U.S. patent application number 11/099939 was filed with the patent office on 2005-10-06 for coating compositions for bioactive agents.
Invention is credited to DeWitt, David M., Finley, Michael J., Lawin, Laurie R., Malinoff, Harrison R..
Application Number | 20050220843 11/099939 |
Document ID | / |
Family ID | 34965640 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220843 |
Kind Code |
A1 |
DeWitt, David M. ; et
al. |
October 6, 2005 |
Coating compositions for bioactive agents
Abstract
A coating composition and related method for use in applying a
bioactive agent to a surface in a manner that will permit the
bioactive agent to be released from the coating in vivo. The
composition is particularly well suited for coating the surface of
implantable medical device, such as a stent or catheter, in order
to permit the device to release bioactive agent to the surrounding
tissue over time. The composition includes a plurality of
compatible polymers having different properties that can permit
them to be combined together to provide an optimal combination of
such properties as durability, biocompatibility, and release
kinetics.
Inventors: |
DeWitt, David M.;
(Minneapolis, MN) ; Finley, Michael J.; (Saint
Louis Park, MN) ; Lawin, Laurie R.; (New Brighton,
MN) ; Malinoff, Harrison R.; (Golden Valley,
MN) |
Correspondence
Address: |
INTELLECTUAL PROPERTY GROUP
FREDRIKSON & BYRON, P.A.
200 SOUTH SIXTH STREET
SUITE 4000
MINNEAPOLIS
MN
55402
US
|
Family ID: |
34965640 |
Appl. No.: |
11/099939 |
Filed: |
April 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60559821 |
Apr 6, 2004 |
|
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Current U.S.
Class: |
424/423 ;
424/487 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61L 29/085 20130101; A61L 2300/602 20130101; A61L 31/16 20130101;
A61L 29/085 20130101; A61L 2300/404 20130101; A61L 2300/42
20130101; A61L 31/10 20130101; C08L 33/10 20130101; C08L 33/06
20130101; A61L 2300/43 20130101; A61F 2/86 20130101; A61L 2300/606
20130101; C08L 33/06 20130101; C08L 71/02 20130101; A61L 2300/222
20130101; A61L 31/10 20130101; A61L 2300/41 20130101; A61F
2250/0067 20130101; A61L 29/16 20130101; A61L 31/10 20130101; A61L
31/10 20130101 |
Class at
Publication: |
424/423 ;
424/487 |
International
Class: |
A61F 002/00; A61K
009/14 |
Claims
What is claimed is:
1. A composition for coating the surface of a medical device with
at least one bioactive agent in a manner that permits the coated
surface to release the bioactive agent over time when implanted in
vivo, the composition comprising at least one bioactive agent in
combination with a plurality of polymers, including a first polymer
component comprising at least one diolefin-derived non-aromatic
polymer or copolymer and a second polymer component comprising a
polymer selected from the group consisting of
poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
2. A composition according to claim 1 wherein the first polymer
component is selected from the group consisting of the polymers of
butadiene and isoprene.
3. A composition according to claim 1 wherein the first polymer
component includes a homopolymer derived from diolefin
monomers.
4. A composition according to claim 3 wherein the homopolymer is
partially hydrogenated.
5. A composition according to claim 1 wherein the first polymer
component includes a copolymer of a diolefin monomer with a
non-aromatic mono-olefin monomer.
6. A composition according to claim 5 wherein the copolymer is
partially hydrogenated.
7. A composition according to claim 1 wherein the first polymer
component is selected from the group consisting of polybutadienes
containing polymerized cis-, trans- and 1,2-monomer units and
polyisoprenes containing polymerized cis-1,4- and trans-1,4-monomer
units, polymerized 1,2-vinyl monomer units, and polymerized
3,4-vinyl monomer units.
8. A composition according to claim 1, the first polymer component
having a molecular weight from about 50 kilodaltons to about 1,000
kilodaltons.
9. A composition according to claim 1, the first polymer component
having a molecular weight from about 150 kilodaltons to about 1,000
kilodaltons.
10. A composition according to claim 1, the first polymer component
having a molecular weight from about 200 kilodaltons to about 600
kilodaltons.
11. A composition according to claim 1, the first polymer component
having a molecular weight from about 100 kilodaltons to about 450
kilodaltons.
12. A composition according to claim 1 wherein the composition
includes at least one additional polymer selected from the group
consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene
copolymers with other alkylenes, polybutenes, aromatic
group-containing copolymers, epichlorohydrin-containing polymers
and poly(ethylene-co-vinyl acetate).
13. A composition according to claim 12 wherein the
poly(alkylene-co-alkyl(meth)acrylates) are selected from the group
consisting of poly(ethylene-co-methyl acrylate),
poly(ethylene-co-ethyl acrylate), poly(ethylene-co-2-ethylhexyl
acrylate) and poly(ethylene-co-butyl acrylate), ethylene copolymers
with other alkylenes are selected from the group consisting of
poly(ethylene-co-propylene), poly(ethylene-co-1-butene),
poly(ethylene-co-1-butene-co-1-hexene) and
poly(ethylene-co-1-octene), the polybutenes are selected from the
group consisting of polyisobutylene, poly-1-butene and
poly-2-butene, the aromatic group-containing copolymers include a
copolymer derived from copolymerization of styrene monomer and one
or more monomers selected from the group consisting of butadiene,
isoprene, acrylonitrile, a C.sub.1-C.sub.4 alkyl (meth)acrylate and
butene, the epichlorohydrin-containing polymers are selected from
the group consisting of epichlorohydrin homopolymers and
poly(epichlorohydrin-co-al- kylene oxide) copolymers and the
poly(ethylene-co-vinyl acetate) polymers have a vinyl acetate
concentration from about 8% to about 90%.
14. A composition according to claim 1 wherein the
poly(alkyl(meth)acrylat- e) includes an alkyl chain length from two
to eight carbons.
15. A composition according to claim 1, the
poly(alkyl(meth)acrylate) having a molecular weight from about 50
kilodaltons to about 900 kilodaltons.
16. A composition according to claim 1 wherein the
poly(alkyl(meth)acrylat- e) is selected from the group consisting
of poly(n-butyl methacrylate), poly(n-butyl
methacrylate-co-isobutyl methacrylate), and poly(t-butyl
methacrylate).
17. A composition according to claim 1 wherein the
poly(aromatic(meth)acry- late) includes aryl groups having from six
to sixteen carbon atoms.
18. A composition according to claim 1, the
poly(aromatic(meth)acrylate) having a molecular weight from about
50 kilodaltons to about 900 kilodaltons.
19. A composition according to claim 1 wherein the
poly(aromatic(meth)acry- late) is selected from the group
consisting of poly(aryl(meth)acrylates),
poly(aralkyl(meth)acrylates), poly(alkaryl(meth)acrylates),
poly(aryloxyalkyl(meth)acrylates), and poly(alkoxyaryl
(meth)acrylates).
20. A composition according to claim 19, wherein the
poly(aryl(meth)acrylates) are selected from the group consisting of
poly(9-anthracenyl methacrylate), poly(chlorophenyl acrylate),
poly(methacryloxy-2-hydroxybenzophenone),
poly(methacryloxybenzotriazole)- , poly(naphthyl acrylate),
poly(naphthylmethacrylate), poly-4-nitrophenylacrylate,
poly(pentachloro(bromo, fluoro)acrylate) and methacrylate,
poly(phenyl acrylate) and poly(phenyl methacrylate); the
poly(aralkyl(meth)acrylates) are selected from the group consisting
of poly(benzyl acrylate), poly(benzyl methacrylate),
poly(2-phenethyl acrylate), poly(2-phenethyl methacrylate) and
poly(1-pyrenylmethyl methacrylate); the poly(alkaryl(meth)acrylates
are selected from the group consisting of poly(4-sec-butylphenyl
methacrylate), poly(3-ethylphenyl acrylate), and
poly(2-methyl-1-naphthyl methacrylate); the
poly(aryloxyalkyl(meth)acrylates) are selected from the group
consisting of poly(phenoxyethyl acrylate), poly(phenoxyethyl
methacrylate), and poly(polyethylene glycol phenyl ether acrylate)
and poly(polyethylene glycol phenyl ether methacrylate) with
varying polyethylene glycol molecular weights; and the
poly(alkoxyaryl(meth)acryl- ates) are selected from the group
consisting of poly(4-methoxyphenyl methacrylate),
poly(2-ethoxyphenyl acrylate) and poly(2-methoxynaphthyl
acrylate).
21. A composition according to claim 1 wherein the composition
further comprises a solvent in which the first and second polymer
components form a true solution.
22. A composition according to claim 1 wherein the bioactive agent
is dissolved or suspended in the coating mixture at a concentration
of 0.01% to 90% by weight.
23. A composition according to claim 1 wherein the device is one
that undergoes flexion and expansion in the course of implantation
or use in vivo.
24. A composition according to claim 1 wherein the composition
permits the amount and rate of release of agent(s) from the medical
device to be controlled by adjusting the relative types and
concentrations of the first and second polymer components in the
mixture.
25. A combination comprising a medical device and a composition for
coating the surface of a medical device with at least one bioactive
agent in a manner that permits the coated surface to release the
bioactive agent over time when implanted in vivo, the composition
comprising at least one bioactive agent in combination with a
plurality of polymers, including a first polymer component
comprising at least one diolefin-derived non-aromatic polymer or
copolymer and a second polymer component comprising a polymer
selected from the group consisting of poly(alkyl(meth)acrylates)
and poly(aromatic(meth)acrylates).
26. A combination according to claim 25 wherein a pretreatment
coating, adapted to alter the surface properties of the medical
device, is applied to the surface of the medical device.
27. A combination according to claim 25 wherein the first polymer
component is selected from the group consisting of the polymers of
butadiene and isoprene.
28. A combination according to claim 25 wherein the first polymer
component includes a homopolymer derived from diolefin
monomers.
29. A combination according to claim 25 wherein the first polymer
component includes a copolymer of a diolefin monomer with a
non-aromatic mono-olefin monomer.
30. A combination according to claim 25 wherein the first polymer
component is selected from the group consisting of polybutadienes
containing polymerized cis-, trans- and 1,2-monomer units and
polyisoprenes containing polymerized cis-1,4- and trans-1,4-monomer
units, polymerized 1,2-vinyl monomer units, and polymerized
3,4-vinyl monomer units.
31. A combination according to claim 25 wherein the composition
includes at least one additional polymer selected from the group
consisting of poly(alkylene-co-alkyl(meth)acrylates), ethylene
copolymers with other alkylenes, polybutenes, aromatic
group-containing copolymers, epichlorohydrin-containing polymers
and poly(ethylene-co-vinyl acetate).
32. A combination according to claim 26 wherein the pretreatment
composition is selected from the group consisting of Parylene.TM.,
silane, photografted polymers, epoxy primers, and polycarboxylate
resins and combinations thereof.
33. A combination according to claim 25 wherein the composition
permits the amount and rate of release of agent(s) from the medical
device to be controlled by adjusting the relative types and
concentrations of the first and second polymer components in the
mixture.
34. A composition for coating the surface of a medical device with
at least one bioactive agent in a manner that permits the coated
surface to release the bioactive agent over time when implanted in
vivo, the composition comprising at least one bioactive agent in
combination with a plurality of polymers, including a first polymer
component comprising at least one diolefin-derived non-aromatic
polymer or copolymer and a second polymer component comprising a
polymer selected from the group consisting of
poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates),
wherein the composition includes at least one additional polymer
selected from the group consisting of ethylene copolymers with
other alkylenes, polybutenes, aromatic group-containing copolymers,
epichlorohydrin-containing polymers, and poly(ethylene-co-vinyl
acetate).
35. A composition according to claim 34 wherein the first polymer
component is selected from the group consisting of the polymers of
butadiene and isoprene.
36. A method of coating the surface of a medical device, the method
comprising the steps of providing a composition including at least
one bioactive agent in combination with a plurality of polymers,
including a first polymer component comprising at least one
diolefin-derived non-aromatic polymer or copolymer and a second
polymer component comprising a polymer selected from the group
consisting of poly(alkyl(meth)acrylates) and
poly(aromatic(meth)acrylates), and applying the composition to the
surface of the device.
37. A combination comprising a stent and a composition for coating
the surface of a stent with at least one bioactive agent in a
manner that permits the coated surface to release the bioactive
agent over time when implanted in vivo, the composition comprising
at least one bioactive agent in combination with a plurality of
polymers, including a first polymer component comprising
polybutadiene, a second polymer component comprising poly(n-butyl
methacrylate), a solvent in which the first and second polymer
components form a true solution, and at least one biocompatible
additive, and further comprising a pretreatment layer including a
multi-interface system to facilitate adhesion and cohesion
interaction relative to the stent and coating composition.
38. A combination according to claim 37, wherein the bioactive
agent is selected from the group consisting of rapamycin,
paclitaxel, dexamethasone, and estradiol.
39. A combination according to claim 37, wherein the stent includes
a material selected from the group consisting of polymers, tissue,
metals, ceramics, and combinations thereof.
40. A combination according to claim 39, wherein the polymers
include polycarbonates and the metals are selected from the group
consisting of titanium, stainless steel, gold, silver, and
nitinol.
41. A combination according to claim 37, wherein the solvent is
selected from the group consisting of tetrahydrofuran, chloroform,
methylene chloride, toluene, cyclohexane and combinations
thereof.
