WO2008127964A2 - Methods and systems for applying therapeutic agent to a medical device - Google Patents

Abstract

In methods and systems for applying a coating to a medical device, such as a coating comprising a therapeutic agent, electrons may be transferred from an electrode to ionize a therapeutic agent dissolved in an electrolytic solution. The ionized therapeutic agent may then be electrochemically delivered to the medical device. The medical device may be a stent, which may have a porous surface.

Description

METHODS AND SYSTEMS FOR APPLYING THERAPEUTIC AGENT TO A MEDICAL DEVICE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 60/911,358, filed April 12, 2007, the disclosure of which is hereby incorporated by reference.

TECHNICAL FIELD

[0002] The present invention generally relates to the application of coating materials, including coating materials containing a therapeutic agent, to medical devices such as implantable stents.

BACKGROUND

[0003] The positioning and deployment of medical devices within a target site of a patient is a common procedure of contemporary medicine. These devices, which may be implantable stents and other devices that may be deployed for short or sustained periods of time, may be used for many medical purposes. These can include the reinforcement of recently re-enlarged lumens, the replacement of ruptured vessels, and the treatment of disease, such as vascular disease by local pharmacotherapy, e.g., delivering therapeutic agent doses to target tissues while minimizing systemic side effects. The targeted delivery areas may include body lumens such as the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, and the like.

[0004] Coatings may be 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.

[0005] Coated medical devices may also provide for the localized delivery of therapeutic agents to target locations within the body. 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 may be achieved, for example, by coating the entire outer surface of the medical device or just those portions of the medical device that directly contact the desired treatment site, such as the inner vessel wall. This drug delivery may be intended for short and/or sustained periods of time.

BRIEF DESCRIPTION

[0006] The present invention is directed to methods and systems for coating, loading, or otherwise applying therapeutic agent to at least a portion of a medical device. In accordance with one embodiment of the present invention, a method for coating at least a portion of a medical device is provided. This method includes transferring electrons from an electrode to ionize therapeutic agent dissolved in an electrolytic solution and electrochemically depositing the ionized therapeutic agent onto the medical device. Thus, a coating including the therapeutic agent may be formed on the medical device.

[0007] In accordance with another embodiment of the present invention, a method for applying therapeutic agent to at least a portion of a medical device with a therapeutic agent is provided wherein electrons may be transferred from an electrode to ionize the therapeutic agent dissolved in an electrolytic solution and the ionized therapeutic agent may be electrochemically applied to a portion of the medical device. [0008] In yet another embodiment of the present invention, a method for coating at least a portion of an electrically charged medical device is provided. The method includes providing a medical device having a porous region and an electrode. The medical device and the electrode may be immersed within an electrolytic solution including therapeutic agent dissolved therein. A voltage source may then be introduced to polarize the electrode for electron reduction. Consequently, electrons are transferred to the electrolytic solution to ionize the therapeutic agent. Then, the therapeutic agent may be electrochemically delivered to the porous region of the medical device.

[0009] In accordance with still another embodiment of the present invention, a system for coating at least a portion of a medical device is provided. The system may include a voltage source, an electrochemical cell including an electrolytic solution having a coating material dissolved therein, and an electrode positioned within the electrolytic solution. The electrode may be connected to the voltage source and configured to transfer electrons to ionize the coating material. The medical device can be connected to the voltage source and positioned within the electrolytic solution so that the ionized coating material is electrochemically deposited onto the medical device to form a coating when current is applied.

BRIEF DESCRIPTION OF THE DRAWINGS

[00010] Referring to the drawings, which form a part of this disclosure: [00011] FIG. 1 illustrates an electrochemical deposition system for coating medical devices with therapeutic agent that may be employed in accordance with an embodiment of the present invention;

[0010] FIG. 2 illustrates the electrochemical deposition system of FIG. 1 loading a porous region of a medical device with therapeutic agent; [0011] FIG. 3 illustrates the electrochemical deposition system of FIG. 1 loading a porous region of a medical device with two different therapeutic agents; and [0012] FIG. 4 shows a flow chart including method steps that may be employed in accordance with an embodiment of the present invention to apply therapeutic agent to a portion of a medical device.

