U.S. patent application number 11/007297 was filed with the patent office on 2006-06-15 for method and apparatus for coating a medical device by electroplating.
This patent application is currently assigned to SCIMED LIFE SYSTEMS, INC.. Invention is credited to Michael N. Helmus, Yixin Xu.
Application Number | 20060124466 11/007297 |
Document ID | / |
Family ID | 35737420 |
Filed Date | 2006-06-15 |
United States Patent
Application |
20060124466 |
Kind Code |
A1 |
Xu; Yixin ; et al. |
June 15, 2006 |
Method and apparatus for coating a medical device by
electroplating
Abstract
Methods and apparatuses for coating surfaces of medical devices
by electroplating are disclosed. In one embodiment, the invention
includes a coating method in which a mixture of a therapeutic
agent, and a plating material are electroplated onto the surface of
the medical device. The electroplating method may be performed at a
relatively low temperature to avoid destruction of the therapeutic
agent. In another embodiment, a coating method is disclosed in
which the coating is formed by suspending a therapeutic agent in an
electrolytic solution and electroplating a plating material onto
the medical device wherein the plating material carries the
suspended therapeutic agent. Thus, the coating of plating material
contains the suspended therapeutic agent. These methods and
apparatuses are used to apply one or more coating materials,
simultaneously or in sequence by varying the electroplating
voltage. In certain embodiments of the invention, the coating
materials include therapeutic agents and cationic drugs.
Inventors: |
Xu; Yixin; (Newton, MA)
; Helmus; Michael N.; (Worcester, MA) |
Correspondence
Address: |
KENYON & KENYON LLP
1500 K STREET N.W.
SUITE 700
WASHINGTON
DC
20005
US
|
Assignee: |
SCIMED LIFE SYSTEMS, INC.
|
Family ID: |
35737420 |
Appl. No.: |
11/007297 |
Filed: |
December 9, 2004 |
Current U.S.
Class: |
205/109 |
Current CPC
Class: |
C25D 9/00 20130101; C25D
9/02 20130101; A61L 2420/02 20130101; A61L 2300/606 20130101; A61L
31/10 20130101; C25D 15/00 20130101; A61L 31/082 20130101; A61L
31/16 20130101; C09D 5/4492 20130101 |
Class at
Publication: |
205/109 |
International
Class: |
C25D 15/00 20060101
C25D015/00 |
Claims
1. A method for coating at least a portion of a medical device
comprising: ionizing a therapeutic agent in an electrolytic
solution; and electroplating a mixture of a plating material and
the ionized therapeutic agent onto the medical device, thereby
forming a coating with the therapeutic agent on a medical
device.
2. The method of claim 1 further comprising dissolving a measured
amount of therapeutic agent in the electrolytic solution.
3. The method of claim 1 wherein the step of electroplating
comprises introducing a voltage source having a measured
voltage.
4. The method of claim 3 further comprising regulating the mixture
of the therapeutic agent and plating material by changing the
voltage.
5. The method of claim 1 further comprising treating a surface of
the medical device to be coated.
6. The method of claim 5 wherein the step of treating a surface to
be coated comprises creating a porous surface layer.
7. The method of claim 6 wherein the porous surface layer is made
by vapor deposition, plasma deposition, sintering, sputtering or
electroplating.
8. The method of claim 1 wherein the plating material is gold,
titanium, halfnium, halfnium oxide, zirconium, iridium, iridium
oxide, alumina, niobium, or niobium oxide.
9. The method of claim 1 wherein the electrolytic solution
comprises an acid or salt of the plating metal.
10. The method of claim 1 wherein the coating comprises a polymeric
material.
11. The method of claim 1 wherein the therapeutic agent is selected
from the group consisting of pharmaceutically active compounds,
proteins, oligonucleotides, DNA compacting agents, recombinant
nucleic acids, gene/vector systems, and nucleic acids.
12. The method of claim 1 wherein the therapeutic agent is a
cationic drug.
13. The method of claim 12 wherein the cationic drug is amiloride,
digoxin, morphine, procainamide, quinidine, quinine, ranitidine,
triamterene, trimethoprim, or vancomycin.
14. The method of claim 1 wherein the medical device is a
stent.
15. A bio-compatible medical device for insertion into a body
prepared according to the method of claim 1.
16. A method for coating at least a portion of a medical device
comprising: suspending a therapeutic agent in an electrolytic
solution; and electroplating a plating material onto the medical
device, wherein the coating of plating material contains suspended
therapeutic agent, thereby forming a coating with the therapeutic
agent on the medical device.
17. The method of claim 16 further comprising treating a surface of
the medical device to be coated.
18. The method of claim 17 wherein the step of treating a surface
to be coated comprises creating a porous surface layer.
19. The method of claim 18 wherein the porous surface layer is made
by vapor deposition, plasma deposition, sintering, sputtering, or
electroplating.
