air at 1.7 KPa air pressure, and placed in an air forced furnace
for 5 minutes at 60.degree. C. Stents were distended with the use
of 3.5 mm PTFE balloons before and after sterilization with EtO at
a total cycle time of 15 hours, including an EtO sterilization time
of 1.3 hours at 67.7.degree. C.
[0151] Stents were examined with the use of a light microscope at
magnification of up to 90.times.. Microscopic examination of
samples before and after expansion with or without EtO
sterilization showed the coating to be tough, well adherent, and
without evidence of cracking.
[0152] FIG. 13A is a light micrograph (about 15.times.
magnification) of a drug-TFE/PPVE-polymer coated stent made
according to this example and subjected to EtO sterilization at
67.7.degree. C., before balloon expansion. FIG. 13B is a light
micrograph (about 30.times. magnification) of the same stent after
balloon expansion using a balloon as described in Example 8.
EXAMPLE 11
[0153] Self-Expanding Stent Having Interstices Coated With TFE/PMVE
to Form a Stent-Graft.
[0154] More of the same TFE/PMVE copolymer, made as described by
Example 1, was obtained in a 2 wt % solution of FC-75. The
copolymer was added to a beaker for submersion of devices for
coating. A self-expanding stent frame (4 cm length, 5 mm inner
diameter) made from 0.152 mm diameter nitinol metal wire was also
obtained. A thin wire was temporarily attached to one end of the
stent as a handle and the stent frame was dipped into the solution,
removed, and completely air-dried. The process was repeated until a
polymer film coating extended between the nitinol wires, as shown
by the finished device of FIG. 14 (about 10.times. magnification).
The film initially contained void spaces, but these voids were
filled as more layers were added. This process can be practiced to
produce a polymer stent cover that is perforated (i.e., containing
occasional void spaces or openings through the coating that extends
between adjacent wires) or continuous (without openings).
EXAMPLE 12
[0155] Balloon-Expandable Stent Having Interstices Coated With
TFE/PMVE to form a Stent-Graft.
[0156] A sample of the same TFE/PMVE copolymer, made as described
by Example 1, was prepared. The polymer was dissolved in FC-75 to
obtain a 4 wt % solution. The working formulation was made by
diluting 2.5 ml of the 4 wt % polymer solution with 5 ml of FC-75
and allowing the system to mix in a 15 ml plastic test tube, with
periodic vortexing. Balloon expandable stents of the same type used
in Example 5 were utilized. Each stent had a small wire temporarily
looped through one end for handling during the subsequent
dipcoating process. Once secured on the wire, the stent was dipped
into the polymer solution, and placed in an air forced furnace for
5 minutes at 60.degree. C. The dipping procedure was repeated until
the void space between the stent elements is spanned with a
continuous solid polymer coating. Once completed the stent-grafts
were distended using a balloon as described in Example 8, and
examined with a light microscope at magnification of up to
90.times.. FIG. 15A is a light micrograph (about 30.times.
magnification) of a TFE/PMVE polymer coated stent-graft according
to this example shown before expansion while FIG. 15B is a light
micrograph (about 30.times. magnification) describing the same
stent after balloon expansion using a balloon as described in
Example 8. The finished, coated stent-graft has occasional
perforations or openings through the graft covering where
substantial amounts of deformation of adjacent stent elements
occurred during expansion. FIG. 15B shows one such opening. The
more opaque regions of the coating adjacent to some stent elements
were determined to be internal void spaces or "pockets" in the
coating that were formed during stent expansion. They do not
represent openings through the coating. While this is believed to
be an artifact of the type of balloon-expandable stent used, it
remains noteworthy that a large majority of the stent-graft
covering was not occupied by these openings. For some applications,
a stent-graft with occasional openings may be desirable. The
stent-graft shown in this figure was not subjected to EtO
sterilization.
EXAMPLE 13
[0157] Balloon-Expandable Stent Having Interstices Coated With
TFE/PMVE To Form a Stent-Graft.
[0158] A sample of the same TFE/PMVE copolymer, made as described
by Example 1, was prepared. The polymer was dissolved in FC-75 to
obtain a 4 wt % solution. The working formulation was made by
diluting 3 ml of the 4 wt % polymer solution with 3 ml of FC-75 and
allowing the system to mix in a 15 ml plastic test tube, with
periodic vortexing.
