U.S. patent application number 11/099911 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 | 20050220841 11/099911 |
Document ID | / |
Family ID | 34965640 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050220841 |
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.: |
11/099911 |
Filed: |
April 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60559821 |
Apr 6, 2004 |
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Current U.S.
Class: |
424/423 ;
424/487 |
Current CPC
Class: |
A61F 2250/0067 20130101;
A61L 2300/42 20130101; A61L 31/10 20130101; A61L 29/16 20130101;
A61F 2/86 20130101; A61L 2300/43 20130101; A61L 29/085 20130101;
C08L 71/02 20130101; C08L 33/10 20130101; A61L 31/10 20130101; A61L
29/085 20130101; A61L 2300/41 20130101; C08L 33/06 20130101; A61L
2300/222 20130101; A61L 2300/602 20130101; C08L 33/06 20130101;
A61L 31/16 20130101; A61L 31/10 20130101; A61L 2300/606 20130101;
A61L 2300/404 20130101; A61L 2300/416 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 polybutene 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 includes a polybutene prepared by the homopolymerization
of isobutylene, 1-butene or 2-butene.
3. A composition according to claim 1 wherein the first polymer
component includes a polybutene prepared by the random
interpolymerization of isobutylene, 1-butene and 2-butene.
4. A composition according to claim 1 wherein the first polymer
component includes a polybutene prepared by the copolymerization of
any two of isobutylene, 1-butene and 2-butene.
5. A composition according to claim 1, the first polymer component
having a molecular weight from about 100 kilodaltons to about 1,000
kilodaltons.
6. A composition according to claim 1, the first polymer component
having a molecular weight from about 150 kilodaltons to about 600
kilodaltons.
7. A composition according to claim 1, the first polymer component
having a molecular weight from about 150 kilodaltons to about 250
kilodaltons.
8. 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
copolymer with other alkylenes, aromatic group-containing
copolymers, diolefin-derived non-aromatic polymers or copolymers,
epichlorohydrin-containing polymers and poly(ethylene-co-vinyl
acetate).
9. A composition according to claim 8 wherein the
poly(alkylene-co-alkyl(m- eth)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), the 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),
poly(ethylene-co-1-octene) and
poly(ethylene-co-propylene-co-5-methylene-- 2-norborene), the
diolefin-derived non-aromatic polymer or copolymer is selected from
the group consisting of polybutadienes prepared by the
polymerization of cis-, trans- and/or 1,2-monomer units, and
polyisoprenes prepared by the polymerization of cis-1,4- and/or
trans-1,4-monomer units, 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%.
10. A composition according to claim 1 wherein the
poly(alkyl(meth)acrylat- e) includes an alkyl chain length from two
to eight carbons.
11. A composition according to claim 1, the
poly(alkyl(meth)acrylate) having a molecular weight from about 50
kilodaltons to about 900 kilodaltons.
12. 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).
13. A composition according to claim 1 wherein the
poly(aromatic(meth)acry- late) includes aryl groups having from six
to sixteen carbon atoms.
14. A composition according to claim 1, the
poly(aromatic(meth)acrylate) having a molecular weight from about
50 kilodaltons to about 900 kilodaltons.
15. 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).
16. A composition according to claim 15, 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).
17. 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.
18. 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.
19. 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.
20. 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.
21. A combination comprising a medical device and a composition for
coating the surface of the 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 polybutene and a second polymer component
comprising a polymer selected from the group consisting of
poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates).
22. The combination of claim 21 wherein a pretreatment coating,
adapted to alter the surface properties of the medical device, is
applied to the surface of the medical device.
23. The combination of claim 21 wherein the first polymer component
includes a polybutene prepared by the homopolymerization of
isobutylene, 1-butene or 2-butene.
24. The combination of claim 21 wherein the first polymer component
includes a polybutene prepared by the random interpolymerization of
isobutylene, 1-butene and 2-butene.