20. The method of claim 16 wherein the therapeutic agent is
selected from the group consisting of pharmaceutically active
compounds, proteins, oligonucleotides, DNA compacting agents,
recombinant nucleic acids, gene/vector systems, and nucleic
acids.
21. The method of claim 16 wherein the medical device is a
stent.
22. A bio-compatible medical device for insertion into a body
prepared according to the method of claim 16.
23. A method for coating at least a portion of a medical device
comprising: providing a medical device having a surface; treating
the surface of the medical device; ionizing a therapeutic agent in
an electrolytic solution; and electroplating a mixture of the
therapeutic agent and a plating material onto the surface of the
medical device.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the coating of medical
devices.
BACKGROUND OF THE INVENTION
[0002] The positioning and deployment of medical devices within a
target site of a patient is a common, often-repeated procedure of
contemporary medicine. These devices or implants are used for
innumerable medical purposes including the reinforcement of
recently re-enlarged lumens, the replacement of ruptured vessels,
and the treatment of disease such as vascular disease by local
pharmacotherapy, i.e., delivering therapeutic drug doses to target
tissues while minimizing systemic side effects. Such medical
devices are implanted or otherwise utilized in body lumina and
organs such as the coronary vasculature, esophagus, trachea, colon,
biliary tract, urinary tract, prostate, brain, and the like.
[0003] Coatings are often applied to the surfaces of these medical
devices to increase their effectiveness. These coatings may provide
a number of benefits including reducing the trauma suffered during
the insertion procedure, facilitating the acceptance of the medical
device into the target site, and improving the post-procedure
effectiveness of the device.
[0004] Coating medical devices also provides for the localized
delivery of therapeutic agents to target locations within the body,
such as to treat localized disease (e.g., heart disease) or
occluded body lumens. Such localized drug delivery avoids the
problems of systemic drug administration, such as producing
unwanted effects on parts of the body which are not to be treated,
or not being able to deliver a high enough concentration of
therapeutic agent to the afflicted part of the body. Localized drug
delivery is achieved, for example, by coating expandable stents,
grafts, or balloon catheters, which directly contact the inner
vessel wall, with the therapeutic agent to be locally delivered.
Stents are often used to support tissue while healing takes place.
Expandable stents are tube-like medical devices that often have a
mesh-like patterned structure designed to support the inner walls
of a lumen. These stents are typically positioned within a lumen
and, then, expanded to provide internal support for it. For
example, an intraluminal coronary stent may be used during a
coronary bypass graft surgery, or other heart surgery, to keep the
grafted vessel open to prevent the reclosure of the blood vessel.
The coating on these medical devices may provide for controlled
release, which includes long-term or sustained release, of a
therapeutic agent.
[0005] Aside from facilitating localized drug delivery, medical
devices are coated with materials to provide beneficial surface
properties. For example, medical devices are often coated with
radioopaque materials to allow for fluoroscopic visualization
during placement in the body. It is also useful to coat certain
devices to achieve enhanced biocompatibility and to improve surface
properties such as lubriciousness.
[0006] Conventionally, coatings have been applied to medical
devices by processes such as dipping and spraying. Dipping and
spraying processes usually cannot apply multiple layers of
different coatings without requiring appropriate drying time
between coating steps, which can increase production time and
costs. Further, dipping and spraying processes may result in uneven
coating thickness.
[0007] There is, therefore, a need for a cost-effective method for
coating the surface of medical devices that results in even and
uniform coatings and measured drug doses per unit device. The
present invention provides methods and apparatus for coating
medical devices by electroplating a plating material with a
therapeutic agent onto the surface of medical devices. The methods
of the present invention permit direct local delivery of
therapeutic agents to targeted diseased locations, minimizing waste
and loss of expensive therapeutic. The methods also allow the
coatings to have uniform thicknesses and mechanical properties, and
uniform drug dose.
SUMMARY OF THE INVENTION
[0008] The present invention regards a method and apparatus for
coating at least a portion of a medical device (e.g., a stent). In
accordance with one embodiment, a method for applying at least a
portion of a coating material on a medical device having a surface
is provided. This method includes forming a coating on a
bio-compatible medical device by electroplating a mixture of a
therapeutic agent, and a plating material onto the surface of the
medical device. The electroplating may be performed at a relatively
low temperature.
[0009] In another embodiment of the present invention, a method for
applying at least a portion of a coating to a bio-compatible
medical device is provided wherein the coating is electroplated
onto the surface of the medical device and formed by varying the
electroplating voltage to regulate the amount of the therapeutic
agent and the amount of plating material that is coated.
[0010] In another embodiment of the present invention, a method for
applying at least a portion of a coating to a bio-compatible
medical device is provided wherein the surface of the medical
device is treated, e.g. creating a porous surface layer, to
increase the amount of the therapeutic agent that may be
electroplated onto the medical device. The coating is formed by
electroplating a therapeutic agent into and/or onto the porous
surface layer.