[0159] Stents made as taught by U.S. Pat. No. 4,733,665 to Palmaz,
of 2 mm compacted diameter, were utilized. Each stent had a small
wire temporarily looped through the end for handling during the
subsequent dip-coating process. Once secured on the wire, the stent
was dipped into the polymer solution, and then placed in a
forced-air furnace set at 60.degree. C. for a period of 5 minutes.
This procedure was repeated to bring the total number of layers to
7. A Medi-tech 4 mm balloon (Boston Scientific, Medi-tech,
Universal Product No. M001164180, Natick Mass.) was utilized to
expand the stent-graft device. Some uneven distention of the device
was noted and was believed to be related to the stent and not the
polymer coating. FIG. 16A is a light micrograph (about 30.times.
magnification) of this TFE/PMVE polymer coated stent-graft before
expansion. FIG. 16B (about 15.times. magnification) shows the same
stent-graft immediately after balloon expansion to 4 mm. The
coating fully covers all of the stent interstices between adjacent
stent elements, without any openings. The more opaque regions of
the coating adjacent to some stent elements were determined to be
internal void spaces or "pockets" in the coating that were formed
during stent expansion. They do not represent openings through the
coating. The stent-graft in this figure was not subjected to
sterilization.
EXAMPLE 14
[0160] Stent-Grafts Having an ePTFE Graft Covering, Coated With
TFE/PMVE Containing Dexamethasone.
[0161] More of the same TFE/PMVE copolymer of Example 1 was
obtained in a 2.5 wt % solution of FC-75. The drug formulation was
a mixture of 2 ml of 2.5 wt % polymer, 8 ml of FC-75, and 120 mg of
dexamethasone. This solution was well-mixed by shaking and then
sprayed with a Badger standard set model 350 airbrush set at 220
KPa gauge air pressure. Nitinol wire-based, self-expanding, stents
having a length of 4 cm, of the type used in Example 11, were
obtained. Porous expanded PTFE material was used to cover both the
internal and external stent frame surfaces. The inner ePTFE layer
was constructed using an ePTFE tubing of about 25 microns
thickness. The outer surface of this inner layer was provided with
a thin coating of the TFE/PMVE copolymer for subsequent use as a
thermally-activated adhesive to join the ePTFE and stent layers.
The outer ePTFE layer was constructed by wrapping a 25 micron thick
ePTFE tape about the outer stent surface. Both of these ePTFE
materials were of about 25 micron average fibril length. These
devices were placed into a convection oven set at 320.degree. C.
for five minutes to activate the adhesive. After removal from the
oven and cooling to room temperature, the resulting 4 cm long
stent-grafts were cut into three sections. The scalloped end
sections were cut to into 1.5 cm lengths and the mid-section was
cut into a 1 cm length. Each of these sections was mounted onto a
mandrel, rotated by hand and spray coated. The airbrush was held
approximately 3.8 cm from the graft surface. Spraying was
continuously performed for 30 seconds, after which time the coated
stent-graft on the mandrel was transferred to an oven set at
60.degree. C. for 2 minutes. This spraying and heating process was
repeated for up to 21 times. The devices were processed in three
groups of 4 where, within each group, one stent-graft was for
loading determination and the remaining 3 for release studies. The
first group received 16 coats, the second 21, and the third 19
coats. Loading was periodically measured with the one stent-graft
and the coating cycles adjusted to yield devices of comparable drug
content.
[0162] A capping layer was applied with a solution of polymer made
from 2 ml of the 2.5 wt % in 8 ml of FC-75. This was sprayed in a
similar manner as was the drug containing formulation. Three groups
consisting of three different capping layers were created by
applying 5, 10 and 15 capping coats to the appropriate stent-graft
group. The capping mass ratios are shown in FIG. 17.
[0163] Samples were subjected to drug release studies,
determination of total drug loading, and SEM analysis. For the
release study, a sample of 1.5 cm length was placed into PBS and
maintained at 37.degree. C. Periodically, the fluid was collected,
stored, and replaced with fresh PBS. Collected samples were assayed
by UV spectrophotometric analysis to measure dexamethasone
concentration. FIG. 17 shows the cumulative mass of dexamethasone
released as a function of time. Loading determinations were
performed by placing the sample in 5 ml of ethanol in a glass test
tube over night at 60.degree. C. After ethanol extraction, the
solution was analyzed by a UV spectrophotometer for dexamethasone
content. Loading values for the 1.5 cm long stent-grafts were
estimated to be 13.3, 12.8 and 15 mg for the respective groups. The
capping mass was determined through gross weight change and
determined to be 3.0, 6.0, and 8.5 mg, respectively.