25. The combination of claim 21 wherein the first polymer component
includes a polybutene prepared by the copolymerization of any two
of isobutylene, 1-butene and 2-butene.
26. The combination of claim 21 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, diolefin-derived non-aromatic polymers or
copolymers, aromatic group-containing copolymers,
epichlorohydrin-containing polymers, and poly(ethylene-co-vinyl
acetate).
27. The combination of claim 22 wherein the pretreatment coating is
selected from the group consisting of Parylene.TM., silane,
photografted polymers, epoxy primers, polycarboxylate resins and
combinations thereof.
28. The combination of claim 21 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.
29. 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 polybutene 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
poly(alkylene-co-alkyl(meth)acrylates), ethylene copolymers with
other alkylenes, diolefin-derived non-aromatic polymers or
copolymers, aromatic group-containing copolymers,
epichlorohydrin-containing polymers, and poly(ethylene-co-vinyl
acetate).
30. A composition according to claim 29 wherein the first polymer
component is selected from the group consisting of polybutene
prepared by the homopolymerization of isobutylene, 1-butene or
2-butene, polybutene prepared by the random interpolymerization of
isobutylene, 1-butene and 2-butene, and polybutene prepared by the
copolymerization of any two of isobutylene, 1-butene and
2-butene.
31. 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
polybutene 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.
32. 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
poly(isobutylene), 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.
33. A combination according to claim 32, wherein the bioactive
agent is selected from the group consisting of rapamycin,
paclitaxel, dexamethasone, and estradiol.
34. A combination according to claim 32, wherein the stent includes
a material selected from the group consisting of polymers, tissue,
metals, ceramics, and combinations thereof.
35. A combination according to claim 34, wherein the polymers
include polycarbonates and the metals are selected from the group
consisting of titanium, stainless steel, gold, silver, and
nitinol.
36. A combination according to claim 32, wherein the solvent is
selected from the group consisting of tetrahydrofuran, chloroform,
methylene chloride, and cyclohexane.
37. A combination according to claim 32, wherein the biocompatible
additive includes one or more antioxidants selected from the group
consisting of butylated hydroxytoluene, vitamin E, BNX, and
dilauryl thiodipropionate.
38. A combination according to claim 32, wherein the pretreatment
layer includes organosilane and Parylene.
39. 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.
40. A composition according to claim 39, wherein the pretreatment
layer includes organosilane and Parylene.
41. 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 poly(isobutylene), 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.
42. A combination according to claim 41, wherein the bioactive
agent is selected from the group consisting of rapamycin,
paclitaxel, dexamethasone, and estradiol.
43. The combination of claim 41 further comprising a topcoat
including poly(butyl methacrylate).
44. The combination of claim 41, wherein the medical device
comprises a stent.
45. 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 polybutene and a second polymer component comprising a polymer
selected from the group consisting of poly(alkyl(meth)acrylates)
and poly(aromatic(meth)acrylates).
46. The method of claim 45 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
biocompatibility enhancement.
47. The method of claim 45 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
delamination protection.
48. The method of claim 45 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
durability enhancement.
49. The method of claim 45 further comprising the step of applying
a topcoat layer to the bioactive agent coating for the purpose of
bioactive agent release control.
50. The method of claim 45 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.
51. The method of claim 45, 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. 9896.166.7, as well as 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 both of which are 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
polybutenes; 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 a preferred
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, in some embodiments, 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] In some embodiments, the ability to form a true solution
using the claimed polymer combinations is preferred 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] In some embodiments, with regard to its delivery, a
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. In various
embodiments, such delivery involves 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 may provide a coated composition
that is homogeneous, and hence substantially optically clear upon
microscopic examination. Even more surprisingly, various
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.
DETAILED DESCRIPTION
[0017] 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.
[0018] Various 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 a
number of the 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.
[0019] Hence the first polymer of this invention will generally
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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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 w = i N i M i 2 i N i M i
[0024] 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).