[0011] In another embodiment of the present invention, a method for
applying at least a portion of a coating to a bio-compatible
medical device is provided wherein the coating is formed by
suspending a therapeutic agent in an electrolytic solution and
electroplating a plating material onto the medical device wherein
the plating material carries the suspended therapeutic agent such
that the coating of plating material contains the suspended
therapeutic agent.
[0012] In another embodiment of the present invention, an apparatus
for applying a coating to a medical device having a surface is
provided wherein the coating is formed by electroplating a mixture
of a therapeutic agent and a plating material.
[0013] The present invention provides methods and apparatus for
coating medical devices having a surface by electroplating a
plating material with a therapeutic agent onto the surface of
medical devices. The methods of the present invention permit
coating the external surface of the medical devices, which, for
example, directly contacts the diseased vessel wall, thereby
permitting direct local delivery of therapeutic agents to targeted
diseased locations. The methods also minimize wasted coating during
the coating process, thereby minimizing the loss of expensive
therapeutic. The methods also allow the coatings to have uniform
thicknesses and mechanical properties, and uniform drug dose.
[0014] Alternate embodiments of the present invention also permit
application of multiple layers of coating material by varying the
electroplating voltage to regulate the amount of a first
therapeutic agent, at least a second therapeutic agent, and a
plating material. These methods of the present invention are time
efficient and cost effective because they facilitate the uniform
application of multiple layers of coating materials in a single
coating process without requiring any intermediate drying step
between the application of coating layers. This results in higher
process efficiency.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 illustrates an electroplating apparatus for coating
medical devices in accordance with a first embodiment of the
present invention.
[0016] FIG. 2 illustrates an electroplating apparatus for coating
medical devices in accordance with an alternative embodiment of the
present invention.
DETAILED DESCRIPTION
[0017] FIG. 1 illustrates an apparatus for coating a medical device
having a surface in accordance with one embodiment of the present
invention. The apparatus in this embodiment, as shown in FIG. 1 and
generally designated as 10, provides for depositing a coating on a
medical device 20 by electroplating a mixture of a therapeutic
agent and a plating material. The coating material is electroplated
onto an external surface 21 of medical device 20. The medical
device 20 can be, for example, a stent having a patterned external
surface as shown in FIG. 1.
[0018] As depicted in FIG. 1, the apparatus for coating a medical
device by electroplating 10 includes an electroplating cell 30,
cathode 40, anode 50, and voltage source 60. The electroplating
cell 30 contains an electrolytic solution 31. The portion of the
medical device 20 to be coated is positioned in the electrolytic
solution 31 within electroplating cell 30 and electrically
connected to voltage source 60 with a cathode wire 61. The medical
device 20 serves as a cathode 40, or negatively charged electrode,
of the electroplating cell 30, and is electrically connected to the
negative pole of voltage source 60. Voltage source 60 may be a
source that delivers constant or varying voltage. In FIG. 1,
voltage source 60 is shown as a battery.
[0019] Referring again to FIG. 1, the plating material 51 is also
placed in the electrolytic solution 31 and electrically connected
to voltage source 60 with an anode wire 62. The plating material 51
serves as an anode 50, or positively charged electrode, of the
electroplating cell 30, and is electrically connected to the
positive pole of voltage source 60. A person of ordinary skill in
the art will appreciate that a variety of electrical connection
devices may be used as the cathode wire 61 or anode wire 62, to
permit the flow of electrical charges between the voltage source 60
and cathode 40 or anode 50 respectively, such as copper wire or
wire made from any other conductive material. The medical device 20
may be made from any bio-compatible metal or alloy. Typically,
medical devices, e.g. stents, are made from stainless steel,
tantalum, platinum, cobalt chrome alloys, elgiloy or nitinol
alloys. The plating material 51 can be the same or different metal
or alloy as that of the medical device to be coated. Examples of
plating materials include, but are not limited to, gold, titanium,
halfnium, zirconium, iridium, alumina, and niobium, as well as the
oxides of some of those materials. The plating material may be a
noble metal, such as platinum, for radioopacity
characteristics.