[0164] Additionally, stainless steel balloon expandable stents
(about 1.5 mm unexpanded diameter) were obtained as described
above. The stent was powder-coated with FEP. An ePTFE tube of about
1.4 mm diameter, 80 micron wall thickness and having a
microstructure having an average fibril length of about 23 microns
was obtained. This ePTFE tube was placed over a mandrel, the
powder-coated stent placed over the tube, and another ePTFE tube of
the same type was placed over the stent. The assembly was
temporarily wrapped with an ePTFE film and placed in an oven set at
320.degree. C. for five minutes. The ePTFE tubes were thereby
bonded to the stent, thereby encapsulating it and forming a
stent-graft. After removal from the oven and cooling to room
temperature, the temporarily-applied ePTFE film was removed.
[0165] Next, three different spray formulations of TFE/PMVE
copolymer made as described by Example 1 were utilized for coating
the stent-graft. All formulations used polymer obtained in a 2.9 wt
% solution of FC-75. The first drug formulation was a mixture of 1
ml of 2.9 wt % polymer, 5 ml of FC-75, and 25 mg of dexamethasone.
This solution was well mixed by vortexing and sprayed with a Badger
standard set model 350 airbrush set at 220 KPa gauge pressure. The
stent-graft devices were placed onto mandrels and rotated by hand
during the spraying process. The airbrush was held about 3.8 cm
from the graft surface. In this manner only the abluminal surfaces
of the devices were coated.
[0166] The second drug formulation was 1 ml of 2.9 wt % polymer, 5
ml of FC-75, 25 mg of dexamethasone, and 500 microliters of
ethanol. The system was mixed by sonication for 15 min. and
vortexed briefly. The third drug formulation was 1 ml of 2.9 wt %
polymer, 5 ml of FC-75, 100 mg of dexamethasone, and 500
microliters of ethanol.
[0167] These coated expandable stent-grafts were balloon-expanded
to a diameter of 4.5 mm and the polymer-drug coating was examined
by SEM for integrity. The coating remained intact on the abluminal
surface of the ePTFE after balloon expansion. Visual examination
indicated that the coating appeared to change dimension with the
diametrically expanding ePTFE in that it appeared to continue to be
well-adhered to the ePTFE surface. Despite being forcibly distended
with a balloon to a diameter three times larger than the compacted
diameter, the coating remained well-adhered to the ePTFE surface of
the stent-grafts.
EXAMPLE 15
[0168] Drug Delivery Effectiveness of Stent-Graft.
[0169] Self-expanding stent-grafts of 15 mm length, of the same
type as described by Examples 11 and 14, were obtained. Polymer was
obtained in a 4 wt % solution of FC-75. The working drug
formulation was a mixture of 6 ml of 4 wt % polymer, 24 ml of
FC-75, and 450 mg of dexamethasone (Pharmacia & UpJohn,
Kalamazoo, Mich. USA). The formulation was made by weighing
dexamethasone into a test tube, adding FC-75, vortexing vigorously
to complete mixing, adding the polymer, and ensuring complete
mixing with additional vortexing. This solution was sprayed with a
Badger, standard set model 350, spray paint gun set at 220 KPa
gauge air pressure to coat devices. Self-expanding stent-grafts of
15 mm length and 4, 4.5, and 5 mm diameters, of the type described
in Example 14, were utilized. After the stent-grafts were mounted
onto a mandrel, the mandrel was rotated by hand as the airbrush was
moved back and forth across the stent-grafts. The airbrush was held
at a constant distance of approximately 6cm from the stent-graft
surface. The coating was continuously sprayed for approximately 15
minutes, after which time the mandrel was transferred to an oven
set at 60.degree. C. for 2 minutes. A capping layer was applied
with a solution of polymer made from 2 ml of the 4 wt % in 8 ml of
FC-75. This was sprayed for about 2.5 minutes, in a similar manner
as the drug containing formulation, to obtain a capping mass of
about 1.7 mg.
[0170] Several samples at this stage of processing were retained
for the determination of drug loading amount.
[0171] In order to provide the stent-grafts with a porous outer
layer that would allow for tissue ingrowth, two layers of
helically-wrapped ePTFE film were applied to the outer surface of
the coated stent grafts. The film-wrapped stent-grafts were then
heated to 200.degree. C. for 3 minutes to bond layers. Ends were
trimmed to allow the film to conform to the profile of the stent
graft ends.