42. A combination according to claim 37, wherein the biocompatible
additive includes one or more antioxidants selected from the group
consisting of butylated hydroxytoluene, vitamin E, BNX, and
dilauryl thiodipropionate.
43. A combination according to claim 37, wherein the pretreatment
layer includes organosilane and Parylene.
44. A composition according to claim 1, further comprising a
pretreatment layer including a multi-interface system to facilitate
adhesion and cohesion interaction relative to the medical device
and composition.
45. A composition according to claim 44, wherein the pretreatment
layer includes organosilane and Parylene.
46. A combination comprising a medical device and a composition for
coating the surface of a medical device with at least one bioactive
agent in a manner that permits the coated surface to release the
bioactive agent over time when implanted in vivo, the composition
comprising at least one bioactive agent in combination with a
plurality of polymers, including a first polymer component
comprising polybutadiene, a second polymer component comprising
poly(n-butyl methacrylate), a solvent in which the first and second
polymer components form a true solution selected from the group
consisting of tetrahydrofuran, chloroform, methylene chloride, and
cyclohexane, and at least one biocompatible additive including one
or more antioxidants selected from the group consisting of
butylated hydroxytoluene, vitamin E, BNX, and dilauryl
thiodipropionate, and further comprising a pretreatment layer
including a multi-interface system to facilitate adhesion and
cohesion interaction relative to the medical device and coating
composition.
47. A combination according to claim 46, wherein the bioactive
agent is selected from the group consisting of rapamycin,
paclitaxel, dexamethasone, and estradiol.
48. The combination of claim 46 further comprising a topcoat
including poly(butyl methacrylate).
49. The combination of claim 46, wherein the medical device
comprises a stent.
50. A method of manufacturing a medical device for delivering one
or more bioactive agents to a subject comprising: providing a
medical device comprising a substrate surface; applying a
pretreatment coating including a plurality of bonding layer-sites
to enhance the cohesion and adhesion of the pretreatment coating
and a bioactive agent coating to at least a portion of the medical
device substrate surface; and bonding the bioactive agent coating
comprising a bioactive agent in combination with a plurality of
polymers, including a first polymer component comprising at least
one diolefin-derived non-aromatic polymer or copolymer and a second
polymer component comprising a polymer selected from the group
consisting of poly(alkyl(meth)acrylates) and
poly(aromatic(meth)acrylates- ).
51. The method of claim 50 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
biocompatibility enhancement.
52. The method of claim 50 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
delamination protection.
53. The method of claim 50 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
durability enhancement.
54. The method of claim 50 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
bioactive agent release control.
55. The method of claim 50 further comprising the step of applying
a topcoat layer to the bioactive agent coating, the topcoat layer
configured to function as a medical device deployment protective
release layer.
56. The method of claim 50, wherein the medical device comprises a
stent.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/559,821, titled Coating Compositions for
Bioactive Agents, filed Apr. 6, 2004, the contents of which are
hereby incorporated by reference. This application is related to
PCT Application Serial No. ______, filed Apr. 6, 2005, titled
Coating Compositions for Bioactive Agents and identified by
Attorney Docket No. 9896.166.8, the contents of which is hereby
incorporated by reference.
TECHNICAL FIELD
[0002] In one aspect, the present invention relates to a method of
treating implantable medical devices with coating compositions to
provide for the controlled release of bioactive (e.g.,
pharmaceutical) agents from the surface of the devices under
physiological conditions. In another aspect, the invention relates
to the coating compositions, per se. In yet another aspect, the
invention relates to devices or surfaces coated with such
compositions. In yet another aspect, the present invention relates
to the local administration of bioactive agents for the prevention
and treatment of diseases, such as vascular and ocular
diseases.
BACKGROUND OF THE INVENTION
[0003] Many surgical interventions require the placement of a
medical device into the body. One prevalent surgical intervention
often requiring such a device is percutaneous transluminal coronary
angioplasty ("PTCA"). Many individuals suffer from circulatory
disease caused by a progressive blockage of the blood vessels,
which often leads to hypertension, ischemic injury, stroke, or
myocardial infarction. Percutaneous transluminal coronary
angioplasty is a medical procedure performed to increase blood flow
through a damaged artery and is now the predominant treatment for
coronary vessel stenosis. The increasing use of this procedure is
attributable to its relatively high success rate and its minimal
invasiveness compared with coronary bypass surgery. A limitation
associated with PTCA is the abrupt closure of the vessel which can
occur soon after angioplasty. Insertion of small spring-like
medical devices called stents into such damaged vessels has proved
to be a better approach to keep the vessels open as compared to
systemic pharmacologic therapy.
[0004] While often necessary and beneficial for treating a variety
of medical conditions, metal or polymeric devices (e.g., stents,
catheters . . . ), after placement in the body, can give rise to
numerous physiological complications. Some of these complications
include: increased risk of infection; initiation of a foreign body
response resulting in inflammation and fibrous encapsulation; and
initiation of a detrimental wound healing response resulting in
hyperplasia and restenosis. These problems have been particularly
acute with the placement of stents in damaged arteries after
angioplasty.
[0005] One promising approach is to provide the device with the
ability to deliver bioactive agents in the vicinity of the implant.
By doing so, some of the harmful effects associated with the
implantation of medical devices can be diminished. Thus, for
example, antibiotics can be released from the surface of the device
to minimize the possibility of infection, and antiproliferative
drugs can be released to inhibit hyperplasia. Another benefit to
the local release of bioactive agents is the avoidance of toxic
concentrations of drugs encountered when given systemically at
sufficiently high doses to achieve therapeutic concentrations at
the site where they are needed.
[0006] Although the potential benefit from using such bioactive
agent-releasing medical devices is great, development of such
medical devices has been slow. Progress has been hampered by many
challenges, including: 1) the requirement, in some instances, for
long term (i.e., at least several weeks) release of bioactive
agents; 2) the need for a biocompatible, non-inflammatory device
surface; 3) the demand for significant durability (and
particularly, resistance to delamination and cracking),
particularly with devices that undergo flexion and/or expansion
when being implanted or used in the body; 4) concerns regarding the
ability of the device to be manufactured in an economically viable
and reproducible manner; and 5) the requirement that the finished
device can be sterilized using conventional methods.
[0007] Implantable medical devices capable of delivering medicinal
agents from hydrophobic polymer coatings have been described. See,
for instance, U.S. Pat. No. 6,214,901; U.S. Pat. No. 6,344,035;
U.S. Publication No. 2002-0032434; U.S. Publication No.
2002-0188037; U.S. Publication No. 2003-0031780; U.S. Publication
No. 2003-0232087; U.S. Publication No. 2003-0232122; PCT
Publication No. WO 99/55396; PCT Publication No. WO 03/105920; PCT
Publication No. WO 03/105918; PCT Publication No. WO 03/105919
which collectively disclose, inter alia, coating compositions
having a bioactive agent in combination with a polymer component
such as polyalkyl(meth)acrylate or aromatic poly(meth)acrylate
polymer and another polymer component such as
poly(ethylene-co-vinyl acetate) for use in coating device surfaces
to control and/or improve their ability to release bioactive agents
in aqueous systems.
SUMMARY OF THE INVENTION
[0008] The present invention provides a coating composition, and
related methods for preparing and using the coating composition to
coat a surface with a bioactive agent, for instance to coat the
surface of an implantable medical device in a manner that permits
the surface to release the bioactive agent over time when implanted
in vivo.
[0009] The coating composition of this invention comprises one or
more bioactive agents in combination with a plurality of polymers,
including: (a) a first polymer component comprising one or more
diolefin derived non-aromatic polymers and copolymers; and (b) a
second polymer component comprising one or more polymers selected
from the group consisting of poly(alkyl(meth)acrylates) and
poly(aromatic (meth)acrylates), where "(meth)" will be understood
by those skilled in the art to include such molecules in either the
acrylic and/or methacrylic form (corresponding to the acrylates
and/or methacrylates, respectively).
[0010] Applicants have discovered a group of first polymers that
when used in combination with one or more second polymers can each
meet or exceed the variety of criteria required of some embodiments
of the composition of this invention, including in terms of its
formulation, delivery, and/or coated characteristics.
[0011] With regard to its formulation, a coating composition of
this invention is may be provided in the form of a true solution by
the use of one or more solvents. Such solvents, in turn, are not
only capable of dissolving the polymers and bioactive agent in
solution, as compared to dispersion or emulsion, but they are also
sufficiently volatile to permit the composition to be effectively
applied to a surface (e.g., as by spraying) and quickly removed
(e.g., as by drying) to provide a stable and desirable coated
composition. In turn, the coated composition is itself homogeneous,
with the first and second polymers effectively serving as
cosolvents for each other, and bioactive agent substantially
equally sequestered within them both.
[0012] The ability to form a true solution using the claimed
polymer combinations is desired when considering the inclusion of
potentially significant amounts of bioactive agent with the polymer
blend. In various embodiments of the present invention, the coating
composition is not only in the form of a true solution, but one in
which bioactive agent is present at saturated or supersaturated
levels. Without intending to be bound by theory, it appears that it
is by virtue of the ability to achieve such solutions, that release
of the bioactive agent from the coated composition is best
accomplished and facilitated. In turn, it appears that the release
of bioactive agent from such a system is due, at least in part, to
its inherent instability within the coated composition itself,
coupled with its physical/chemical preference for surrounding
tissues and fluids. In turn, those skilled in the art will
appreciate the manner in which the various ingredients and amounts
in a composition of this invention can be adjusted to provide
desired release kinetics and for any particular bioactive agent,
solvent and polymer combination.
[0013] With regard to its delivery, a some embodiments of the
composition of this invention meets or exceeds further criteria in
its ability to be sterilized, stored, and delivered to a surface in
a manner that preserves its desired characteristics, yet using
conventional delivery means, such as spraying. Such delivery may
involve spraying the composition onto a device surface in a manner
that avoids or minimizes phase separation of the polymer
components.
[0014] Finally, and with regard to its coated characteristics, a
composition of this invention permits polymer ratios to be varied
in a manner that provides not only an optimal combination of such
attributes as biocompatibility, durability, and bioactive agent
release kinetics, but also that provides a coated composition that
is homogeneous, and hence substantially optically clear upon
microscopic examination. Even more surprisingly, some embodiments
of compositions of this invention will provide these and other
features, with or without optional pretreatment of a metallic
surface. The ability to achieve or exceed any of these criteria,
let alone most if not all of them, was not expected.
[0015] In turn, compositions of the present invention provide
properties that are comparable or better than those obtained with
previous polymer blend compositions. This, in turn, provides a
variety of new and further opportunities, including with respect to
both the type and concentration of bioactive agents that can be
coated, as well as the variety of medical devices, and surfaces,
themselves. In turn, the present invention also provides a
combination that includes a medical device coated with a
composition of this invention, as well as a method of preparing and
using such a combination.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 depicts a graph illustrating the cumulative bioactive
agent release profiles for coating compositions according to the
present invention applied to stents, as described in Example 1.
[0017] FIG. 1A depicts a bar chart illustrating the durability
profiles for coating compositions according to the present
invention applied to stents, as described in Example 1.
[0018] FIG. 2 depicts a graph illustrating the cumulative bioactive
agent release profiles for coating compositions according to the
present invention applied to stents, as described in Example 2.
[0019] FIG. 3 depicts a graph illustrating the cumulative bioactive
agent release profiles for coating compositions according to the
present invention applied to stents, as described in Example 3.
[0020] FIG. 4 depicts a graph illustrating the stress/strain
measurements of first polymer components used in coating
compositions according to the present invention, as described in
Example 5.
[0021] FIG. 5 depicts a scanning electron microscope image a coated
stent including a coating composition according to the present
invention after conventional crimping and balloon expansion
procedures.
[0022] FIG. 6 depicts a graph illustrating the cumulative bioactive
agent release profiles for coating compositions according to the
present invention applied to stents, as described in Example 7.
[0023] FIG. 7 depicts a graph illustrating the cumulative bioactive
agent release profiles for coating compositions according to the
present invention applied to stents, as described in Example 7.
DETAILED DESCRIPTION
[0024] Without intending to be bound by theory, it appears that
suitable first polymers for use in a composition of this invention
provide an optimal combination of such properties as glass
transition temperature (T.sub.g) and diffusion constant for the
particular bioactive agent of choice. Along with melting
temperature (T.sub.m), T.sub.g is an important parameter of a given
polymer (including copolymer), and particularly amorphous polymers,
that can be used to characterize its properties over a wide
temperature range. A polymer is typically brittle at temperatures
below its T.sub.g, and flexible at temperatures above. Both T.sub.m
and T.sub.g can be affected by such things as polymer structure and
backbone flexibility, molecular weight, attractive forces, and
pressure. For random copolymers and compatible polymer blends, only
a single T.sub.g is observed, usually lying intermediate between
the T.sub.g of the corresponding pure homopolymers. Different
T.sub.g's are exhibited for incompatible polymer blends, and
between the microdomains of block copolymers with mutually
incompatible blocks. T.sub.g can be measured by any suitable
technique, e.g., dilatometry, refractive index, differential
scanning calorimetry, dynamic mechanical measurement, and
dielectric measurement.