[0025] 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,
and in various 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.
[0026] 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.
[0027] 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)acry- late)) 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.
[0028] 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 various
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.
[0029] 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.
[0030] In some embodiments, the coating composition includes 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 many embodiments is one that
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).
[0031] 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.
[0032] In various 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.
[0033] 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. Various first
polymers include polybutenes. Examples of suitable polymers are
commercially available from sources such as Sigma-Aldrich.
[0034] First polymers may include polybutenes. "Polybutenes"
suitable for use in the present invention may 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 various
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).
[0035] In various 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 about 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. Other examples of suitable copolymers
of this type are commercially available from sources such as
Sigma-Aldrich.
[0036] Other examples of suitable copolymers of this type are
commercially available from sources such as Sigma-Aldrich and
include the following products. For example, suitable copolymers of
this type and their related descriptions may be found in the
2003-2004 Aldrich Handbook of Fine Chemicals and Laboratory
Equipment, the entire contents of which are incorporated by
reference herein.
[0037] 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 comprises
at least one second polymer component selected from the group
consisting of poly(alkyl(meth)acrylates- ) and
poly(aromatic(meth)acrylates).
[0038] 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
various 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, and in some
embodiments from about 200 kilodaltons to about 400 kilodaltons. An
example of one embodiment 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).
[0039] 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).
[0040] 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.).
[0041] 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) diolefin derived non-aromatic polymers
and copolymers, (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.
[0042] 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. In some embodiments, such alkyl groups comprise
from 1 to 8 carbon atoms, inclusive, and in some embodiments, from
1 to 4 carbon atoms, inclusive. In various embodiments, the alkyl
group is methyl.
[0043] In turn, copolymers that include such alkyl groups may
comprise from about 15% to about 80% (wt) of alkyl acrylate. In
various embodiments, when the alkyl group is methyl, the polymer
contains 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, in some embodiments, contains
from about 15% to about 40% ethyl acrylate, and when the alkyl
group is butyl, the polymer, in some embodiments, contains from
about 20% to about 40% butyl acrylate.
[0044] The alkylene groups are selected from ethylene and/or
propylene, and in some embodiments, the alkylene group is ethylene.
In various embodiments, the (meth)acrylate comprises an acrylate
(i.e., no methyl substitution on the acrylate group). Various
copolymers provide a molecular weight (Mw) of about 50 kilodaltons
to about 500 kilodaltons, and in some embodiments, Mw is 50
kilodaltons to about 200 kilodaltons.
[0045] The glass transition temperature for these copolymers varies
with ethylene content, alkyl length on the (meth)acrylate and
whether the first copolymer 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.
[0046] 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.
[0047] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich and
include, but are not limited to, poly(ethylene-co-methyl acrylate),
poly(ethylene-co-ethyl acrylate), and poly(ethylene-co-butyl
acrylate).
[0048] 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, in some embodiments, alkylene groups that
comprise from 3 to 4 branched or linear carbon atoms, inclusive,
and in some embodiments, the alkylene group contains 3 carbon atoms
(e.g., propylene). In various embodiments, the other alkylene is a
straight chain alkylene (e.g., 1-alkylene).
[0049] Various 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).
[0050] 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, in
some embodiments, from about 100 kilodaltons to about 200
kilodaltons.
[0051] 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. Various
terpolymers of this type can include up to about 5% (mole) of the
third diene monomer.
[0052] Other examples of suitable additional polymers of this type
are commercially available from sources such as Sigma-Aldrich and
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).
[0053] Alternative additional polymers 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
[0054] 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
[0055] In some embodiments, the additional 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.
[0056] Alternatively, the additional 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 various 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.
[0057] 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, polybutadiene,
poly(butadiene-co-acrylonitrile), polybutadiene-block-polyisoprene,
polybutadiene-graft-poly(methyl acrylate-co-acrylonitrile),
polyisoprene, and partially hydrogenated polyisoprene.