DETAILED DESCRIPTION

[0013] FIG. 1 illustrates a electrochemical deposition system for applying a therapeutic agent to a medical device in accordance with one embodiment of the present invention. The electrochemical deposition system in this embodiment, as shown in FIG. 1 and generally designated as 10, provides for depositing a coating on a medical device 20 by electrochemically depositing a therapeutic agent. The therapeutic agent is deposited onto an external surface 22 of medical device 20. The medical device 20 can be, for example, a stent having a patterned external surface 22 as shown in FIG. 1.

[0014] As depicted in FIG. 1, the system 10 for coating a medical device by electrochemical deposition includes an electrochemical cell 30 including medical device 20, a counter electrode 40, and voltage source 60. In addition, in FIG. 1, it may also be seen that the circuit may include potentiostats 80. Potientiostats 80 may control the voltage difference between electrodes and can implement this control by injecting current into the electrochemical cell. The electrochemical cell 30 contains an electrolytic solution 31 including a therapeutic agent 21. The portion of the medical device 20 to be coated is positioned in the electrolytic solution 31 within electrochemical cell 30 and electrically connected to voltage source 60 with a anode wire 61. The medical device 20 serves as an anode, or positively charged electrode, of the electrochemical cell 30, and is electrically connected to the positive pole of voltage source 60. [0015] Voltage source 60 may be any suitable source that delivers constant or varying voltage. In FIG. 1, voltage source 60 is shown as a battery. The voltage source 60 may be designed to operate at any desired voltage or range of voltages. For example, in one example, the accumulation voltage may be set between 0 and (-)800 millivolts (mV). Alternatively, a reverse reaction, in which the drug is oxidized to a cation and accumulated on the negative electrode, may be used. In such a configuration, the volatage may range from +/- 2 V. Other arrangements are possible.

[0016] Also as shown in FIG. 1, the counter electrode 40 is also placed in the electrolytic solution 31 and electrically connected to voltage source 60 with a cathode wire 62. The counter electrode 40 serves as a cathode, or negatively charged electrode, of the electrochemical cell 30, and is electrically connected to the negative pole of voltage source 60. The counter electrode may be an inert material. In the example, the counter electrode may be formed of platinum, however, any material that can be negatively charged to act as the source of electrons in the cell may be used. For example, copper, iron, graphite, mercury, and other materials may be suitable depending on the application. [0017] A person of ordinary skill in the art will also appreciate that a variety of electrical connection devices may be used as the anode and cathode wires 61, 62 to permit the flow of electrical charges between the voltage source 60 and counter electrode 40 and medical device 20 respectively, such as copper wire or wire made from any other suitable conductive material.

[0018] The medical device 20 may be made from any bio-compatible metal, alloy, ceramic or polymer. Typically, medical devices, e.g., stents, are made from stainless steel, tantalum, platinum, cobalt chrome alloys, elgiloy, nitinol alloys, ceramics, and polymers. The medical device may also be semi-conductive. The device may have two layers where the first layer is conductive and the second outer layer is a porous non-conductive layer (e.g., ceramic) which permits electrical contact between the first layer and solution contacting the second layer.

[0019] Medical devices 20 to which therapeutic agent 21 may be applied in accordance with the invention may be 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. Examples of such medical devices include stents, stent grafts, vascular grafts, and other devices used in connection with therapeutic agent or drug-loaded coatings. Such medical devices are implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, and the like.

[0020] The medical devices, such as stents, themselves may be self-expanding, mechanically expandable, or hybrid implants which may have both self-expanding and mechanically expandable characteristics. The medical device may be made in a wide variety of designs and configurations.

[0021] 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.

[0022] One of ordinary skill in the art will appreciate that a variety of suitable electrolytic solutions 31, e.g., aqueous or alcohol based buffer solutions, may be used as the electrolytic solution 31 to carry a charge, complete the electrical circuit, and to ionize the therapeutic agent 21. Benign physiological buffers such as borate and phosphate may be used. For example, the electrolytic solution may include a phosphate buffer saline (PBS) solution. In one example the PBS solution may be dissolved in water and can have a pH of 1.2-1 A. However, it should be understood that a variety of controllable parameters are possible.