[0025] Second polymers (e.g., poly(n-butyl methacrylate)) of the
present composition generally provide a T.sub.g in the range of
room to body temperature (e.g., from about 20.degree. C. to about
40.degree. C.), and hence tend to be somewhat stiffer polymers, in
turn, providing a slower diffusion constant for many bioactive
agents. Applicants have discovered the manner in which certain new
polymers can be used as a first polymer component, to essentially
balance, or temper the desired properties of the second polymer.
Such first polymers will generally provide a lower glass transition
temperature (e.g., below room temperature, and in some embodiments
in the range of about 0.degree. C. or less), together with a
relatively high diffusion constant for the bioactive agent. By
appropriately combining the two polymers with bioactive agent,
those skilled in the art, given the present description, will be
able to vary both the selection and ratios of first and second
polymers, in order to determine an optimal combination of physical
and mechanical properties, including bioactive agent diffusion and
release kinetics, as well as durability and tenacity of the coating
itself upon a particular surface, that best fits their particular
needs.
[0026] Hence the first polymer of this invention may provide an
optimal combination of glass transition temperature (e.g., at or
lower than that of the second polymer), compatibility with the
bioactive agent of choice, acceptable solubility in the solvents of
choice, as well as commercial availability and cost.
[0027] The term "coating composition", as used herein, will refer
to one or more vehicles (e.g., solutions, mixtures, emulsions,
dispersions, blends, etc.) used to effectively coat a surface with
bioactive agent, first polymer component and/or second polymer
component, either individually or in any suitable combination.
[0028] The term "coated composition" will refer to the effective
combination, upon the surface of a device, of bioactive agent,
first polymer component and second polymer component, whether
formed as the result of one or more coating vehicles or in one or
more layers and/or steps.
[0029] Unless defined otherwise, the term "coating" will refer to
the effective combination of bioactive agent, first polymer
component and second polymer component, independent of the device
surface, and whether formed as the result of one or more coating
vehicles or in one or more layers.
[0030] Unless otherwise indicated, the term "molecular weight" and
all polymeric molecular weights described herein are "weight
average" molecular weights ("Mw"). As used herein "weight average
molecular weight" or M.sub.w, is an absolute method of measuring
molecular weight and is particularly useful for measuring the
molecular weight of a polymer preparation. The weight average
molecular weight (M.sub.w) can be defined by the following formula:
1 M v = i N i M i 2 i N i M i
[0031] wherein N represents the number of moles of a polymer in the
sample with a mass of M, and .SIGMA..sub.i is the sum of all
N.sub.iM.sub.i (species) in a preparation. The M.sub.w can be
measured using common techniques, such as light scattering or
ultracentrifugation. Discussion of M.sub.w and other terms used to
define the molecular weight of polymer preparations can be found
in, for example, Allcock, H. R. and Lampe, F. W., Contemporary
Polymer Chemistry; pg 271 (1990).
[0032] As described and exemplified herein, a resultant composition
can be coated using a plurality of individual steps or layers,
including for instance, an initial layer having only bioactive
agent (or bioactive agent with one or both of the polymer
components), over which are coated one or more additional layers
containing suitable combinations of bioactive agent, first polymer
component and/or second polymer component, the combined result of
which is to provide a coated composition of the invention. In turn,
in some embodiments, the invention further provides a method of
reproducibly controlling the release (e.g., elution) of a bioactive
agent from the surface of a medical device implanted in vivo. Those
skilled in the art will appreciate the manner in which the combined
effect of these various layers can be used and optimized to achieve
various effects in vivo. In addition, the surface to which the
composition is applied can itself be pretreated in a manner
sufficient to improve attachment of the composition to the
underlying (e.g., metallic) surface. Examples of such pretreatments
include the use of compositions such as Parylene.TM. coatings, as
described herein. Additional examples of such pretreatments include
silane coupling agents, photografted polymers, epoxy primers,
polycarboxylate resins, and physical roughening of the surface. It
is further noted that the pretreatment compositions may be used in
combination with each other or may be applied in separate layers to
form a pretreatment coating on the surface of the medical
device.
[0033] While not intending to be bound by theory, the release
kinetics of the bioactive agent in vivo are thought to generally
include both a short term ("burst") release component, within the
order of minutes to hours after implantation, and a longer term
release component, which can range from on the order of hours to
days or even months or years of useful release.
[0034] Additionally, the ability to coat a device in the manner of
the present invention provides greater latitude in the composition
of various coating layers, e.g., permitting more or less of the
second polymer component (i.e., poly(alkyl(meth)acrylate) and/or
poly(aromatic (meth)acrylate)) to be used in coating compositions
used to form different layers (e.g., as a topcoat layer). This, in
turn, provides the opportunity to further control release and
elution of the bioactive agent from the overall coating.
[0035] The coating composition and method can be used to control
the amount and rate of bioactive agent (e.g., drug) release from
one or more surfaces of implantable medical devices. In some
embodiments, the method employs a mixture of hydrophobic polymers
in combination with one or more bioactive agents, such as a
pharmaceutical agent, such that the amount and rate of release of
agent(s) from the medical device can be controlled, e.g., by
adjusting the relative types and/or concentrations of hydrophobic
polymers in the mixture. For a given combination of polymers, for
instance, this approach permits the release rate to be adjusted and
controlled by simply adjusting the relative concentrations of the
polymers in the coating mixture. This provides an additional means
to control rate of bioactive agent release besides the conventional
approach of varying the concentration of bioactive agent in a
coated composition.
[0036] Some embodiments of the invention include a method of
coating a device comprising the step of applying the composition to
the device surface under conditions of controlled relative humidity
(at a given temperature), for instance, under conditions of
increased or decreased relative humidity as compared to ambient
humidity. Humidity can be "controlled" in any suitable manner,
including at the time of preparing and/or using (as by applying)
the composition, for instance, by coating the surface in a confined
chamber or area adapted to provide a relative humidity different
than ambient conditions, and/or by adjusting the water content of
the coating or coated composition itself. Without intending to be
bound by theory, it appears that the elution rate of a bioactive
agent from a coating composition generally increases as relative
humidity increases.
[0037] Some embodiments of a coating composition of this invention
include a mixture of two or more polymers having complementary
physical characteristics, and a bioactive agent or agents
applicable to the surface of an implantable medical device. The
device can be of any suitable type or configuration, and in some
embodiments undergoes flexion and/or expansion upon implantation or
use, as in the manner of a stent or catheter. The applied coating
composition is cured (e.g., by solvent evaporation) to provide a
tenacious and flexible bioactive-releasing composition on the
surface of the medical device. Such coating compositions are
particularly well suited for devices that are themselves
sufficiently small, or have portions that are sufficiently small
(as in the struts of an expandable stent or the twists of an ocular
coil), to permit the coated composition to form a contiguous, e.g.,
circumferential, coating, thereby further improving the ability of
the coating to remain intact (e.g., avoid delamination).
[0038] The complementary polymers are selected such that a broad
range of relative polymer concentrations can be used without
detrimentally affecting the desirable physical characteristics of
the polymers. By use of the polymer combinations (including
mixtures and blends) of the invention the bioactive release rate
from a coated medical device can be manipulated by adjusting the
relative concentrations of the polymers.
[0039] In some embodiments, the present invention relates to a
coating composition and related method for coating an implantable
medical device which undergoes flexion and/or expansion upon
implantation. However it is noted that the coating composition may
also be utilized with medical devices that have minimal or do not
undergo flexion and/or expansion. The structure and composition of
the underlying device can be of any suitable, and medically
acceptable, design and can be made of any suitable material that is
compatible with the coating itself. The natural or pretreated
surface of the medical device is provided with a coating containing
one or more bioactive agents.
[0040] A first polymer component of this invention provides an
optimal combination of similar properties, and particularly when
used in admixture with the second polymer component. First polymers
include diolefin derived non-aromatic polymers and copolymers.
Examples of suitable polymers are commercially available from
sources such as Sigma-Aldrich.
[0041] First polymers may include diolefin-derived, non-aromatic
polymers and copolymers, including those in which the diolefin
monomer used to prepare the polymer or copolymer is selected from
butadiene (CH.sub.2.dbd.CH--CH.dbd.CH.sub.2) and/or isoprene
(CH.sub.2.dbd.CH--C(CH.sub.3).dbd.CH.sub.2). A butadiene polymer
can include one or more butadiene monomer units which can be
selected from the monomeric unit structures (a), (b), or (c): 1
[0042] An isoprene polymer can include one or more isoprene monomer
units which can be selected from the monomeric unit structures (d),
(e), (f) or (g): 2
[0043] In some embodiments, the polymer is a homopolymer derived
from diolefin monomers or is a copolymer of diolefin monomer with
non-aromatic mono-olefin monomer, and optionally, the homopolymer
or copolymer can be partially hydrogenated. Such polymers can be
selected from the group consisting of polybutadienes containing
polymerized cis-, trans- and/or 1,2-monomer units, and in some
embodiments a mixture of all three co-polymerized monomer units,
and polyisoprenes containing polymerized cis-1,4- and/or
trans-1,4-monomer units, polymerized 1,2-vinyl monomer units,
polymerized 3,4-vinyl monomer units and/or others as described in
the Encyclopedia of Chemical Technology, Vol. 8, page 915 (1993),
the entire contents of which is hereby incorporated by
reference.
[0044] Alternatively, the first polymer is a copolymer, including
graft copolymers, and random copolymers based on a non-aromatic
mono-olefin co-monomer such as acrylonitrile, an alkyl
(meth)acrylate and/or isobutylene. In some embodiments, when the
mono-olefin monomer is acrylonitrile, the interpolymerized
acrylonitrile is present at up to about 50% by weight; and when the
mono-olefin monomer is isobutylene, the diolefin monomer is
isoprene (e.g., to form what is commercially known as a "butyl
rubber"). In some embodiments, the polymers and copolymers have a
Mw between about 50 kilodaltons and about 1,000 kilodaltons. In
other embodiments, the polymers and copolymers have a Mw between
about 100 kilodaltons and about 450 kilodaltons. In yet other
embodiments the polymers and copolymers have a Mw between about 150
kilodaltons and about 1,000 kilodaltons, and optionally between
about 200 kilodaltons and about 600 kilodaltons.
[0045] Other examples of suitable first polymers of this type are
commercially available from sources such as Sigma-Aldrich, such as
the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment, the contents of which are hereby incorporated by
reference. For example, suitable first polymers include, but are
not limited to, polybutadiene, poly(butadiene-co-acrylonitrile),
polybutadiene-block-polyisoprene, polybutadiene-graft-poly(methyl
acrylate-co-acrylonitrile), polyisoprene, and partially
hydrogenated polyisoprene.
[0046] A second polymer component of this invention provides an
optimal combination of various structural/functional properties,
including hydrophobicity, durability, bioactive agent release
characteristics, biocompatibility, molecular weight, and
availability. In one such an embodiment, the composition may
comprise at least one second polymer component selected from the
group consisting of poly(alkyl(meth)acrylates- ) and poly(aromatic
(meth)acrylates).
[0047] In some embodiments, the second polymer component is a
poly(alkyl)methacrylate, that is, an ester of a methacrylic acid.
Examples of suitable poly(alkyl(meth)acrylates) include those with
alkyl chain lengths from 2 to 8 carbons, inclusive, and with
molecular weights from 50 kilodaltons to 900 kilodaltons. In some
embodiments the polymer mixture includes a poly(alkyl
(meth)acrylate) with a molecular weight of from about 100
kilodaltons to about 1000 kilodaltons, in some embodiments from
about 150 kilodaltons to about 500 kilodaltons, in some embodiments
from about 200 kilodaltons to about 400 kilodaltons. An example of
a second polymer is poly(n-butyl methacrylate). Examples of other
polymers are poly(n-butyl methacrylate-co-methyl methacrylate, with
a monomer ratio of 3:1, poly(n-butyl methacrylate-co-isobutyl
methacrylate, with a monomer ratio of 1:1 and poly(t-butyl
methacrylate). Such polymers are available commercially (e.g., from
Sigma-Aldrich, Milwaukee, Wis.) with molecular weights ranging from
about 150 kilodaltons to about 350 kilodaltons, and with varying
inherent viscosities, solubilities and forms (e.g., as slabs,
granules, beads, crystals or powder).
[0048] Examples of suitable poly(aromatic (meth)acrylates) include
poly(aryl(meth)acrylates), poly(aralkyl(meth)acrylates),
poly(alkaryl(meth)acrylates), poly(aryloxyalkyl(meth)acrylates),
and poly(alkoxyaryl(meth)acrylates). Such terms are used to
describe polymeric structures wherein at least one carbon chain and
at least one aromatic ring are combined with (meth)acrylic groups,
typically esters, to provide a composition of this invention. For
instance, and more specifically, a poly(aralkyl(meth)acrylate) can
be made from aromatic esters derived from alcohols also containing
aromatic moieties, such as benzyl alcohol. Similarly, a
poly(alkaryl (meth)acrylate) can be made from aromatic esters
derived from aromatic alcohols such as p-anisole. Suitable
poly(aromatic (meth)acrylates) include aryl groups having from 6 to
16 carbon atoms and with molecular weights from about 50 to about
900 kilodaltons. Examples of suitable poly(aryl(meth)acrylates)
include poly(9-anthracenyl methacrylate), poly(chlorophenyl
acrylate), poly(methacryloxy-2-hydroxybenzophenone),
poly(methacryloxybenzotriazole)- , poly(naphthyl acrylate),
poly(naphthylmethacrylate), poly-4-nitrophenylacrylate,
poly(pentachloro(bromo, fluoro)acrylate) and methacrylate,
poly(phenyl acrylate) and poly(phenyl methacrylate). Examples of
suitable poly(aralkyl(meth)acrylates) include poly(benzyl
acrylate), poly(benzyl methacrylate), poly(2-phenethyl acrylate),
poly(2-phenethyl methacrylate) and poly(1-pyrenylmethyl
methacrylate). Examples of suitable poly(alkaryl(meth)acrylates
include poly(4-sec-butylphenyl methacrylate), poly(3-ethylphenyl
acrylate), and poly(2-methyl-1-naphthyl methacrylate). Examples of
suitable poly(aryloxyalkyl (meth)acrylates) include
poly(phenoxyethyl acrylate), poly(phenoxyethyl methacrylate), and
poly(polyethylene glycol phenyl ether acrylate) and
poly(polyethylene glycol phenyl ether methacrylate) with varying
polyethylene glycol molecular weights. Examples of suitable
poly(alkoxyaryl(meth)acrylates) include poly(4-methoxyphenyl
methacrylate), poly(2-ethoxyphenyl acrylate) and
poly(2-methoxynaphthyl acrylate).
