WO2006062627A1

WO2006062627A1 - Method and apparatus for coating a medical device by electroplating

Info

Publication number: WO2006062627A1
Application number: PCT/US2005/039461
Authority: WO
Inventors: Yixin Xu; Michael N. Helmus
Original assignee: Boston Scientific Limited
Priority date: 2004-12-09
Filing date: 2005-11-01
Publication date: 2006-06-15
Also published as: EP1825030A1; US20060124466A1

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 supended 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.

Description

METHOD AND APPARATUS FOR COATING A MEDICAL DEVICE

BY ELECTROPLATING

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,

I 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 [αveαtion

[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. [00010] 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.

[00011] 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.

[00012] 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.

[00013] 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. [00014] 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

[00015] Fig. 1 illustrates an electroplating apparatus for coating medical devices in

accordance with a first embodiment of the present invention.

[00016] Fig. 2 illustrates an electroplating apparatus for coating medical devices in

accordance with an alternative embodiment of the present invention.

Detailed Description

[00017] Figure I 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 Figure 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 Figure I. [00018] As depicted in Figure 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 Figure 1, voltage source 60 is shown as a battery.

[00019] Referring again to Figure I, 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, halfhium, 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.

[00020] 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(NH₃)2(NO₂)₂, in an ammoniacal bath medium may

be used. Solutions containing 5-10 gms/liter of Pd, operated at 40-50C, using fairly low current

density of 0.5 amps/dm² 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, hi 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). ha addition, an electrolyte

containing Pd ammine salts (e.g., Pd(NH₃)4X) in a solution of up to 30 gms/liter of Pd

maintained at a pH of 9, a temperature of 50C, and a current density of 4 amps/dm² 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.

[00021] Referring to Figure I, 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.

[00022] 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.

[00023] 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. La 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 Figure 1 (labeled as "D" for drug, in this embodiment).

[00024] The electrolytic solution also ionizes into positively and negatively charged ions.

As one example, the electrolytic solution may be Pd(NH₃)(NO₂)₂, which contains positively

charged metal ions, Pd⁴⁺, as generally illustrated as 71 in Figure 1 (labeled as "M". in this embodiment).

[00025] 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 Figure L 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.

[00026] 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 Fe⁴⁺ into the electrolytic solution 31 , thereby replacing the Fe^ that is plated out of the electrolytic solution 31 (where the solution is FeSO₄ which ionizes into Fe^+* and SCV^") 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⁺" + ne => M

A corresponding reaction occurs at the anode.

[00027] 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.

[00028] 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-

[00029] 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 maybe 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.

[00030] 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.

[00031] 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.

H [00032] 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 x 10^"5 m²/g, whereas the surface area of nanoporous gold

made by a de-alloying process is about 2 m²/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.

[00033] 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.

[00034] 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.

[00035] 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 serial number 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.

[00036] In Figure 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 Figure 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.

[00037] 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.

[00038] 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.

[00039] Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such

as heparin, heparin derivatives, prostaglandin (including micellar prostaglandin El), 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-fluorouracϊl, 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)ethylenegIycol-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.

[00040] 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. [00041] Non-limiting examples of proteins include monocyte chemoattractant proteins

("MCP-I) 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-I), BMP-8, BMP-9, BMP-10, BMP-U, 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 DNA¹S encoding them. Non-

limiting examples of genes include survival genes that protect against cell death, such as anti-

apoptotic Bcl-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 α and β, platelet-derived

endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, 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 pl5, pl6,

pl8, pl9, p2l, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase ("TK") and

combinations thereof and other agents useful for interfering with cell proliferation.

[00042] Exemplary small molecules include hormones, nucleotides, amino acids, sugars,

and lipids and compounds have a molecular weight of less than 10OkD. [00043] Exemplary cells include stem cells, progenitor cells, endothelial cells, adult

cardϊomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic)

or from an animal source (xenogenic), or genetically engineered.

[00044] Any of the therapeutic agents may be combined to the extent such combination is

biologically compatible.

[00045] 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 (SEBS); 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®);

squalene emulsions; and mixtures and copolymers of any of the foregoing.

[00046] 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-capro lactone) 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.

[00047] hi a preferred embodiment, the polymer is polyacrylic acid available as

HYDROPLUS® (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.

[00048] 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.

[00049] 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.

[00050] 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. [00051] 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

oxychloride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.

[00052] 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.

[00053] 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.

Claims

What Is Claimed Is:

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 I 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, halfhium, halmium

oxide, zirconium, indium, 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.

I L 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 I 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.