[0020] One of ordinary skill in the art will appreciate that a
variety of acid or salt solutions may be used as the electrolytic
solution 31 to ionize the therapeutic agent and carry ions of the
plating material. The electrolytic solution 31 may be a solution of
an acid or salt of the plating metal 51. For example, Pd salt, or
Pd(NH.sub.3).sub.2(NO.sub.2).sub.2, in an ammoniacal bath medium
may be used. Solutions containing 5-10 gms/liter of Pd, operated at
40-50 C, using fairly low current density of 0.5 amps/dm.sup.2 can
produce coatings having 200-300 DPN and a thickness of up to 5
microns. Ammonium phosphate or sulfamate may also be used as
conducting salts. In addition, the electrolytic solution may
contain Pd chelates. This electrolytic solution may contain 5-10
gms/liter of Pd, buffered with monopotassium phosphate, and can
produce very bright coatings over a wide range of operating
solution conditions (e.g., pH of 4-12). In addition, an electrolyte
containing Pd ammine salts (e.g., Pd(NH.sub.3)4.times.) in a
solution of up to 30 gms/liter of Pd maintained at a pH of 9, a
temperature of 50 C, and a current density of 4 amps/dm.sup.2 may
be used to obtain high ductile coatings with low internal stresses
at high deposition rates. The properties of the deposited coating
may be varied from the previously expressed conditions by varying
the electrolyte composition, agitation, temperature, pH, metal
loading, current density, and voltage wave form. For example, if a
high density coating deposition is desired, the metal ion
concentration may be raised, the current densities may be lowered,
and a mild to moderate agitation should be introduced. If a porous
or less dense deposition is desired, then these same parameters may
be changed in the opposite direction. However, a skilled artisan
would appreciate that the acid or salt solution selected should not
destroy the dissolved therapeutic agent.
[0021] Referring to FIG. 1, the portion of the medical device 20 to
be coated is immersed in the electrolytic solution 31 in the
electroplating cell 30. The medical device 20 may be freely
immersed in electrolytic solution 31 or secured by a holder (not
shown). The holder can be, for example, an inflatable balloon or a
mandrel which secures the medical device by exerting a force upon
the internal surface of the medical device, thereby permitting the
external surface to be plated. It will be appreciated by one of
ordinary skill in the art that a variety of holder devices can be
designed to secure the medical device and permit access to portions
of surface.
[0022] By holding the medical device 20 from its internal surface
with a holder extending the length of the medical device, the
holder may mask the internal surface, thereby preventing the
coating material from adhering to the internal surface, if desired.
Alternatively, if it is desired to coat the entire medical device
20, the holder may be omitted. Also, a person of ordinary skill in
the art will appreciate that medical device 20 can be masked by a
variety of masking methods known in the art to prevent coating
certain portions of medical device 20. The holder, as one example,
can be an inflatable balloon made with any material that is
flexible and resilient. Latex, silicone, polyurethane, rubber
(including styrene and isobutylene styrene), and nylon, are each
examples of materials that may be used in manufacturing the
inflatable balloon.
[0023] Forming a coating on medical device 20 by electroplating a
mixture of a therapeutic agent and a plating material may be
achieved by several methods. In one embodiment, the therapeutic
agent is dissolved into the electrolytic solution 31 and
dissociated, producing positively and negatively charged drug ions.
As one example, the ionization of amiloride, a cationic drug has an
excess of positively charged ionized groups that allows it to be
attached to the cathode. The positively charged ions of the
therapeutic agent are generally illustrated as 70 in FIG. 1
(labeled as "D" for drug, in this embodiment).
[0024] The electrolytic solution also ionizes into positively and
negatively charged ions. As one example, the electrolytic solution
may be Pd(NH.sub.3)(NO.sub.2).sub.2, which contains positively
charged metal ions, Pd.sup.++, as generally illustrated as 71 in
FIG. 1 (labeled as "M" in this embodiment).
[0025] At the anode 50 of the electroplating cell 30, negatively
charged electrons are removed from the plating material 51 and flow
in the direction depicted by direction arrow A in FIG. 1 from the
anode 50 to the cathode 40. The medical device 20, electrically
connected to the negative pole of voltage source 60 and positioned
as the cathode 40, receives the negatively charged electrons and
thereby attracts the positively charged ions 70 and 71 in the
electrolytic solution 31. Thus, at the negatively charged cathode
40 of the electroplating cell 30, a coating is formed onto the
medical device 20 by electroplating a mixture of the therapeutic
agent and plating material.
[0026] The plating material 51, electrically connected to the
positive pole of voltage source 60, as anode 50, becomes positively
charged as electrons are removed. For example, if the plating
material 51 were Iron metal, the Iron would oxidize into a
positively charged state as electrons travel towards the cathode
40. The Iron metal anode, in its positively charged state, would
then dissolve as Fe.sup.++ into the electrolytic solution 31,
thereby replacing the Fe.sup.++ that is plated out of the
electrolytic solution 31 (where the solution is FeSO.sub.4 which
ionizes into Fe.sup.++ and SO.sub.4.sup.--) onto the medical device
20. The anode material can either be the metal to be deposited (as
in the example above, where the electrode reaction is the
electrodissolution of Fe that continuously supplies Fe ions), or
the anode can be an inert material where the anodic reaction is
oxygen evolution (in which the plating solution may eventually be
depleted of metal ions). In some cases, the anode material may not
be the same material as the plating material (e.g., Pd), in which
case the electroplating reaction reduces metal ions from aqueous,
organic, or fused salt electrolytes. This type of reaction at the
cathode may generally be represented by the following equation:
M.sup.+n+ne.sup.-=>M A corresponding reaction occurs at the
anode.