[0049] Acrylate or methacrylate monomers or polymers and/or their
parent alcohols are commercially available from Sigma-Aldrich
(Milwaukee, Wis.) or from Polysciences, Inc, (Warrington, Pa.).
[0050] Optionally, the coating composition may include one or more
additional polymers in combination with the first and second
polymer components, the additional polymers being, for example,
selected from the group consisting of (i)
poly(alkylene-co-alkyl(meth)acrylates), (ii) ethylene copolymers
with other alkylenes, (iii) polybutenes, (iv) aromatic
group-containing copolymers, (v) epichlorohydrin-containing
polymers and (vi) poly(ethylene-co-vinyl acetate). In some
embodiments, the additional polymers may act as substitutes for a
portion of the first polymer. For example, the additional polymers
may substitute up to about 25% of the first polymer. In other
embodiments, the additional polymers may substitute up to about 50%
of the first polymer.
[0051] Suitable poly(alkylene-co-alkyl(meth)acrylates) include
those copolymers in which the alkyl groups are either linear or
branched, and substituted or unsubstituted with non-interfering
groups or atoms. Such alkyl groups may comprise from 1 to 8 carbon
atoms, inclusive, and in some embodiments, from 1 to 4 carbon
atoms, inclusive. In some embodiments, the alkyl group is
methyl.
[0052] In turn, copolymers that include such alkyl groups may
comprise from about 15% to about 80% (wt) of alkyl acrylate. When
the alkyl group is methyl, the polymer may contain from about 20%
to about 40% methyl acrylate, and in some embodiments, from about
25 to about 30% methyl acrylate. When the alkyl group is ethyl, the
polymer may contain from about 15% to about 40% ethyl acrylate, and
when the alkyl group is butyl, the polymer may contain from about
20% to about 40% butyl acrylate.
[0053] The alkylene groups are selected from ethylene and/or
propylene, and in some embodiments, the alkylene group is ethylene.
In some embodiments, the (meth)acrylate comprises an acrylate
(i.e., no methyl substitution on the acrylate group). Some
embodiments of copolymers provide a molecular weight (Mw) of about
50 kilodaltons to about 500 kilodaltons, and in various
embodiments, Mw is 50 kilodaltons to about 200 kilodaltons.
[0054] The glass transition temperature for these copolymers varies
with ethylene content, alkyl length on the (meth)acrylate, and
whether the co-polymer is an acrylate or methacrylate. At higher
ethylene content, the glass transition temperature tends to be
lower, and closer to that of pure polyethylene (-120.degree. C.). A
longer alkyl chain also lowers the glass transition temperature. A
methyl acrylate homopolymer has a glass transition temperature of
about 10.degree. C. while a butyl acrylate homopolymer has one of
-54.degree. C.
[0055] Copolymers such as poly(ethylene-co-methyl acrylate),
poly(ethylene-co-butyl acrylate) and poly(ethylene-co-2-ethylhexyl
acrylate) copolymers are available commercially from sources such
as Atofina Chemicals, Inc., Philadelphia, Pa., and can be prepared
using methods available to those skilled in the respective art.
[0056] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich, such
as the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment. For example, suitable additional polymers include, but
are not limited to, poly(ethylene-co-methyl acrylate),
poly(ethylene-co-ethyl acrylate), and poly(ethylene-co-butyl
acrylate).
[0057] Suitable additional polymers also include ethylene
copolymers with other alkylenes, which in turn, can include
straight chain and branched alkylenes, as well as substituted or
unsubstituted alkylenes. Examples include copolymers prepared from
alkylenes that comprise from 3 to 8 branched or linear carbon
atoms, inclusive, alkylene groups that comprise from 3 to 4
branched or linear carbon atoms, inclusive, and alkylene groups
containing 3 carbon atoms (e.g., propylene). In some embodiments,
the other alkylene is a straight chain alkylene (e.g.,
1-alkylene).
[0058] Copolymers of this type can comprise from about 20% to about
90% (based on moles) of ethylene, and in some embodiments, from
about 35% to about 80% (mole) of ethylene. Such copolymers will
have a molecular weight of between about 30 kilodaltons to about
500 kilodaltons. Examples of copolymers are selected from the group
consisting of poly(ethylene-co-propylene),
poly(ethylene-co-1-butene), polyethylene-co-1-butene-co-1-hexene)
and/or poly(ethylene-co-1-octene).
[0059] Examples of copolymers include poly(ethylene-co-propylene)
random copolymers in which the copolymer contains from about 35% to
about 65% (mole) of ethylene; and in some embodiments, from about
55% to about 65% (mole) ethylene, and the molecular weight of the
copolymer is from about 50 kilodaltons to about 250 kilodaltons,
and in some embodiments from about 100 kilodaltons to about 200
kilodaltons.
[0060] Copolymers of this type can optionally be provided in the
form of random terpolymers prepared by the polymerization of both
ethylene and propylene with optionally one or more additional diene
monomers, such as those selected from the group consisting of
ethylidene norborane, dicyclopentadiene and/or hexadiene. In some
embodiments terpolymers of this type can include up to about 5%
(mole) of the third diene monomer.
[0061] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich, such
as the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment. For example, suitable additional polymers include, but
are not limited to, poly(ethylene-co-propylene),
poly(ethylene-co-1-butene), poly(ethylene-co-1-butene-co-1-hexene),
poly(ethylene-co-1-octene), and
poly(ethylene-co-propylene-co-5-methylene-2-norborene).
[0062] "Polybutenes" suitable for use in the present invention as
additional polymers include polymers derived by homopolymerizing or
randomly interpolymerizing isobutylene, 1-butene and/or 2-butene.
The polybutene can be a homopolymer of any of the isomers or it can
be a copolymer or a terpolymer of any of the monomers in any ratio.
In some embodiments, the polybutene contains at least about 90%
(wt) of isobutylene or 1-butene, and in some embodiments, the
polybutene contains at least about 90% (wt) of isobutylene. The
polybutene may contain non-interfering amounts of other ingredients
or additives, for instance it can contain up to 1000 ppm of an
antioxidant (e.g., 2,6-di-tert-butyl-methylphenol).
[0063] In some embodiments, the polybutene has a molecular weight
between about 100 kilodaltons and about 1,000 kilodaltons, in some
embodiments, between about 150 kilodaltons and about 600
kilodaltons, and in some embodiments, between abot 150 kilodaltons
and about 250 kilodaltons. In other embodiments, the polybutene has
a molecular weight between about 150 kilodaltons and about 1,000
kilodaltons, optionally, between about 200 kilodaltons and about
600 kilodaltons, and further optionally, between about 350
kilodaltons and about 500 kilodaltons. Polybutenes having a
molecular weight greater than about 600 kilodaltons, including
greater than 1,000 kilodaltons are available but are expected to be
more difficult to work with and, will in turn, be less desired.
Other examples of suitable copolymers of this type are commercially
available from sources such as Sigma-Aldrich.
[0064] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich, such
as the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment.
[0065] Other additional polymers include aromatic group-containing
copolymers, including random copolymers, block copolymers and graft
copolymers. In some embodiments, the aromatic group is incorporated
into the copolymer via the polymerization of styrene, and in some
embodiments, the random copolymer is a copolymer derived from
copolymerization of styrene monomer and one or more monomers
selected from butadiene, isoprene, acrylonitrile, a C.sub.1-C.sub.4
alkyl(meth)acrylate (e.g., methyl methacrylate) and/or butene
(e.g., isobutylene). Useful block copolymers include copolymer
containing (a) blocks of polystyrene, (b) blocks of a polyolefin
selected from polybutadiene, polyisoprene and/or polybutene (e.g.,
isobutylene), and (c) optionally a third monomer (e.g., ethylene)
copolymerized in the polyolefin block.
[0066] The aromatic group-containing copolymers may contain about
10% to about 50% (wt) of polymerized aromatic monomer and the
molecular weight of the copolymer may be from about 50 kilodaltons
to about 500 kilodaltons. In some embodiments, the molecular weight
of the copolymer may be from about 300 kilodaltons to about 500
kilodaltons. In other embodiments, the molecular weight of the
copolymer may be from about 100 kilodaltons to about 300
kilodaltons.
[0067] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich, such
as the 2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment. For example, suitable additional polymers include, but
are not limited to, poly(styrene-co-butadiene) (random),
polystyrene-block-polybutadiene,
polystyrene-block-polybutadiene-block-polystyrene,
polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene,
polystyrene-block-polyisoprene-block-polystyrene,
polystyrene-block-polyi- sobutylene-block-polystyrene,
poly(styrene-co-acrylonitrile),
poly(styrene-co-butadiene-co-acrylonitrile), and
poly(styrene-co-butadien- e-co-methyl methacrylate).
[0068] Other suitable additional polymers include epichlorohydrin
homopolymers and poly(epichlorohydrin-co-alkylene oxide)
copolymers. In some embodiments in the case of the copolymer, the
copolymerized alkylene oxide is ethylene oxide. In some
embodiments, epichlorohydrin content of the
epichlorohydrin-containing polymer is from about 30% to 100% (wt),
and in some embodiments from about 50% to 100% (wt). In some
embodiments, the epichlorohydrin-containing polymers have an Mw
from about 100 kilodaltons to about 300 kilodaltons.
[0069] Other examples of suitable additional copolymers of this
type are commercially available from sources such as Sigma-Aldrich,
such as the 2003-2004 Aldrich Handbook of Fine Chemicals and
Laboratory Equipment. For example, suitable additional polymers
include, but are not limited to, polyepichlorohydrin, and
poly(epichlorohydrin-co-ethylene oxide).
[0070] One additional polymer that may be utilized in the coating
composition of the present invention includes
poly(ethylene-co-vinyl acetate) (pEVA). Examples of suitable
polymers of this type are available commercially and include
poly(ethylene-co-vinyl acetate) having vinyl acetate concentrations
of from about 8% and about 90%, in some embodiments from about 20
to about 40 weight percent and in some embodiments from about 30 to
about 34 weight percent. Such polymers are generally found in the
form of beads, pellets, granules, etc. It has generally been found
that pEVA co-polymers with lower percent vinyl acetate become
increasingly insoluble in typical solvents.
[0071] Coating compositions for use in this invention may include
mixtures of first and second polymer components as described
herein. Optionally, both first and second polymer components are
purified for such use to a desired extent and/or provided in a form
suitable for in vivo use. Moreover, biocompatible additives such as
antioxidants (e.g., butylated hydroxytoluene (BHT), vitamin E
(tocopherol), BNX.TM., and/or dilauryl thiodipropionate (DLTDP))
and permeation enhancers (e.g., vitamin C) may be added. Other
suitable additives include dyes and pigments (e.g., titanium
dioxide, Solvent Red 24, iron oxide, and Ultramarine Blue); slip
agents (e.g., amides such as oleyl palmitamide, N,N'-ethylene
bisoleamide, erucamide, stearamide, and oleamide); antioxidants
(e.g. Irganox.TM. series, phenolic and hindered phenolic
antioxidants, organophosphites (e.g., trisnonylphenyl phosphite,
Irgafos.TM. 168), lactones (e.g., substituted benzofuranone),
hydroxylamine, and MEHQ (monomethyl ether of hydroquinone));
surfactants (e.g., anionic fatty acid surfactants (e.g., sodium
lauryl sulfate, sodium dodecylbenzenesulfonate, sodium stearate,
and sodium palmitate), cationic fatty acid surfactants (e.g.,
quaternary ammonium salts and amine salts), and nonionic
ethoxylated surfactants (e.g., ethoxylated p-octylphenol)); and
leachable materials (i.e., permeation enhancers) (e.g., hydrophilic
polymers (e.g., poly(ethylene glycol), polyvinylpyrrolidone, and
poly(vinyl alcohol)) and hydrophilic small molecules (e.g., sodium
chloride, glucose)). In addition, any impurities may be removed by
conventional methods available to those skilled in the art.
[0072] In some embodiments the polymer mixture includes a first
polymer component comprising one or more polymers selected from the
group consisting of diolefin derived non-aromatic polymers and
copolymers, and a second polymer component selected from the group
consisting of poly(alkyl(meth)acrylates) and
poly(aromatic(meth)acrylates) and having a molecular weight of in
some embodiments from about 150 kilodaltons to about 500
kilodaltons, and in some embodiments from about 200 kilodaltons to
about 400 kilodaltons.