[0058] Suitable additional polymers may also include aromatic
group-containing copolymers, including random copolymers, block
copolymers and graft copolymers. In various 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.
[0059] 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.
[0060] Other examples of suitable copolymers of this type are
commercially available from sources such as Sigma-Aldrich and
include, but are not limited to, poly(styrene-co-butadiene)
(random), polystyrene-block-polybu- tadiene,
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-butadiene- -co-methyl methacrylate).
[0061] 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 various
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.
[0062] Other examples of suitable copolymers of this type are
commercially available from sources such as Sigma-Aldrich and
include, but are not limited to, polyepichlorohydrin and
poly(epichlorohydrin-co-ethylene oxide).
[0063] 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.
[0064] In many embodiments, the coating compositions for use in
this invention includes 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 may be added, such as 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. butylated hydroxytoluene (BHT),
vitamin E (tocopherol), BNX.TM., dilauryl thiodipropionate (DLTDP),
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.
[0065] In various embodiments of the present invention, the polymer
mixture includes a first polymer component comprising one or more
polymers selected from the group consisting of polybutenes, 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 from about 150 kilodaltons to about 500
kilodaltons, and in some embodiments, from about 200 kilodaltons to
about 400 kilodaltons.
[0066] 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). Various polymer
mixtures contain at least about 10 percent by weight of either the
first polymer or the second polymer.
[0067] 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 various
embodiments, the composition may comprise about 15% to about 85% of
the first and/or second polymers. In some embodiments, the
composition may include about 25% to about 75% of the first and/or
second polymers.
[0068] 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
various embodiments, the bioactive agent may comprise about 5% to
about 60% of such a mixture. In some 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 in some embodiments, from about 0.1 to about 50
percent by weight.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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 various 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 in some embodiments, no greater than about 1.5 kilodaltons).
For example, hydrophobic drugs such as rapamycin, paclitaxel,
dexamethasone, lidocaine, triamcinolone acetonide, retinoic acid,
estradiol, pimecrolimus, tacrolimus or tetracaine can be included
in the coating and are released over several hours or longer.
[0074] 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.
[0075] 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, geldanamycin, cephalosporins, and
analogues thereof. Examples of cephalosporins include cephalothin,
cephapirin, cefazolin, cephalexin, cephradine, cefadroxil,
cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid,
ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone, and
cefoperazone.
[0076] 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.
[0077] 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.
[0078] 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-.alpha.-methylbenzylamine (DCMB),
8,9-dichloro-2,3,4,5-tetra- hydro-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.
[0079] 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.
[0080] Local anesthetics are substances which inhibit pain signals
in a localized region. Examples of such anesthetics include
procaine, lidocaine, tetracaine and dibucaine.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] In some embodiments, in order to provide 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 dioxene), 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 effective
solvents due to their excellent solvency for a variety of polymers
and bioactive agents of the present invention.
[0087] 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.
[0088] The coated composition provides a means to deliver bioactive
agents from a variety of biomaterial surfaces. Various 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.
[0089] 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.
[0090] Optionally, and in some embodiments, 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] 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).
[0098] 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.
[0099] 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.
[0100] 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").
[0101] 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.
[0102] In one 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.
[0103] 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.
[0104] In other 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.
[0105] 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. In various
embodiments, these different layers, in turn, can cooperate in the
resultant composite coating to provide an overall release profile
having certain desired characteristics, and may be used with
bioactive agents of high molecular weight. In some 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.
[0106] 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 without the inclusion of a bioactive
agent. In various 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.
[0107] 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, and 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.
[0108] 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 in some embodiments <5% (wt) weight change when
exposed to water.
[0109] 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. Various 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.
[0110] 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.
[0111] The overall weight of the coating upon the surface may vary
depending on the application. However, in some embodiments, the
weight of the coating attributable to the bioactive agent is 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 various embodiments, the
weight of the coating attributable to the bioactive agent is
between about 0.005 mg and about 10 mg, and in some embodiments,
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.