[0172] Each stent-graft was diametrically compacted to an outer
diameter of approximately 2.1 mm; this may be accomplished by
various means known to those of skill in the art of self-expanding
stents. The stent-grafts were constrained in the compacted state
with a constraint wrap of more ePTFE film (not adhered), and were
subjected to EtO sterilization with a total cycle time of 15 hours,
including an EtO sterilization time of 1.3 hrs at 54.4.degree.
C.
[0173] Some of the stent-graft devices were mounted onto a 3 mm
angioplasty balloon, distended to the point of breaking the ePTFE
film constraint wrap, and then fully distended with appropriate
balloon sizes consistent with stent-graft diameters.
[0174] The following tests were performed on the stent-grafts:
total drug loading measurement, drug release characteristics,
balloon deployment, and SEM analysis. Loading determinations were
performed by placing each sample in 5 ml of ethanol in a glass test
tube over night at 60.degree. C. After ethanol extraction, the
solution was analyzed by a UV spectrophotometer for dexamethasone
content. For the drug release study, a small drop of alcohol was
applied to the abluminal surface of the ePTFE stent-graft. The
alcohol-wetted samples were immediately placed into PBS and
maintained at 37.degree. C. Periodically, the fluid was collected,
stored, and replaced with fresh PBS. Collected samples were assayed
by UV spectrophotometric analysis to measure dexamethasone
concentration.
[0175] Total loading of dexamethasone was determined to be
approximately 10 to 14 mg per stent-graft, and the polymer-drug
layer was calculated to contain 63 wt % dexamethasone. FIG. 18
shows the cumulative mass of dexamethasone released as a function
of time for the control device (filled triangles) and test devices
(open and filled circles). The control device was not compacted,
sterilized, nor balloon distended; the test devices were subjected
to all of these steps. The absence of spikes in the curves for the
test grafts indicates the absence of cracking of the coating. Had
the coating cracked, the drug elution curve would have demonstrated
discontinuities associated with non-uniform delivery. The two test
stent-grafts show remarkable consistency in the release of
dexamethasone after having been subjected to the physically
challenging thermal and mechanical stresses. Furthermore, the test
stent-grafts have retained the basic release characteristics of the
control device with minimum deviation. From visual inspection of
the curves in FIG. 18, it is evident that the curves are all very
similar. From a pharmacokinetic standpoint two systems are
generally equivalent if they deliver the same total quantity of
drug and at the same rate (duration of delivery). The total drug
delivered is take at the plateau regions of FIG. 18, and is
determined to be 7.66 mg for control, and 6.935 mg and 6.811 mg for
test samples. On a percentage basis the test samples are within 11
% of the control. This is remarkable in that the total drug loading
for the devices is 10 mg, but only a consistent fraction of this is
released as some remains trapped within the matrix. The test
samples that underwent mechanical and thermal stress did not
provide a total dose meaningfully different than the control.
[0176] These results attest to the surprising robustness of the
drug delivery matrix under the conditions of high drug loading,
severe mechanical and thermal stress, including balloon distention.
These findings are even more significant inasmuch as the amount of
drug loading was so high that it exceeded typical therapeutic
levels.
EXAMPLE 16
[0177] Balloon-Expandable Stent Having Interstices Coated With
TFE/PPVE to Form a Stent-Graft.
[0178] A sample of TFE/PPVE copolymer described by Example 9 was
prepared. The polymer was dissolved in FC-75 to obtain a 20 wt %
solution. The working formulation was made by diluting 2 ml of the
20 wt % polymer solution with 8 ml of FC-75 and allowing the system
to mix in a 15 ml plastic test tube, with periodic vortexing.
[0179] Balloon expandable stents of the same type used in Example 5
were utilized. Each stent had a small wire temporarily looped
through one end for handling during the subsequent dip-coating
process. Once secured on the wire, the stent was dipped into the
polymer solution, and placed in an air forced furnace for 5 minutes
at 60.degree. C. The dipping procedure was repeated to bring the
total number of layers to 6. A portion of the stent-grafts were
expanded before sterilization with a balloon as described in
Example 8, and examined with the use of a light microscope.