[0073] These mixtures of polymers have proven useful with absolute
polymer concentrations (i.e., the total combined concentrations of
both polymers in the coating composition), of between about 0.1 and
about 50 percent (by weight), and in some embodiments between about
0.1 and about 35 percent (by weight). In various embodiments, the
polymer mixtures contain at least about 10 percent by weight of
either the first polymer or the second polymer.
[0074] In some embodiments, the polymer composition may comprise
about 5% to about 95% of the first and/or second polymers based on
the total weights of the first and second polymers. In some
embodiments, the composition may comprise about 15% to about 85% of
the first and/or second polymers. In various embodiments, the
composition may include about 25% to about 75% of the first and/or
second polymers.
[0075] In some embodiments, the bioactive agent may comprise about
1% to about 75% of the first polymer, second polymer, and bioactive
agent mixture (i.e., excluding solvents and other additives). In
some embodiments, the bioactive agent may comprise about 5% to
about 60% of such a mixture. In various embodiments, the bioactive
agent may comprise about 25% to about 45% of such a mixture. The
concentration of the bioactive agent or agents dissolved or
suspended in the coating mixture can range from about 0.01 to about
90 percent, by weight, based on the weight of the final coating
composition, and optionally from about 0.1 to about 50 percent by
weight.
[0076] The term "bioactive agent", as used herein, will refer to a
wide range of biologically active materials or drugs that can be
incorporated into a coating composition of the present invention.
In some embodiments, the bioactive agent(s) to be incorporated do
not chemically interact with the coating composition during
fabrication or during the bioactive agent release process.
[0077] Bioactive agent will, in turn, refer to a peptide, protein,
carbohydrate, nucleic acid, lipid, polysaccharide or combinations
thereof, or synthetic or natural inorganic or organic molecule,
that causes a biological effect when administered in vivo to an
animal, including but not limited to birds and mammals, including
humans. Nonlimiting examples are antigens, enzymes, hormones,
receptors, peptides, and gene therapy agents. Examples of suitable
gene therapy agents include a) therapeutic nucleic acids, including
antisense DNA and antisense RNA, and b) nucleic acids encoding
therapeutic gene products, including plasmid DNA and viral
fragments, along with associated promoters and excipients. Examples
of other molecules that can be incorporated include nucleosides,
nucleotides, antisense, vitamins, minerals, and steroids.
[0078] Controlled release of bioactive agent is vitally important
in many medical areas, including cardiology, oncology, central
nervous system disorders, neurology, immunology, diabetes control,
musculoskeletal and joint diseases, ophthalmology, vaccination,
respiratory, endocrinology, dermatology, and
diagnostics/imaging.
[0079] Furthermore, it is recognized that thrombus formation on or
around medical devices such as stents may create variations in
biological agent uptake in target tissue sites and can act to
either increase or decrease wall deposition according to the clot
and device geometry. The embodiments of this invention further
enable reliable and predictable delivery and update of bioactive
agents through enhancement of the conformable, durable and stable
coatings which result, regardless of flexion or other motion of the
medical device substrate.
[0080] Coating compositions prepared according to this process can
be used to deliver drugs such as nonsteroidal anti-inflammatory
compounds, anesthetics, chemotherapeutic agents, immunotoxins,
immunosuppressive agents, steroids, antibiotics, antivirals,
antifungals, steroidal antiinflammatories, anticoagulants,
antiproliferative agents, angiogenic agents, and anti-angiogenic
agents. In some embodiments, the bioactive agent to be delivered is
a hydrophobic drug having a relatively low molecular weight (i.e.,
a molecular weight no greater than about two kilodaltons, and
optionally no greater than about 1.5 kilodaltons). For example,
hydrophobic drugs such as rapamycin, paclitaxel, dexarnethasone,
lidocaine, triamcinolone acetonide, retinoic acid, estradiol,
pimecrolimus, tacrolimus or tetracaine can be included in the
coating and are released over several hours or longer.
[0081] Classes of medicaments which can be incorporated into
coatings of this invention include, but are not limited to,
anti-AIDS substances, anti-neoplastic substances, antibacterials,
antifungals and antiviral agents, enzyme inhibitors, neurotoxins,
opioids, hypnotics, antihistamines, immunomodulators (e.g.,
cyclosporine), tranquilizers, anti-convulsants, muscle relaxants
and anti-Parkinsonism substances, anti-spasmodics and muscle
contractants, miotics and anti-cholinergics, immunosuppressants
(e.g. cyclosporine), anti-glaucoma solutes, anti-parasite and/or
anti-protozoal solutes, anti-hypertensives, analgesics,
anti-pyretics and anti-inflammatory agents (such as NSAIDs), local
anesthetics, ophthalmics, prostaglandins, anti-depressants,
anti-psychotic substances, anti-emetics, imaging agents, specific
targeting agents, neurotransmitters, proteins, and cell response
modifiers. A more complete listing of classes of medicaments may be
found in the Pharmazeutische Wirkstoffe, ed. A. Von Kleemann and J.
Engel, Georg Thieme Verlag, Stuttgart/New York, 1987, incorporated
herein by reference.
[0082] Antibiotics are recognized as substances which inhibit the
growth of or kill microorganisms. Antibiotics can be produced
synthetically or by microorganisms. Examples of antibiotics include
penicillin, tetracycline, chloramphenicol, minocycline,
doxycycline, vancomycin, bacitracin, kanamycin, neomycin,
gentamycin, erythromycin, cephalosporins, geldanamycin and analogs
thereof. Examples of cephalosporins include cephalothin,
cephapirin, cefazolin, cephalexin, cephradine, cefadroxil,
cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid,
ceforanide, cefotaxime, moxalactam, ceflizoxime, ceftriaxone, and
cefoperazone.
[0083] Antiseptics are recognized as substances that prevent or
arrest the growth or action of microorganisms, generally in a
nonspecific fashion, e.g., either by inhibiting their activity or
destroying them. Examples of antiseptics include silver
sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium
hypochlorite, phenols, phenolic compounds, iodophor compounds,
quaternary ammonium compounds, and chlorine compounds.
[0084] Anti-viral agents are substances capable of destroying or
suppressing the replication of viruses. Examples of anti-viral
agents include methyl-P-adamantane methylamine,
hydroxy-ethoxymethylguanine, adamantanamine,
5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine
arabinoside.
[0085] Enzyme inhibitors are substances which inhibit an enzymatic
reaction. Examples of enzyme inhibitors include edrophonium
chloride, N-methylphysostigmine, neostigmine bromide, physostigmine
sulfate, tacrine HCl, tacrine, 1-hydroxymaleate, iodotubercidin,
p-bromotetramisole,
10-(.alpha.-diethylaminopropionyl)-phenothiazine hydrochloride,
calmidazolium chloride, hemicholinium-3,3,5-dinitrocatecho- l,
diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor
II, 3-phenylpropargylamine, N-monomethyl-L-arginine acetate,
carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl,
clorgyline HCl, deprenyl HCl, L(-), deprenyl.HCl, D(+),
hydroxylamine HCl, iproniazid phosphate,
6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl,
quinacrine HCl, semicarbazide HCl, tranylcypromine HCl,
N,N-diethylaminoethyl-2,2-di- phenylvalerate hydrochloride,
3-isobutyl-1-methylxanthne, papaverine HCl, indomethacin,
2-cyclooctyl-2-hydroxyethylamine hydrochloride,
2,3-dichloro-a-methylbenzylamine (DCMB),
8,9-dichloro-2,3,4,5-tetrahydro-- 1H-2-benzazepine hydrochloride,
p-aminoglutethimide, p-aminoglutethimide tartrate, R(+),
p-aminoglutethimide tartrate, S(-), 3-iodotyrosine,
alpha-methyltyrosine, L(-), alpha-methyltyrosine, D L(-),
cetazolamide, dichlorphenamide,
6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.
[0086] Anti-pyretics are substances capable of relieving or
reducing fever. Anti-inflammatory agents are substances capable of
counteracting or suppressing inflammation. Examples of such agents
include aspirin (acetylsalicylic acid), indomethacin, sodium
indomethacin trihydrate, salicylamide, naproxen, colchicine,
fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium
salicylamide.
[0087] Local anesthetics are substances which inhibit pain signals
in a localized region. Examples of such anesthetics include
procaine, lidocaine, tetracaine and dibucaine.
[0088] Imaging agents are agents capable of imaging a desired site,
e.g., tumor, in vivo. Examples of imaging agents include substances
having a label which is detectable in vivo, e.g., antibodies
attached to fluorescent labels. The term antibody includes whole
antibodies or fragments thereof.
[0089] Cell response modifiers are chemotactic factors such as
platelet-derived growth factor (pDGF). Other chemotactic factors
include neutrophil-activating protein, monocyte chemoattractant
protein, macrophage-inflammatory protein, SIS (small inducible
secreted), platelet factor, platelet basic protein, melanoma growth
stimulating activity, epidermal growth factor, transforming growth
factor (alpha), fibroblast growth factor, platelet-derived
endothelial cell growth factor, estradiols, insulin-like growth
factor, nerve growth factor, bone growth/cartilage-inducing factor
(alpha and beta), and matrix metallo proteinase inhibitors. Other
cell response modifiers are the interleukins, interleukin
inhibitors or interleukin receptors, including interleukin 1
through interleukin 10; interferons, including alpha, beta and
gamma; hematopoietic factors, including erythropoietin, granulocyte
colony stimulating factor, macrophage colony stimulating factor and
granulocyte-macrophage colony stimulating factor; tumor necrosis
factors, including alpha and beta; transforming growth factors
(beta), including beta-1, beta-2, beta-3, inhibin, activin, DNA
that encodes for the production of any of these proteins, antisense
molecules, androgenic receptor blockers and statin agents.
[0090] Examples of bioactive agents include sirolimus, including
analogues and derivatives thereof (including rapamycin, ABT-578,
everolimus). Sirolimus has been described as a macrocyclic lactone
or triene macrolide antibiotic and is produced by Streptomyces
hygroscopicus, having a molecular formula of
C.sub.51H.sub.79O.sub.13 and a molecular weight of 914.2. Sirolimus
has been shown to have antifungal, antitumor and immunosuppressive
properties. Another suitable bioactive agent includes paclitaxel
(Taxol) which is a lipophilic (i.e., hydrophobic) natural product
obtained via a semi-synthetic process from Taxus baccata and having
antitumor activity.
[0091] Other suitable bioactive agents include, but are not limited
to, the following compounds, including analogues and derivatives
thereof: dexamethasone, betamethasone, retinoic acid, vinblastine,
vincristine, vinorelbine, etoposide, teniposide, dactinomycin
(actinomycin D), daunorubicin, doxorubicin, idarubicin,
anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin),
mitomycin, mechlorethamine, cyclophosphamide and its analogs,
melphalan, chlorambucil, ethylenimines and methylmelamines, alkyl
sulfonates-busulfan, nitrosoureas, carmustine (BCNU) and analogs,
streptozocin, trazenes-dacarbazinine, methotrexate, fluorouracil,
floxuridine, cytarabine, mercaptopurine, thioguanine, pentostatin,
2-chlorodeoxyadenosine, cisplatin, carboplatin, procarbazine,
hydroxyurea, mitotane, aminoglutethimide, estrogen, heparin,
synthetic heparin salts, tissue plasminogen activator,
streptokinase, urokinase, dipyridamole, ticlopidine, clopidogrel,
abciximab, breveldin, cortisol, cortisone, fludrocortisone,
prednisone, prednisolone, 6U-methylprednisolone, triamcinolone,
triamcinolone acetonide, acetaminophen, etodalac, tolmetin,
ketorolac, ibuprofen and derivatives, mefenamic acid, meclofenamic
acid, piroxicam, tenoxicam, phenylbutazone, oxyphenthatrazone,
nabumetone, auranofin, aurothioglucose, gold sodium thiomalate,
tacrolimus (FK-506), azathioprine, mycophenolate mofetil, vascular
endothelial growth factor (VEGF), angiotensin receptor blocker,
nitric oxide donors, anti-sense oligonucleotides and combinations
thereof, cell cycle inhibitors, mTOR inhibitors, and growth factor
signal transduction kinase inhibitors. Another suitable bioactive
agent includes morpholino phosphorodiamidate oligmer.
[0092] A comprehensive listing of bioactive agents can be found in
The Merck Index. Thirteenth Edition, Merck & Co. (2001), the
entire contents of which is incorporated by reference herein.
Bioactive agents are commercially available from Sigma Aldrich
(e.g., vincristine sulfate). The concentration of the bioactive
agent or agents dissolved or suspended in the coating mixture can
range from about 0.01 to about 90 percent, by weight, based on the
weight of the final coated composition. Additives such as inorganic
salts, BSA (bovine serum albumin), and inert organic compounds can
be used to alter the profile of bioactive agent release, as known
to those skilled in the art.