[0027] Some examples, among others, of therapeutic agents that may
be ionized are cationic drugs, such as amiloride, digoxin,
morphine, procainamide, quinidine, quinine, ranitidine,
triamterene, trimethoprim, and vancomycin. One of ordinary skill in
the art will appreciate that a variety of other acid-stable drugs
that may be dissociated in an electrolytic solution into ions may
be used. Selection of the drug and plating formulation may be
limited to a combination that does not result in the destruction of
the drug during the electroplating process. Further, since
electroplating, when compared to other processes such as
sputtering, may be conducted at ambient or relatively low
temperatures, less drug may be destroyed.
[0028] In another embodiment, the ratio of metal ions 71 and
therapeutic agent ions 70 in the electrolytic solution 31 can be
varied to control the amount and concentration of the therapeutic
agent in the coating. A skilled artisan can appreciate that the
ratio of metal to therapeutic agent ions can be controlled, for
example, by initially dissolving a greater concentration of
therapeutic agent into the electrolytic solution 31.
[0029] In another embodiment, the voltage can be varied to
intermittently plate metal and therapeutic agent coating layers.
One of ordinary skill in the art will appreciate that the plating
material 51 and therapeutic agent may be selected such that they
have disparate plating voltages. Thus, alternating coatings of
metal and therapeutic agent layers can be achieved by first setting
the voltage source 60 at the specific plating voltage for plating
metal ions, and then subsequently changing the voltage of voltage
source 60 to plate therapeutic agent ions.
[0030] In still another embodiment, two or more therapeutic agents
with disparate plating voltages may be dissolved and ionized in the
electrolytic solution 31. By varying the voltage of voltage source
60 alternately between the different plating voltages, multiple
coatings of two or more therapeutic agents may be plated in a
unitary coating process step without requiring an intermediate
drying step between application of coating layers.
[0031] In yet another embodiment, the surface of the medical device
is first treated to create a porous layer to increase the amount of
the therapeutic agent that may be electroplated onto the medical
device. Thereafter, the coating is formed by electroplating the
therapeutic agent onto the treated surface and into the pores of
the porous layer. Due to the large surface area of the porous
structure, large amount of therapeutic agents can be drawn into the
pores, and a larger concentration of therapeutic agent can be
applied.
[0032] The porous layer can be created by several methods,
including vapor deposition processes, CVD, PVD, plasma deposition,
electroplating, sintering, sputtering or other methods known in the
art. The deposited porous material may be the same as the substrate
or the metal being electroplated. The amount of plated drug which
can be loaded onto the porous layer is much greater than the amount
of plated drug that can be loaded onto a flat surface. This is
because the pores not only add more surface area upon which to load
the plated drug, but also because the volume of the pores are
filled with the plated drug. For example, the surface area of I
gram of non-porous gold is about 8.times.10.sup.-5 m.sup.2/g,
whereas the surface area of nanoporous gold made by a de-alloying
process is about 2 m.sup.2/g. Although this embodiment described
above involves a two-step process, by forming the porous layer
first at relatively high temperatures, or annealing the substrate
at relatively high temperatures to enhance the adhesion, the second
step of therapeutic agent plating can be done at a lower
temperature or room temperature. The shape of the pores in the
porous surface may serve as a means to control the release rate of
the therapeutic agent. For example, a pore with a narrow opening
and a wide bottom may release drugs more slowly than a pore with a
wide opening and a narrow bottom. Also, a pore with a jagged inner
surface, or with varying narrow and wide radiuses throughout the
depth of the pore, or a pore with an elongated tortuous passageway
may also serve to meter the release rate of the drug.
[0033] Alternatively, the process of forming the porous layer and
plating the therapeutic agent may be conducted in one step. Since
the porous layer can be created by electroplating, a mixture of the
therapeutic agent and porous plating material may be electroplated
in one step similar to the electroplating process described
herein.
[0034] Also, the coating density may vary depending on the
concentration of the therapeutic agent in the coating layer. If the
concentration is relatively high, the coating can be denser.
Further, the concentration of the therapeutic agent may be higher
at the outer surface of the treated layer than the interior porous
layers. Thus, more therapeutic agents may be released first from
the outer surface once the device is deployed in a patient, which
may be preferred. Thereafter, the release can be slower as the
therapeutic agent is released from the interior porous layers. One
of ordinary skill in the art will appreciate that the concentration
of the therapeutic agent in the coating layer can be varied by
increasing or decreasing the porosity of the porous layer, which
permits more or less of the therapeutic agent to be plated, upon
treating the surface of the medical device.
[0035] By first treating the surface of the medical device to
create an interconnected porous network layer of coating,
therapeutic agents may be released in a slow and controlled manner.