[0112] In turn, and in some embodiments, the final coating
thickness of a coated composition will typically be in the range of
about 0.1 micrometers to about 100 micrometers, and in some
embodiments, between 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.
[0113] 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
[0114] 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. Not all of
these test procedures were used in connection with the example
included in this application, but they are described here to enable
consistent comparison of coatings in accordance with the
invention.
[0115] Sample Preparation Procedure
[0116] Stainless steel stents used in the following example were
manufactured by Laserage Technology Corporation, Waukegan, Ill. In
some cases, the metal surface of the stents may be coated without
any pretreatment beyond washing. In other cases, a primer may be
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
may be 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.) is
vapor-deposited at a thickness of about 1 mm. Prior to coating, the
stents should be weighed on a microbalance to determine a tare
weight.
[0117] 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.
[0118] Rapamycin Release Assay Procedure
[0119] 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.
[0120] Dexamethasone Release Assay Procedure
[0121] A Dexamethasone Release Assay Procedure can be used to
determine the extent and rate of dexamethasone release under in
vitro conditions. Spray-coated stents made using the Sample
Preparation Procedure may be placed in 10 milliliters of pH 7
phosphate buffer solution ("PBS") contained in an amber vial. A
magnetic stirrer bar is added to the vial, and the vial with its
contents are placed into a 37.degree. C. water bath. After a sample
interval, the stent is removed and placed into a new buffer
solution contained in a new vial. Dexamethasone concentration in
the buffer is measured using ultraviolet spectroscopy and the
concentration converted to mass of bioactive agent released from
the coating. After the experiment, the stent should be dried and
weighed to correlate actual mass loss to the loss measured by the
elution experiment.
[0122] Durability Test Procedure
[0123] 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.
[0124] The stent is then examined by optical and scanning electron
microscopy to determine the amount of coating damage caused by
cracking and/or delamination. Coatings with extensive damage are
considered unacceptable for a commercial medical device. A "Rating"
coresponding to a qualitatitive scale used to describe the amount
of damage to the coating from the stent crimping and expansion
procedure can be assigned 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 I will show a majority of the
coating damaged to the point where clinical efficacy maybe
diminished. Commercially attractive coatings typically have a
rating of nine or higher.
[0125] Stress-Strain Measurement Test Procedure
[0126] Polymer films are 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 can be cut into strips
using a razor blade. A Q800 Dynamic Mechanical Analyzer (available
from Texas Instruments, Dallas, Tex.) is fitted with a film tension
clamp. Each sample is equilibrated at 35.degree. C. for five
minutes prior to straining the sample. Then the sample is loaded
into the clamp such that the sample length was between 5 and 7 mm
in length. A static force of 0.01N is applied to each sample
throughout the measurements. Simultaneously, a 0.5 N/min force is
applied to the sample until the movable clamp reaches its maximum
position. Films are elongated at constant stress and the average
tensile modulus (i.e., the initial slope of the stress-strain
curve, in MPa) is determined.
Example 1
Release of Rapamycin from Poly(isobutylene) and Poly(butyl
methacrylate)
[0127] Three solutions were prepared for coating the stents. The
solutions included mixtures of poly(isobutylene) ("PIB", available
from Scientific Polymer Products as Catalog #681, CAS #9003-27-4,
Mw approx. 85 kilodaltons), ("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.
[0128] The solutions were prepared to include the following
ingredients at the stated weights per milliliter of THF:
[0129] 1) 16 mg/ml PIB/4 mg/ml PBMA/10 mg/ml RAPA
[0130] 2) 10 mg/ml PIB/10 mg/ml PBMA/10 mg/ml RAPA
[0131] 3) 4 mg/ml PEB/16 mg/ml PBMA/10 mg/ml RAPA
[0132] 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.
[0133] 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
PIB and PBMA in the polymer mixture as described herein.
[0134] 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.
* * * * *