[0093] In order to provide a some embodiments of a coating, a
coating composition is prepared to include one or more solvents, a
combination of complementary polymers dissolved in the solvent, and
the bioactive agent or agents dispersed in the polymer/solvent
mixture. The solvent may be one in which the polymers form a true
solution. The pharmaceutical agent itself may either be soluble in
the solvent or form a dispersion throughout the solvent. Suitable
solvents include, but are not limited to, alcohols (e.g., methanol,
butanol, propanol and isopropanol), alkanes (e.g., halogenated or
unhalogenated alkanes such as hexane, cyclohexane, methylene
chloride and chloroform), amides (e.g., dimethylformamide), ethers
(e.g., tetrahydrofuran (THF), dioxolane, and dioxane), ketones
(e.g., methyl ethyl ketone), aromatic compounds (e.g., toluene and
xylene), nitriles (e.g., acetonitrile) and esters (e.g., ethyl
acetate). THF and chloroform have been found to be desirable
solvents due to their excellent solvency for a variety of polymers
and bioactive agents of the present invention.
[0094] A coating composition of this invention can be used to coat
the surface of a variety of devices, and is particularly useful for
those devices that will come in contact with aqueous systems. Such
devices are coated with a coating composition adapted to release
bioactive agent in a prolonged and controlled manner, generally
beginning with the initial contact between the device surface and
its aqueous environment.
[0095] The coated composition provides a means to deliver bioactive
agents from a variety of biomaterial surfaces. Biomaterials include
those formed of synthetic polymers, including oligomers,
homopolymers, and copolymers resulting from either addition or
condensation polymerizations. Examples of suitable addition
polymers include, but are not limited to, acrylics such as those
polymerized from methyl acrylate, methyl methacrylate, hydroxyethyl
methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic
acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and
acrylamide; vinyls, such as those polymerized from ethylene,
propylene, styrene, vinyl chloride, vinyl acetate, vinyl
pyrrolidone, and vinylidene difluoride. Examples of condensation
polymers include, but are not limited to, nylons such as
polycaprolactam, poly(lauryl lactam), poly(hexamethylene
adipamide), and poly(hexamethylene dodecanediamide), and also
polyurethanes, polycarbonates, polyamides, polysulfones,
poly(ethylene terephthalate), poly(lactic acid), poly(glycolic
acid), poly(lactic acid-co-glycolic acid), polydimethylsiloxanes,
polyetheretherketone, poly(butylene terephthalate), poly(butylene
terephthalate-co-polyethylene glycol terephthalate), esters with
phosphorus containing linkages, non-peptide polyamino acid
polymers, polyiminocarbonates, amino acid-derived polycarbonates
and polyarylates, and copolymers of polyethylene oxides with amino
acids or peptide sequences.
[0096] Certain natural materials are also suitable biomaterials,
including human tissue such as bone, cartilage, skin and teeth; and
other organic materials such as wood, cellulose, compressed carbon,
and rubber. Other suitable biomaterials include metals and
ceramics. The metals include, but are not limited to, titanium,
stainless steel, and cobalt chromium. A second class of metals
include the noble metals such as gold, silver, copper, and
platinum. Alloys of metals may be suitable for biomaterials as
well, such as nitinol (e.g., MP35). The ceramics include, but are
not limited to, silicon nitride, silicon carbide, zirconia, and
alumina, as well as glass, silica, and sapphire. Yet other suitable
biomaterials include combinations of ceramics and metals, as well
as biomaterials that are fibrous or porous in nature.
[0097] Optionally, the surface of some biomaterials can be
pretreated (e.g., with a silane and/or Parylene.TM. coating
composition in one or more layers) in order to alter the surface
properties of the biomaterial. For example, in various embodiments
of the present invention a layer of silane may be applied to the
surface of the biomaterial followed by a layer of Parlene.TM..
Parylene.TM. C is the polymeric form of the low-molecular-weight
dimer of para-chloro-xylylene. Silane and/or Parylene.TM. C (a
material supplied by Specialty Coating Systems (Indianapolis)) can
be deposited as a continuous coating on a variety of medical device
parts to provide an evenly distributed, transparent layer. In one
embodiment, the deposition of Parylene.TM. is accomplished by a
process termed vapor deposition polymerization, in which dimeric
Parylene.TM. C is vaporized under vacuum at 150.degree. C.,
pyrolyzed at 680.degree. C. to form a reactive monomer, then pumped
into a chamber containing the component to be coated at 25.degree.
C. At the low chamber temperature, the monomeric xylylene is
deposited on the part, where it immediately polymerizes via a
free-radical process. The polymer coating reaches molecular weights
of approximately 500 kilodaltons.
[0098] Deposition of the xylylene monomer takes place in only a
moderate vacuum (0.1 torr) and is not line-of-sight. That is, the
monomer has the opportunity to surround all sides of the part to be
coated, penetrating into crevices or tubes and coating sharp points
and edges, creating what is called a "conformal" coating. With
proper process control, it is possible to deposit a pinhole-free,
insulating coating that will provide very low moisture permeability
and high part protection to corrosive biological fluids.
[0099] Adherence is a function of the chemical nature of the
surface to be coated. It has been reported, for instance, that
tantalum and silicon surfaces can be overcoated with silicon
dioxide, then with plasma-polymerized methane, and finally with
Parylene.TM. C to achieve satisfactory adherence.
[0100] Most applications of Parylene.TM. C coating in the medical
device industry are for protecting sensitive components from
corrosive body fluids or for providing lubricity to surfaces.
Typical anticorrosion applications include blood pressure sensors,
cardiac-assist devices, prosthetic components, bone pins,
electronic circuits, ultrasonic transducers, bone-growth
stimulators, and brain probes. Applications to promote lubricity
include mandrels, injection needles, cannulae, and catheters.
[0101] Also, as previously described above, the surface to which
the composition is applied can itself be pretreated in other
manners sufficient to improve attachment of the composition to the
underlying (e.g., metallic) surface. Additional examples of such
pretreatments include photografted polymers, epoxy primers,
polycarboxylate resins, and physical roughening of the surface. It
is further noted that the pretreatment compositions and/or
techniques may be used in combination with each other or may be
applied in separate layers to form a pretreatment coating on the
surface of the medical device.
[0102] In some embodiments, a tie-in layer may be utilized to
facilitate one or more physical and/or covalent bonds between
layers. For example, the pretreatment layer may include a
multi-interface system to facilitate adhesion and cohesion
interaction relative to the different materials positioned at the
interface of each layer. For example, the application of Parylene
pretreatments to metal surfaces may be aided by a first application
of a reactive organosilane reagent. A reactive organosilane reagent
containing an unsaturated pendant group is capable of participating
with the Parylene radicals as they deposit on the surface from the
vapor phase. After cleaning of the metal surface, an organosilane
reagent with an unsaturated pendant group may be applied to the
metal oxide surface on a metal substrate. Without intending to be
bound by theory, it appears that the silicon in the organosilane
reagent couples covalently to the metal oxide, linking the
organosilane group to the surface. The substrate may then be placed
in a Parylene reactor and exposed to the vapor-phase Parylene
process. During this process, the unsaturated pendant groups on the
organosilane-treated surface can react with the Parylene diradicals
depositing from the vapor phase. This forms a covalent link between
the Parylene and the organosilane layer. The Parylene also forms
covalent bonds to itself as it deposits. Thus, this process yields
a layered surface in which the layers are covalently bonded to each
other. This forms a very strong bond between the Parylene and the
metal surface, resulting in high durability to mechanical
challenges. Further, in some embodiments, the Parylene may
physically bond with the bioactive agent delivery coating or may
include a reactive acrylate group that can be reacted with the
bioactive agent delivery coating to improve durability to
mechanical challenges.
[0103] The coating composition of the present invention can be used
in combination with a variety of devices, including those used on a
temporary, transient, or permanent basis upon and/or within the
body.
[0104] Compositions of this invention can be used to coat the
surface of a variety of implantable devices, for example:
drug-delivering vascular stents (e.g., self-expanding stents
typically made from nitinol, balloon-expanded stents typically
prepared from stainless steel); other vascular devices (e.g.,
grafts, catheters, valves, artificial hearts, heart assist
devices); implantable defibrillators; blood oxygenator devices
(e.g., tubing, membranes); surgical devices (e.g., sutures,
staples, anastomosis devices, vertebral disks, bone pins, suture
anchors, hemostatic barriers, clamps, screws, plates, clips,
vascular implants, tissue adhesives and sealants, tissue
scaffolds); membranes; cell culture devices; chromatographic
support materials; biosensors; shunts for hydrocephalus; wound
management devices; endoscopic devices; infection control devices;
orthopedic devices (e.g., for joint implants, fracture repairs);
dental devices (e.g., dental implants, fracture repair devices),
urological devices (e.g., penile, sphincter, urethral, bladder and
renal devices, and catheters); colostomy bag attachment devices;
ophthalmic devices (e.g. ocular coils); glaucoma drain shunts;
synthetic prostheses (e.g., breast); intraocular lenses;
respiratory, peripheral cardiovascular, spinal, neurological,
dental, ear/nose/throat (e.g., ear drainage tubes); renal devices;
and dialysis (e.g., tubing, membranes, grafts).
[0105] Examples of useful devices include urinary catheters (e.g.,
surface-coated with antimicrobial agents such as vancomycin or
norfloxacin), intravenous catheters (e.g., treated with
antithrombotic agents (e.g., heparin, hirudin, coumadin), small
diameter grafts, vascular grafts, artificial lung catheters, atrial
septal defect closures, electro-stimulation leads for cardiac
rhythm management (e.g., pacer leads), glucose sensors (long-term
and short-term), degradable coronary stents (e.g., degradable,
non-degradable, peripheral), blood pressure and stent graft
catheters, birth control devices, benign prostate and prostate
cancer implants, bone repair/augmentation devices, breast implants,
cartilage repair devices, dental implants, implanted drug infusion
tubes, intravitreal drug delivery devices, nerve regeneration
conduits, oncological implants, electrostimulation leads, pain
management implants, spinal/orthopedic repair devices, wound
dressings, embolic protection filters, abdominal aortic aneurysm
grafts, heart valves (e.g., mechanical, polymeric, tissue,
percutaneous, carbon, sewing cuff), valve annuloplasty devices,
mitral valve repair devices, vascular intervention devices, left
ventricle assist devices, neuro aneurysm treatment coils,
neurological catheters, left atrial appendage filters, hemodialysis
devices, catheter cuff, anastomotic closures, vascular access
catheters, cardiac sensors, uterine bleeding patches, urological
catheters/stents/implants, in vitro diagnostics, aneurysm exclusion
devices, and neuropatches.
[0106] Examples of other suitable devices include, but are not
limited to, vena cava filters, urinary dialators, endoscopic
surgical tissue extractors, atherectomy catheters, clot extraction
catheters, percutaneous transluminal angioplasty catheters, PTCA
catheters, stylets (vascular and non-vascular), coronary
guidewires, drug infusion catheters, esophageal stents, circulatory
support systems, angiographic catheters, transition sheaths and
dilators, coronary and peripheral guidewires, hemodialysis
catheters, neurovascular balloon catheters, tympanostomy vent
tubes, cerebro-spinal fluid shunts, defibrillator leads,
percutaneous closure devices, drainage tubes, thoracic cavity
suction drainage catheters, electrophysiology catheters, stroke
therapy catheters, abscess drainage catheters, biliary drainage
products, dialysis catheters, central venous access catheters, and
parental feeding catheters.
[0107] Examples of medical devices suitable for the present
invention include, but are not limited to catheters, implantable
vascular access ports, blood storage bags, vascular stents, blood
tubing, arterial catheters, vascular grafts, intraaortic balloon
pumps, cardiovascular sutures, total artificial hearts and
ventricular assist pumps, extracorporeal devices such as blood
oxygenators, blood filters, hemodialysis units, hemoperfusion
units, plasmapheresis units, hybrid artificial organs such as
pancreas or liver and artificial lungs, as well as filters adapted
for deployment in a blood vessel in order to trap emboli (also
known as "distal protection devices").
[0108] The compositions are particularly useful for those devices
that will come in contact with aqueous systems, such as bodily
fluids. Such devices are coated with a coating composition adapted
to release bioactive agent in a prolonged and controlled manner,
generally beginning with the initial contact between the device
surface and its aqueous environment. It is important to note that
the local delivery of combinations of bioactive agents may be
utilized to treat a wide variety of conditions utilizing any number
of medical devices, or to enhance the function and/or life of the
device. Essentially, any type of medical device may be coated in
some fashion with one or more bioactive agents that enhances
treatment over use of the individual use of the device or bioactive
agent.
[0109] In some embodiments, the coating composition can also be
used to coat stents, e.g., either self-expanding stents, which are
typically prepared from nitinol, or balloon-expandable stents,
which are typically prepared from stainless steel. Other stent
materials, such as cobalt chromium alloys, can be coated by the
coating composition as well.
[0110] Devices which are particularly suitable include vascular
stents such as self-expanding stents and balloon expandable stents.
Examples of self-expanding stents useful in the present invention
are illustrated in U.S. Pat. Nos. 4,655,771 and 4,954,126 issued to
Wallsten and U.S. Pat. No. 5,061,275 issued to Wallsten et al.
Examples of suitable balloon-expandable stents are shown in U.S.
Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued
to Gianturco and U.S. Pat. No. 4,886,062 issued to Wiktor.
[0111] In various embodiments, the coating composition can also be
used to coat ophthalmic devices, e.g. ocular coils. A therapeutic
agent delivery device that is particularly suitable for delivery of
a therapeutic agent to limited access regions, such as the vitreous
chamber of the eye and inner ear is described in U.S. Pat. No.