The therapeutic agent is released through the path in the metal
matrix. Further, by creating a nano-porous layer, the therapeutic
agent may be applied without a polymer binder. The treatment
process of creating a porous layer is further described in the
following pending patent applications: "Functional Coatings and
Designs for Medical Implants," by Weber, Holman, Eidenschink and
Chen, application Ser. No. 10/759,605; and "Medical Devices Having
Nanostructured Regions for Controlled Tissue Biocompatibility and
Drug Delivery," by Helmus, Xu and Ranada, filed on even date with
the instant application. These applications are incorporated
herein.
[0036] In FIG. 2, an apparatus for coating a medical device in
accordance with another embodiment of the present invention is
illustrated. In this embodiment, generally designated as 20, an
electroplating cell 30 is shown which contains an electrolytic
solution 31 having metal ions 71 and drug particles, generally
illustrated as 72 in FIG. 2, suspended within the electrolytic
solution 31. Where the desired therapeutic agent or drug coating
cannot be dissolved in the electrolytic solution 31 and become
ionized, the therapeutic agent or drug may be produced in fine
particles, e.g. nano-meter sized particles, and suspended. During
the plating process, these particles will become trapped by the
metal ions 71, and will plate to the medical device 20--similar to
the way that contamination elements are trapped by plating material
ions and become plated to a substrate in conventional
electroplating processes. The amount of the therapeutic agent or
drug particles 72 that are deposited onto the surface of medical
device 20 varies with the concentration of the therapeutic agent or
drug suspended in the electrolytic plating solution 31. One of
ordinary skill in the art will appreciate that particles of two or
more therapeutic agents or drugs may be suspended in the
electrolytic solution to allow multiple coatings.
[0037] The medical devices used in conjunction with the present
invention include any device amenable to the coating processes
described herein. The medical device, or portion of the medical
device, to be coated or surface modified may be made of metal,
polymers, ceramics, composites or combinations thereof. Whereas the
present invention is described herein with specific reference to a
vascular stent, other medical devices within the scope of the
present invention include any devices which are used, at least in
part, to penetrate the body of a patient. Non-limiting examples of
medical devices according to the present invention include
catheters, guide wires, balloons, filters (e.g., vena cava
filters), stents, stent grafts, vascular grafts, intraluminal
paving systems, soft tissue and hard tissue implants, such as
orthopedic reair plates and rods, joint implants, tooth and jaw
implants, metallic alloy ligatures, vascular access ports,
artificial heart housings, heart valve struts and stents (used in
support of biologic heart valves), aneurysm filling coils and other
coiled coil devices, trans myocardial revascularization ("TMR")
devices, percutaneous myocardial revascularization ("PMR") devices,
hypodermic needles, soft tissue clips, holding devices, and other
types of medically useful needles and closures, and other devices
used in connection with drug-loaded polymer coatings. Such medical
devices may be implanted or otherwise utilized in body lumina and
organs such as the coronary vasculature, esophagus, trachea, colon,
biliary tract, urinary tract, prostate, brain, lung, liver, heart,
skeletal muscle, kidney, bladder, intestines, stomach, pancreas,
ovary, cartilage, eye, bone, and the like. Any exposed surface of
these medical devices may be coated with the methods and
apparatuses of the present invention.
[0038] The coating materials used in conjunction with the present
invention are any desired, suitable substances. In some
embodiments, the coating materials comprise therapeutic agents,
applied to the medical devices alone or in combination with
solvents in which the therapeutic agents are at least partially
soluble or dispersible or emulsified, and/or in combination with
polymeric materials as solutions, dispersions, suspensions,
latices, etc. The solvents may be aqueous or non-aqueous. Coating
materials with solvents may be dried or cured, with or without
added external heat, after being deposited on the medical device to
remove the solvent. The therapeutic agent may be any
pharmaceutically acceptable agent such as a non-genetic therapeutic
agent, a biomolecule, a small molecule, or cells. The coating on
the medical devices may provide for controlled release, which
includes long-term or sustained release, of a therapeutic
agent.