Additional coated stent-grafts underwent EtO sterilization with a
total cycle time of 15 hours, including an EtO sterilization time
of 1.3 hours at 67.7.degree. C. After sterilization the stent-graft
was distended using a balloon as described in Example 8, and
examined with a light microscope at magnification of up to
90.times.. As the occlusive stent-graft expands, openings through
the coating are created, the size, location, and morphology of
which are related to the metal stent design. The implications of
this are that the metal stent design can be utilized to produce a
stent-graft having openings through the coating when expanded of
predetermined size, and the metal stent design could be made to not
facilitate the formation of openings resulting in an occlusive
stent-graft post expansion.
[0180] FIG. 19A is a light micrograph (about 15.times.
magnification) of the TFE/PPVE-polymer coated stent-graft of this
example shown before expansion, while FIG. 19B (about 20.times.
magnification) shows the same stent-graft after balloon expansion
using a balloon as described in Example 8. Stent-grafts in this
figure were EtO sterilized as described for previous examples.
EXAMPLE 17
[0181] TFE/PPVE Stent-Graft With TFE/PMVE Drug Layer.
[0182] A sample of the TFE/PPVE copolymer described by Example 9
was prepared. The polymer was dissolved in FC-75 to obtain a 20 wt
% solution. The working formulation was made by diluting 2 ml of
the 20 wt % polymer solution with 8 ml of FC-75 and allowing the
system to mix in a 15 ml plastic test tube, with periodic
vortexing.
[0183] A TFE/PMVE copolymer formulation containing the drug
dexamethasone was also prepared. The TFE/PMVE copolymer was
dissolved in FC-75 to obtain a 4 wt % solution. One hundred and
twenty mg of dexamethasone as a powder was weighed into a 15 ml
plastic test tube, 6 ml of FC-75 was added, and the system was
mixed vigorously to ensure complete mixing. Two grams of the 4 wt %
TFE/PMVE polymer solution was added and the mixture was vortexed.
This formulation is 60 wt % dexamethasone on a total solids
basis.
[0184] Balloon expandable stents of the same type used in Example 5
were utilized. Each stent had a small wire temporarily looped
through one end for handling during the subsequent dip-coating
process. Once secured on the wire, the stent was dipped into the
TFE/PPVE polymer solution, and placed in an air forced furnace for
5 minutes at 60.degree. C. The dipping procedure was repeated to
bring the total number of layers to 6. An additional layer
containing the drug dexamethasone in TFE/PMVE was applied to the
abluminal stent-graft surface. This was sprayed onto the
stent-graft using a Badger, standard set model 350 airbrush set at
220 KPa gauge air pressure. An end portion of the stent-graft was
mounted onto a mandrel and then the mandrel was rotated by hand as
the airbrush was moved back and forth across the stent-graft
surface. The coating was continuously sprayed for approximately 15
seconds, after which time the mandrel was transferred to an oven
set at 60.degree. C. for 2 minutes.
[0185] A portion of the stent-grafts were expanded with a balloon
as described in Example 8, and examined with the use of a light
microscope. A coated stent-graft underwent EtO sterilization with a
total cycle time of 15 hours, including an EtO sterilization time
of 1.3 hours at 67.7.degree. C. After sterilization the stent-graft
was distended using a 3.5 mm PTFE balloon and examined with a light
microscope at magnification of up to 90.times.. The drug-containing
layer of TFE/PMVE did not separate from the base material of
TFE/PPVE; and appeared to be tough, well adherent, and without
evidence of cracking, demonstrating a high degree of stability. It
is apparent that different copolymers of the PAVE family can be
easily integrated into a single device construct, with or without
additives.
[0186] FIG. 20A is a light micrograph (about 25.times.
magnification) of the TFE/PPVE-polymer coated stent-graft including
the TFE/PMVE drug-containing layer, shown before expansion. FIG.
20B (about 30.times. magnification) shows the same stent-graft
following expansion with a balloon of the type described in Example
8. While the covering shows occasional periodic and well-defined
perforations or openings through the expanded stent-graft, the
large majority of the stent-graft is unperforated. The stent-graft
shown in these figures was not subjected to EtO sterilization.
[0187] While the principles of the invention have been made clear
in the illustrative embodiments set forth herein, it will be
obvious to those skilled in the art to make various modifications
to the structure, arrangement, proportion, elements, materials and
components used in the practice of the invention. To the extent
that these various modifications do not depart from the spirit and
scope of the appended claims, they are intended to be encompassed
therein.
* * * * *