6,719,750 and U.S. Patent Application Publication No. 2005/0019371
A1.
[0112] The resultant coating composition can be applied to the
device in any suitable fashion (e.g., the coating composition can
be applied directly to the surface of the medical device, or
alternatively, to the surface of a surface-modified medical device,
by dipping, spraying, ultrasonic deposition, or using any other
conventional technique). The suitability of the coating composition
for use on a particular material, and in turn, the suitability of
the coated composition can be evaluated by those skilled in the
art, given the present description. In one such embodiment, for
instance, the coating comprises at least two layers which are
themselves different. For instance, a base layer may be applied
having bioactive agent(s) alone, or together with or without one or
more of the polymer components, after which one or more topcoat
layers are coated, each with either first and/or second polymers as
described herein, and with or without bioactive agent. These
different layers, in turn, can cooperate in the resultant composite
coating to provide an overall release profile having certain
desired characteristics, and, in some embodiments, for use with
bioactive agents of high molecular weight. In various embodiments,
the composition is coated onto the device surface in one or more
applications of a single composition that includes first and second
polymers, together with bioactive agent. However, as previously
suggested a pretreatment layer or layers may be first applied to
the surface of the device, wherein subsequent coating with the
composition may be performed onto the pretreatment layer(s). The
method of applying the coating composition to the device is
typically governed by the geometry of the device and other process
considerations. The coating is subsequently cured by evaporation of
the solvent. The curing process can be performed at room or
elevated temperature, and optionally with the assistance of vacuum
and/or controlled humidity.
[0113] It is also noted that one or more additional layers may be
applied to the coating layer(s) that include bioactive agent. Such
layer(s) or topcoats can be utilized to provide a number of
benefits, such as biocompatibility enhancement, delamination
protection, durability enhancement, bioactive agent release
control, to just mention a few. In one embodiment the topcoat may
include one or more of the first, second, and/or additional
polymers described herein with or without the inclusion of a
bioactive agent, as appropriate to the application. In some
embodiments, the topcoat includes a second polymer that is a
poly(alkyl(meth)acrylate). An example of a
poly(alkyl(meth)acrylate) includes poly(n-butyl methacrylate). In
another embodiment, the first or second polymers could further
include functional groups (e.g. hydroxy, thiol, methylol, amino,
and amine-reactive functional groups such as isocyanates,
thioisocyanates, carboxylic acids, acyl halides, epoxides,
aldehydes, alkyl halides, and sulfonate esters such as mesylate,
tosylate, and tresylate) that could be utilized to bind the topcoat
to the adjacent coating composition. In another embodiment of the
present invention one or more of the pretreatment materials (e.g.
Parylene.TM.) may be applied as a topcoat. Additionally,
biocompatible topcoats (e.g. heparin, collagen, extracellular
matrices, cell receptors . . . ) may be applied to the coating
composition of the present invention. Such biocompatible topcoats
may be adjoined to the coating composition of the present invention
by utilizing photochemical or thermochemical techniques known in
the art. Additionally, release layers may be applied to the coating
composition of the present invention as a friction barrier layer or
a layer to protect against delamination. Examples of biocompatible
topcoats that may be used include those disclosed in U.S. Pat. Nos.
4,979,959 and 5,744,515.
[0114] In some embodiments, the polymer composition for use in this
invention is biocompatible, e.g., such that it results in no
significant induction of inflammation or irritation when implanted.
In addition, the polymer combination may be useful throughout a
broad spectrum of both absolute concentrations and relative
concentrations of the polymers. This means that the physical
characteristics of the coating, such as tenacity, durability,
flexibility and expandability, will typically be adequate over a
broad range of polymer concentrations. In turn, in some
embodiments, the ability of the coating to control the release
rates of a variety of bioactive agents can be manipulated by
varying the absolute and relative concentrations of the
polymers.
[0115] Additionally, the coatings of the present invention are
generally hydrophobic and limit the intake of aqueous fluids. For
example, many embodiments of the present invention are coating
compositions including two or more hydrophobic polymers wherein the
resulting coating shows <10% (wt) weight change when exposed to
water, and optionally <5% (wt) weight change when exposed to
water.
[0116] A coating composition can be provided in any suitable form,
e.g., in the form of a true solution, or fluid or paste-like
emulsion, mixture, dispersion or blend. In some embodiments,
polymer combinations of this invention are capable of being
provided in the form of a true solution, and in turn, can be used
to provide a coating that is both optically clear (upon microscopic
examination), while also containing a significant amount of
bioactive agent. In turn, the coated composition will generally
result from the removal of solvents or other volatile components
and/or other physical-chemical actions (e.g., heating or
illuminating) affecting the coated composition in situ upon the
surface.
[0117] A further example of a coating composition embodiment may
include a configuration of one or more bioactive agents within an
inner matrix structure, for example, bioactive agents within or
delivered from a degradable encapsulating matrix or a microparticle
structure formed of semipermeable cells and/or degradable polymers.
One or more inner matrices may be placed in one or more locations
within the coating composition and at one or more locations in
relation to the substrate. Examples of inner matrices, for example
degradable encapsulating matrices formed of semipermeable cells
and/or degradable polymers, are disclosed and/or suggested in U.S.
Publication No. 20030129130, U.S. Patent Application Ser. No.
60/570,334 filed May 12, 2004, U.S. Patent Application Ser. No.
60/603,707, filed Aug. 23, 2004, U.S. Publication No. 20040203075,
filed Apr. 10, 2003, U.S. Publication No. 20040202774 filed on Apr.
10, 2003, and U.S. patent application Ser. No. 10/723,505, filed
Nov. 26, 2003, the entire contents of which are incorporated by
reference herein.
[0118] The overall weight of the coating upon the surface may vary
depending on the application. However, the weight of the coating
attributable to the bioactive agent is optionally in the range of
about one microgram to about 10 milligram (mg) of bioactive agent
per cm.sup.2 of the effective surface area of the device. By
"effective" surface area it is meant the surface amenable to being
coated with the composition itself. For a flat, nonporous, surface,
for instance, this will generally be the macroscopic surface area
itself, while for considerably more porous or convoluted (e.g.,
corrugated, pleated, or fibrous) surfaces the effective surface
area can be significantly greater than the corresponding
macroscopic surface area. In some embodiments, the weight of the
coating attributable to the bioactive agent is between about 0.005
mg and about 10 mg, and optionally between about 0.01 mg and about
1 mg of bioactive agent per cm.sup.2 of the gross surface area of
the device. This quantity of bioactive agent is generally required
to provide desired activity under physiological conditions.
[0119] In turn, the final coating thickness of some embodiments of
the coated composition will typically be in the range of about 0.1
micrometers to about 100 micrometers, and optionally about 0.5
micrometers and about 25 micrometers. This level of coating
thickness is generally required to provide an adequate
concentration of drug to provide adequate activity under
physiological conditions.
[0120] The invention will be further described with reference to
the following non-limiting Examples. It will be apparent to those
skilled in the art that many changes can be made in the embodiments
described without departing from the scope of the present
invention. Thus the scope of the present invention should not be
limited to the embodiments described in this application, but only
by the embodiments described by the language of the claims and the
equivalents of those embodiments. Unless otherwise indicated, all
percentages are by weight.
EXAMPLES
Test Procedures
[0121] The potential suitability of particular coated compositions
for in vivo use can be determined by a variety of screening
methods, examples of each of which are described herein.
[0122] Sample Preparation Procedure
[0123] Stainless steel stents used in the following examples were
manufactured by Laserage Technology Corporation, Waukegan, Ill. In
some cases, the metal surface of the stents were coated without any
pretreatment beyond washing. In other cases, a primer was applied
to the stents by first cleaning the stents with aqueous base, then
pre-treating with a silane followed by vapor deposition of
Parylene.TM. polymer. The silane used was
[3-(methacroyloxy)propyl]trimethoxysilane, available from
Sigma-Aldrich Fine Chemicals as Product No. 44,015-9. The silane
was applied as essentially a monolayer by mixing the silane at a
low concentration in 50/50 (vol) isopropanol/water, soaking the
stents in the aqueous silane solution for a suitable length of time
to allow the water to hydrolyze the silane and produce some
cross-linking, washing off residual silane, then baking the
silane-treated stent at 100.degree. C. for conventional periods of
time. Following the silane treatment, Parylene.TM. C coating
(available from Union Carbide Corporation, Danbury, Conn.) was
vapor-deposited at a thickness of about 1 mm. Prior to coating, the
stents were weighed on a microbalance to determine a tare
weight.
[0124] Bioactive agent/polymer solutions were prepared at a range
of concentrations in an appropriate solvent (typically
tetrahydrofuran or chloroform), in the manner described herein. In
all cases the coating solutions were applied to respective stents
by spraying, and the solvent was allowed to evaporate under ambient
conditions. The coated stents were then re-weighed to determine the
mass of coating and consequently the mass of polymer and bioactive
agent.
[0125] Rapamycin Release Assay Procedure
[0126] The Rapamycin Release Assay Procedure, as described herein,
was used to determine the extent and rate of release of an
exemplary bioactive agent, rapamycin, under in vitro elution
conditions. Spray-coated stents prepared using the Sample
Preparation Procedure were placed in sample baskets into 10
milliliters of Sotax.TM. dissolution system (elution media
containing 2% (wt) surfactant/water solution, available from Sotax
Corporation, Horsham, Pa.). Amount of bioactive agent elution was
monitored by UV spectrometry over the course of several days. The
elution media was held at 37.degree. C. After the elution
measurements, the stents were removed, rinsed, dried, and weighed
to compare measured bioactive agent elution to weighed mass
loss.
[0127] Dexamethasone Release Assay Procedure
[0128] The Dexamethasone Release Assay Procedure, as described
herein, was used to determine the extent and rate of dexamethasone
release under in vitro conditions. Spray-coated stents made using
the Sample Preparation Procedure were placed in 10 milliliters of
pH 7 phosphate buffer solution ("PBS") contained in an amber vial.
A magnetic stirrer bar was added to the vial, and the vial with its
contents were placed into a 37.degree. C. water bath. After a
sample interval, the stent was removed and placed into a new buffer
solution contained in a new vial. Dexamethasone concentration in
the buffer was measured using ultraviolet spectroscopy and the
concentration converted to mass of bioactive agent released from
the coating. After the experiment, the stent was dried and weighed
to correlate actual mass loss to the loss measured by the elution
experiment.
[0129] Durability Test Procedure
[0130] The durability of the coated composition can be determined
by the following manner. To simulate use of the coated devices, the
coated stents are placed over sample angioplasty balloons. The
stent is then crimped onto the balloon using a laboratory test
crimper (available from Machine Solutions, Brooklyn, N.Y.). The
stent and balloon are then placed in a phosphate buffer bath having
a pH of 7.4 and temperature of 37.degree. C. After 5 minutes of
soaking, the balloon is expanded using air at 5 atmospheres (3800
torr) of pressure. The balloon is then deflated, and the stent is
removed.
[0131] The stent is then examined by optical and scanning electron
microscopy to determine the amount of coating damage caused by
cracking and/or delamination and a rating may be assigned. Coatings
with extensive damage are considered unacceptable for a commercial
medical device. The "Rating" is a qualitatitive scale used to
describe the amount of damage to the coating from the stent
crimping and expansion procedure based on optical microscopy
examination by an experienced coating engineer. A low rating
indicates a large percentage of the coating cracked, smeared,
and/or delaminated from the surface. For example, a coating with a
rating of ten shows no damage while one with a rating of 1 will
show a majority of the coating damaged to the point where clinical
efficacy may be diminished. Commercially attractive coatings
typically have a rating of nine or higher.
[0132] Stress-Strain Measurement Test Procedure
[0133] Polymer films were prepared by hot pressing polymer beads at
100.degree. C. in a constant film maker kit to a thickness of
approximately 0.5 mm. The resulting films were cut into strips
using a razor blade. A Q800 Dynamic Mechanical Analyzer (available
from Texas Instruments, Dallas, Tex.) was fitted with a film
tension clamp. Each sample was equilibrated at 35.degree. C. for
five minutes prior to straining the sample. Then the sample was
loaded into the clamp such that the sample length was between 5 and
7 mm in length. A static force of 0.01N was applied to each sample
throughout the measurements. Simultaneously, a 0.5 N/min force was
applied to the sample until the movable clamp reached its maximum
position. Films were elongated at constant stress and the average
tensile modulus (i.e., the initial slope of the stress-strain
curve, in MPa) was determined.
Example 1
Release of Rapamycin from Poly(butadiene) and Poly(butyl
methacrylate)
[0134] Three solutions were prepared for coating the stents. The
solutions included mixtures of poly(1,2-butadiene) ("PBD",
available from Scientific Polymers Products, Inc., Ontario, N.Y.,
as Catalog # 688; CAS #31567-90-5; 7% cis 1,4; 93% vinyl 1,2; Mw
approx. 100 kilodaltons), poly(butyl methacrylate) ("PBMA",
available from Sigma-Aldrich Fine Chemicals as Product No.
18,152-8, having a weight average molecular weight (Mw) of about
337 kilodaltons), and rapamycin ("RAPA", available from LC
Laboratories, Woburn, Mass.) dissolved in THF to form a homogeneous
solution. The stents were not given a primer pre-treatment.