[0039] Exemplary non-genetic therapeutic agents include
anti-thrombogenic agents such as heparin, heparin derivatives,
prostaglandin (including micellar prostaglandin E1), urokinase, and
PPack (dextrophenylalanine proline arginine chloromethylketone);
anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus
(rapamycin), tacrolimus, everolimus, monoclonal antibodies capable
of blocking smooth muscle cell proliferation, hirudin, and
acetylsalicylic acid; anti-inflammatory agents such as
dexamethasone, rosiglitazone, prednisolone, corticosterone,
budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic
acid, mycophenolic acid, and mesalamine;
anti-neoplastic/anti-proliferative/anti-mitotic agents such as
paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,
doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,
vincristine, epothilones, endostatin, trapidil, halofuginone, and
angiostatin; anti-cancer agents such as antisense inhibitors of
c-myc oncogene; anti-microbial agents such as triclosan,
cephalosporins, aminoglycosides, nitrofurantoin, silver ions,
compounds, or salts; biofilm synthesis inhibitors such as
non-steroidal anti-inflammatory agents and chelating agents such as
ethylenediaminetetraacetic acid,
O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid and
mixtures thereof, antibiotics such as gentamycin, rifampin,
minocyclin, and ciprofolxacin; antibodies including chimeric
antibodies and antibody fragments; anesthetic agents such as
lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide
(NO) donors such as lisidomine, molsidomine, L-arginine,
NO-carbohydrate adducts, polymeric or oligomeric NO adducts;
anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD
peptide-containing compound, heparin, antithrombin compounds,
platelet receptor antagonists, anti-thrombin antibodies,
anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin
sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet
aggregation inhibitors such as cilostazol and tick antiplatelet
factors; vascular cell growth promotors such as growth factors,
transcriptional activators, and translational promotors; vascular
cell growth inhibitors such as growth factor inhibitors, growth
factor receptor antagonists, transcriptional repressors,
translational repressors, replication inhibitors, inhibitory
antibodies, antibodies directed against growth factors,
bifunctional molecules consisting of a growth factor and a
cytotoxin, bifunctional molecules consisting of an antibody and a
cytotoxin; cholesterol-lowering agents; vasodilating agents; agents
which interfere with endogeneus vascoactive mechanisms; inhibitors
of heat shock proteins such as geldanamycin; and any combinations
and prodrugs of the above.
[0040] Exemplary biomolecules include peptides, polypeptides and
proteins; oligonucleotides; nucleic acids such as double or single
stranded DNA (including naked and cDNA), RNA, antisense nucleic
acids such as antisense DNA and RNA, small interfering RNA (siRNA),
and ribozymes; genes; carbohydrates; angiogenic factors including
growth factors; cell cycle inhibitors; and anti-restenosis agents.
Nucleic acids may be incorporated into delivery systems such as,
for example, vectors (including viral vectors), plasmids or
liposomes.
[0041] Non-limiting examples of proteins include monocyte
chemoattractant proteins ("MCP-1) and bone morphogenic proteins
("BMP's"), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6
(Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12,
BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3,
BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as
homdimers, heterodimers, or combinations thereof, alone or together
with other molecules. Alternatively, or in addition, molecules
capable of inducing an upstream or downstream effect of a BMP can
be provided. Such molecules include any of the "hedghog" proteins,
or the DNA's encoding them. Non-limiting examples of genes include
survival genes that protect against cell death, such as
anti-apoptotic Bc1-2 family factors and Akt kinase and combinations
thereof. Non-limiting examples of angiogenic factors include acidic
and basic fibroblast growth factors, vascular endothelial growth
factor, epidermal growth factor, transforming growth factor .alpha.
and .beta., platelet-derived endothelial growth factor,
platelet-derived growth factor, tumor necrosis factor .alpha.,
hepatocyte growth factor, and insulin like growth factor. A
non-limiting example of a cell cycle inhibitor is a cathespin D
(CD) inhibitor. Non-limiting examples of anti-restenosis agents
include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F
decoys, thymidine kinase ("TK") and combinations thereof and other
agents useful for interfering with cell proliferation.
[0042] Exemplary small molecules include hormones, nucleotides,
amino acids, sugars, and lipids and compounds have a molecular
weight of less than 100 kD.
[0043] Exemplary cells include stem cells, progenitor cells,
endothelial cells, adult cardiomyocytes, and smooth muscle cells.
Cells can be of human origin (autologous or allogenic) or from an
animal source (xenogenic), or genetically engineered.
[0044] Any of the therapeutic agents may be combined to the extent
such combination is biologically compatible.
[0045] Any of the above mentioned therapeutic agents may be
incorporated into a polymeric coating on the medical device or
applied onto a polymeric coating on a medical device. The polymers
of the polymeric coatings may be biodegradable or
non-biodegradable. Non-limiting examples of suitable
non-biodegradable polymers include polyisobutylene copolymers and
styrene-isobutylene-styrene block copolymers such as
styrene-isobutylene-styrene tert-block copolymers (SIBS);
polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone;
polyvinyl alcohols, copolymers of vinyl monomers such as EVA;
polyvinyl ethers; polyvinyl aromatics; polyethylene oxides;
polyesters including polyethylene terephthalate; polyamides;
polyacrylamides; polyethers including polyether sulfone;
polyalkylenes including polypropylene, polyethylene and high
molecular weight polyethylene; polyurethanes; polycarbonates,
silicones; siloxane polymers; cellulosic polymers such as cellulose
acetate; polymer dispersions such as polyurethane dispersions
(BAYHDROL.RTM.); squalene emulsions; and mixtures and copolymers of
any of the foregoing.