[0135] The solutions were prepared to include the following
ingredients at the stated weights per milliliter of THF:
[0136] 1) 16 mg/ml PBD/4 mg/ml PBMA/10 mg/ml RAPA
[0137] 2) 10 mg/ml PBD/10 mg/ml PBMA/10 mg/ml RAPA
[0138] 3) 4 mg/ml PBD/16 mg/ml PBMA/10 mg/ml RAPA
[0139] Using the Sample Preparation Procedure, two stents were
spray coated using each solution. After solvent removal via ambient
evaporation, the drug elution for each coated stent was monitored
using the Rapamycin Release Assay Procedure.
[0140] Results, provided in FIG. 1, demonstrate the ability to
control the elution rate of rapamycin, a pharmaceutical agent, from
a coated stent surface by varying the relative concentrations of
PBD and PBMA in the polymer mixture as described herein. The lines
in FIG. 1 and similar figures are expressed in terms of percent by
weight of the first and second polymers, respectively, in the
coated compositions. This can be compared to the amounts provided
above, which are stated in terms of "mg/ml" of the respective
polymers in the coating compositions themselves, which are applied
to the stents. Hence "54/13" corresponds to the coated compositions
that results from the use of the first coating composition above,
which upon removal of the solvent provides a coated composition
having 54% PBD and 13% PBMA respectively, by weight. Alternatively,
solutions such as the second solution above, e.g., which includes
equal amounts (by weight) of the ingredients, will alternatively be
referred to herein as "33/33/33", representing the weight ratio of
ingredients to each other.
[0141] Additionally, the durability for PBD/PBMA coatings was also
analyzed. Stents were coated with PBD and PBMA in a procedure as
described above but without any bioactive agent. The stents were
then tested according to the method described in the Durability
Test Procedure section. The results are displayed in FIG. 1A. The
PBD/PBMA coatings showed very little damage in the form of some
small cracks that did not appear to reach the stent surface. These
coatings were applied to bare metal stents before ethylene oxide
sterilization ("sterilization"), Parylene.TM. coated stents before
sterilization, and Parylene.TM. coated stents after sterilization.
These were labeled in FIG. 1A "Bare Metal Pre-Sterile," "Parylene
Pre-Sterile," and "Parylene Post-Sterile," respectively.
Parylene.TM. treatments and sterilization had little effect on the
exceptional durability of the PBD/PBMA coatings.
Example 2
Release of Rapamycin from Poly(butadiene-co-acrylonitrile) and
Poly(butyl methacrylate)
[0142] Three solutions were prepared for coating the stents. The
solutions included mixtures of poly(butadiene-co-acrylonitrile)
("PBDA," available from Scientific Polymer Products, Inc., Catalog
#533, contains 41% (wt) acrylonitrile), "PBMA" and "RAPA" ("PBMA"
and "RAPA" were obtained and used as described in Example 1)
dissolved in THF to form a homogeneous solution. The stents were
not given a primer pre-treatment.
[0143] The solutions were prepared to include the following
ingredients at the stated weights per milliliter of THF:
[0144] 1) 16 mg/ml PBDA/4 mg/ml PBMA/0 mg/ml RAPA
[0145] 2) 10 mg/ml PBDA/0 mg/ml PBMA/0 mg/ml RAPA
[0146] 3) 4 mg/ml PBDA/16 mg/ml PBMA/10 mg/ml RAPA
[0147] Using the Sample Preparation Procedure, two stents were
spray coated using each solution. After solvent removal via ambient
evaporation, the drug elution for each coated stent was monitored
using the Rapamycin Release Assay Procedure.
[0148] Results, provided in FIG. 2, demonstrate the ability to
control the elution rate of rapamycin, a pharmaceutical agent, from
a coated stent surface by varying the relative concentrations of
PBDA and PBMA in the polymer mixture as described herein.
Example 3
Release of Dexamethasone from Poly(butadiene) and Poly(butyl
methacrylate)
[0149] Three solutions were prepared for coating the stents. All
three solutions included mixtures of poly(1,2-butadiene) "PBD",
poly(butyl methyl acrylate) ("PBMA"), and dexamethasone ("DEXA")
dissolved in THF to form a homogeneous solution. The stents were
not given a primer pre-treatment.
[0150] The solutions were prepared to include the following
ingredients at the stated weights per milliliter of THF:
[0151] 1) 20 mg/ml PBD/0 mg/ml PBMA/10 mg/ml DEXA
[0152] 2) 10 mg/ml PBD/10 mg/ml PBMA/10 mg/ml DEXA
[0153] 3) 0 mg/ml PBD/20 mg/ml PBMA/10 mg/ml DEXA
[0154] Using the Sample Preparation Procedure, two stents were
spray coated using each solution. After solvent removal via ambient
evaporation, the drug elution for each coated stent was monitored
using the Dexamethasone Release Assay Procedure.
[0155] Results, provided in FIG. 3, demonstrate the ability to
control the elution rate of dexamethasone, a pharmaceutical agent,
from a stent surface by varying the relative concentrations of PBD
and PBMA in the polymer mixture.
Example 4
Surface Characterization of Coated Stents after Crimping and
Expansion
[0156] Using the Sample Preparation Procedure, stents were sprayed
with a coating of second polymer/poly(butyl
methacrylate)("PBMA")/rapamycin ("RAPA"), mixed at a weight ratio
of 33/33/33 at 10 mg/ml each of THF. The first polymer was
polybutadiene ("PBD", available from Scientific Polymers Products,
Inc., Ontario, N.Y., as Catalog # 688; CAS #31567-90-5; 7% cis 1,4;
93% vinyl 1,2; Mw approx. 100 kilodaltons), and a polymer from the
additional polymer class was poly(ethylene-co-methyl acrylate)
("PEMA", available from Focus Chemical Corp. Portsmouth, N.H.,
containing 28% (wt) methyl acrylate). The second polymer used was
PBMA from Sigma-Aldrich Fine Chemicals as Product No. 18,152-8,
having a weight average molecular weight (Mw) of about 337
kilodaltons. Stents were either used as received (i.e., uncoated
metal), were pre-treated with a silane/Parylene.TM. primer using
the primer procedure described in the Sample Preparation Procedure,
were not pre-treated with primer but were given a subsequent PBMA
topcoat using the spraying process described in the Sample
Preparation Procedure, or were given both a silane/Parylene.TM.
pre-treatment primer and subsequent PBMA topcoat.
[0157] After preparing the coated stents and allowing all solvents
to dry at ambient conditions, the stents were examined with an
optical microscope under both "bright field" and "dark field"
conditions. All coatings were optically transparent (i.e., clear,
showing no cloudiness). Raman microscopy taken of the coated stents
of (PEMA as the additional polymer, applied to bare metal stent)
and (PBD as the first polymer, applied to bare metal stent)
indicated a high degree of homogeneity of mixing of drug and
polymers.
[0158] The coated stents were crimped down on balloons and were
expanded following the Durability Test Procedure, which showed
that, overall, all the coatings remained intact (i.e., the coating
did not peel off or flake off, etc.), with only a few localized
sites where coating delaminated from the metal stent. When primer
coatings were used, essentially no delamination was evident and
cracks were all smaller than about 10 microns in width. Almost all
stents had some degree of cracking of the coating around bends in
the struts, as well as some mechanical damage caused by handling or
balloon expansion. Adding a PBMA topcoat did not adversely affect
the mechanical integrity of the coating on the stent after crimping
and expansion, as might be expected with an overall thicker stent
coating.
[0159] Based on both the drug-eluting test results and mechanical
test results, coatings containing bioactive agents incorporated
into blends of PBMA with either PEMA or PBD as the other polymer
are viable candidates for commercial applications in drug-eluting
stents and are expected to be particularly effective in minimizing
the onset of restenosis after stent implantation.
Example 5 and Comparative Examples C1-C3
Stress-Strain Measurements for Polymers
[0160] Tensile properties of various first and additional polymers
of this invention were tested and average tensile modulus
calculated using the Stress-Strain Measurement Test Procedure. The
first polymer evaluated was polybutadiene ("PBD", same as used in
Example 1), and the additional polymers evaluated were
poly(ethylene-co-methyl acrylate) ("PEMA", available from Focus
Chemical Corp. Portsmouth, N.H., containing 28% (wt) methyl
acrylate), poly(ethylene-co-butyl acrylate) ("PEBA", containing 35%
(wt) butyl acrylate, available from Focus Chemical Corp.,
Portsmouth, N.H.), and poly(ethylene-co-vinyl acetate) ("PEVA",
available as Product No. 34,691-8 from Sigma-Aldrich Fine
Chemicals). These polymers were run as comparative examples.
[0161] Stress-strain curves are shown in FIG. 4. The calculated
average tensile modulus for each of the four tested polymers is
shown in Table 1.
1TABLE 1 Average Tensile Example Polymer Modulus, MPa (SD) C1 PEMA
5.54 (0.49) C2 PEBA 3.66 (0.67) 18c PBD 34.87 (4.83) C3 PEVA 2.17
(0.46
[0162] The data from Table 1 show that the average tensile modulus
for the PBD was significantly higher than that for any of the other
polymers.
Example 6
Scanning Electron Microscopy
[0163] Scanning Electron Microscopy can be used to observe coating
quality and uniformity on stents at any suitable point in their
manufacture or use. Crimped and expanded stents were examined for
coating failures in fine microscopic detail using a scanning
electron microscope (SEM) at magnifications varying from 150.times.
to 5000.times..
[0164] Various coating defects tend to affect the manufacture and
use of most polymer coated stents in commercial use today,
including the appearance of cracks or tears within the coating,
smearing or displacement of the coating, as well as potentially
even delamination of the coating in whole or in part. Such defects
can occur upon formation of the coating itself, or more commonly,
in the course of its further fabrication, including crimping the
stent upon an inflatable balloon, or in surgical use, which would
include manipulating the stent and expanding the balloon to
position the stent in vivo.
[0165] FIG. 5 shows a scanning electron microscope image from a LEO
Supra-35 VP at 250.times. of a 33/33/33 PBD/PBMA/rapamycin coating
on a stent after conventional crimping and balloon expansion
procedures. The image shows that the coated composition maintains
integrity after expansion, showing no evidence of delamination or
cracks.
[0166] When observed by SEM, many other compositions tended to show
cracks, however, typically of a type and number that are certainly
on par with those in commercial use today, and would tend to be
well within acceptable range, particularly considering that neither
the coating compositions, or manner of applying particular
compositions, have yet been optimized for any particular
combination of surface, polymers, bioactive agent. The cracks were
typically a few microns in width, with thin strands of polymer
stretching between the edges of the crack. Overall, however, the
coatings looked smooth, uniform, and in good condition.
[0167] Almost all the stents had some degree of cracking of the
coating around bends in the struts, as well as some mechanical
damage caused by handling or balloon expansion. Most surprisingly,
polybutadiene-containin- g coatings exhibited less cracking and in
one case no cracks, and when cracks occurred, they were typically
smaller in size in comparison with the cracks found in PEMA or
PEVA-containing coatings. For comparison, cracks which opened up
and delaminated from the metal stent surface were found in coatings
containing PEMA and PEVA in the absence of a Parylene.TM. primer
coating. Polybutadiene-containing coatings without Parylene.TM.
primer, as well as comparative PEMA (or comparative
PEVA)-containing coatings with Parylene.TM. primer, showed cracks
which tended to not result in delamination.
Example 7
Release of Rapamycin from Poly(butadiene) and Poly(butyl
methacrylate) Provided with a Topcoat
[0168] Several solutions were prepared for coating non-sterile,
non-deployed, self-expanding nitinol coronary stents having a
primer layer. The solutions included mixtures of
poly(1,2-butadiene) ("PBD", available from Scientific Polymers
Products, Inc., Ontario, N.Y.), poly(butyl methacrylate) ("PBMA",
available from Sigma-Aldrich Fine Chemicals), and rapamycin
("RAPA", available from LC Laboratories, Woburn, Mass.) dissolved
to form a homogeneous solution. In addition, a topcoat of PBMA was
also prepared and applied to the coating composition on some of the
stents, and the elution rate profiles into a 2% SLS buffer on a
Sotax USP IV Apparatus were determined.
[0169] Results, provided in FIG. 6, illustrates several elution
rates of rapamycin, a pharmaceutical agent, from a coated stent
surface by varying the relative concentrations of rapamycin, PBD,
and PBMA with and without utilizing a topcoat. Further, FIG. 7
demonstrates the ability to control the elution rate of a bioactive
agent by varying the amount of topcoat provided relative to the
coating composition.
[0170] The lines in FIG. 6 and FIG. 7 are expressed in terms of
percent by weight of the Rapamycin, PBD, and PBMA, respectively, in
the coated compositions. Hence "40/30/30" corresponds to the coated
compositions that results from the use of 40% Rapamycin, 30% PBD,
and 30% PBMA, respectively, by weight. In FIG. 7, the weight of the
topcoat relative to the weight of the coating composition is shown.
For example, 6% topcoat corresponds to an amount of topcoat
totaling 6% by weight of the coating composition weight.
[0171] Other embodiments of this invention will be apparent to
those skilled in the art upon consideration of this specification
or from practice of the invention disclosed herein. Various
omissions, modifications, and changes to the principles and
embodiments described herein may be made by one skilled in the art
without departing from the true scope and spirit of the invention
which is indicated by the following claims. All patents, patent
documents, and publications cited herein are hereby incorporated by
reference as if individually incorporated.
* * * * *