[0046] Non-limiting examples of suitable biodegradable polymers
include polycarboxylic acid, polyanhydrides including maleic
anhydride polymers; polyorthoesters; poly-amino acids; polyethylene
oxide; polyphosphazenes; polylactic acid, polyglycolic acid and
copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA),
poly(D,L,-lactide), poly(lactic acid-co-glycolic acid), 50/50
(DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate;
polydepsipeptides; polycaprolactone and co-polymers and mixtures
thereof such as poly(D,L-lactide-co-caprolactone) and
polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and
blends; polycarbonates such as tyrosine-derived polycarbonates and
arylates, polyiminocarbonates, and polydimethyltrimethylcarbonates;
cyanoacrylate; calcium phosphates; polyglycosaminoglycans;
macromolecules such as polysaccharides (including hyaluronic acid;
cellulose, and hydroxypropylmethyl cellulose; gelatin; starches;
dextrans; alginates and derivatives thereof), proteins and
polypeptides; and mixtures and copolymers of any of the foregoing.
The biodegradable polymer may also be a surface erodable polymer
such as polyhydroxybutyrate and its copolymers, polycaprolactone,
polyanhydrides (both crystalline and amorphous), maleic anhydride
copolymers, and zinc-calcium phosphate.
[0047] In a preferred embodiment, the polymer is polyacrylic acid
available as HYDROPLUS.RTM. (Boston Scientific Corporation, Natick,
Mass.), and described in U.S. Pat. No. 5,091,205, the disclosure of
which is incorporated by reference herein. In a more preferred
embodiment, the polymer is a co-polymer of polylactic acid and
polycaprolactone.
[0048] Such coatings used with the present invention may be formed
by any method known to one in the art. For example, an initial
polymer/solvent mixture can be formed and then the therapeutic
agent added to the polymer/solvent mixture. Alternatively, the
polymer, solvent, and therapeutic agent can be added simultaneously
to form the mixture. The polymer/solvent mixture may be a
dispersion, suspension or a solution. The therapeutic agent may
also be mixed with the polymer in the absence of a solvent. The
therapeutic agent may be dissolved in the polymer/solvent mixture
or in the polymer to be in a true solution with the mixture or
polymer, dispersed into fine or micronized particles in the mixture
or polymer, suspended in the mixture or polymer based on its
solubility profile, or combined with micelle-forming compounds such
as surfactants or adsorbed onto small carrier particles to create a
suspension in the mixture or polymer. The coating may comprise
multiple polymers and/or multiple therapeutic agents.
[0049] The release rate of drugs from drug matrix layers is largely
controlled, for example, by variations in the polymer structure and
formulation, the diffusion coefficient of the matrix, the solvent
composition, the ratio of drug to polymer, potential chemical
reactions and interactions between drug and polymer, the thickness
of the drug adhesion layers and any barrier layers, and the process
parameters, e.g., drying, etc. The coating(s) applied by the
methods and apparatuses of the present invention may allow for a
controlled release rate of a coating substance with the controlled
release rate including both long-term and/or sustained release.
[0050] The coatings of the present invention are applied such that
they result in a suitable thickness, depending on the coating
material and the purpose for which the coating(s) is applied. It is
also within the scope of the present invention to apply multiple
layers of polymer coatings onto the medical device. Such multiple
layers may contain the same or different therapeutic agents and/or
the same or different polymers, which may perform identical or
different functions. Methods of choosing the type, thickness and
other properties of the polymer and/or therapeutic agent to create
different release kinetics are well known to one in the art.
[0051] The medical device may also contain a radio-opacifying agent
within its structure to facilitate viewing the medical device
during insertion and at any point while the device is implanted.
Non-limiting examples of radio-opacifying agents are bismuth
subcarbonate, bismuth oxychtoride, bismuth trioxide, barium
sulfate, tungsten, and mixtures thereof.
[0052] In addition to the previously described coating layers and
their purposes, in the present invention the coating layer or
layers may be applied for any of the following additional purposes
or combination of the following purposes: to alter surface
properties such as lubricity, contact angle, hardness, or barrier
properties; to improve corrosion, humidity and/or moisture
resistance; to improve fatigue, mechanical shock, vibration, and
thermal cycling; to change/control composition at surface and/or
produce compositionally graded coatings; to apply controlled
crystalline coatings; to apply conformal pinhole free coatings; to
minimize contamination; to change radiopacity; to impact
bio-interactions such as tissue/blood/fluid/cell compatibility,
anti-organism interactions (fungus, microbial, parasitic
microorganisms), immune response (masking); to control release of
incorporated therapeutic agents (agents in the base material,
subsequent layers or agents applied using the above techniques or
combinations thereof); or any combinations of the above using
single or multiple layers.
[0053] One of skill in the art will realize that the examples
described and illustrated herein are merely illustrative, as
numerous other embodiments may be implemented without departing
from the spirit and scope of the present invention.
* * * * *