[0023] For example, the amount and properties of the deposited therapeutic agent coating may be controlled by varying, for example, the porosity of the substrate or the deposition conditions (e.g., electrolyte composition, agitation, concentrations, temperature, pH, current, time, and voltage). In some instances, if a high density coating deposition is desired, the temperature may be raised to increase the solubility and the diffusion of the therapeutic agent. In other instances, the temperature may be raised from, for example, 15°C to 37⁰C to increase the solubility and the diffusion of therapeutic agent. Still in other examples, if increased solubility and diffusion is desired, the time the medical device is oxidizing may be changed. For instance, the oxidation time may be increased from, for example, three minutes to an hour. In yet another example, depending upon the therapeutic agent, the pH of the solution may be varied. For instance, the pH of the solution may be changed from, for example, 5.0 to 9.0. 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 a multitude of parameters may be varied to achieve a wide range of release profile time lines.

[0024] Referring again to FIG. 1, the portion of the medical device 20 to be coated is immersed in the electrolytic solution 31 in the electrochemical cell 30. The medical device 20 may be freely immersed in the electrolytic solution 31 or secured by a holder 70. The holder 70 can be, for example, an inflatable balloon or a mandrel which secures the medical device 20 by exerting a force upon the internal surface of the medical device, thereby permitting therapeutic agent 21 to be electrochemically deposited on the external surface 22 of the medical device 20. 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 the desired coating surface. For example, alligator clips, wires, and twists may be used. [0025] By holding the medical device 20 from its internal surface with a holder 70 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, the holder 70 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 the medical device 20. The holder 70, 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.

[0026] In use, the electrochemical deposition system 10 may deliver a therapeutic agent 21 to a medical device 20 by several methods.

[0027] In the embodiment shown in FIG. 1, the therapeutic agent 21 is dissolved into the electrolytic solution 31. A voltage source 60 is then introduced to apply a current to the counter electrode 40 to polarize the counter electrode 40 for electron reduction. The counter electrode 40 then releases electrons to negatively charge the therapeutic agent 21. The negatively charged ions of the therapeutic agent 21 are also generally illustrated as 21 in FIG. 1.

[0028] At the medical device 20 or anode of the electrochemical cell 30, the medical device 20 is positively charged so that ions are oxidized from the medical device 20 and electrons flow in the direction depicted by direction arrow A in FIG. 1 from the medical device 20 to the counter electrode 40. The medical device 20, electrically connected to the positive pole of voltage source 60 and positioned as the anode, receives the negatively charged ions of the therapeutic agent. Thus, the negatively charged therapeutic agent 21 is delivered and applied to the medical device 20 by electrochemically depositing the therapeutic agent on a portion thereof.

[0029] As noted above, the method of FIG. 1 may employ electron reduction and oxidation to induce the accumulation of therapeutic agent 21 onto a surface of the medical device 20. For example, if a voltage source 60 is introduced and electron reduction occurs, the therapeutic agent 21 is ionized with a negative charge. Using paclitaxel as an example of a therapeutic agent 21, the reactions taking place in the electrolytic solution may generally be represented by the following equations: e^" + [PTx] => [PTx]^(at the counter electrode) and [PTx]°=> e^" + [PTx] (at the medical device).

[0030] The therapeutic agent 21, in its negatively charged state, will be attracted to the positively charged medical device. Some examples, among others, of therapeutic agents that may be ionized are paclitaxel, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin, and a broad range of macro lides including sirolimus and everolimus type compounds are suitable. One of ordinary skill in the art will appreciate that a variety of other drugs that may be ionized while in an electrolytic solution 31 may be used.

[0031] The concentration of the therapeutic agent in the electrolytic solution 31 can be varied to control the amount and concentration of the therapeutic agent in the coating. For example, in one instance 1 microgram of paclitaxel per milliliter of solution may be suitable. However, a skilled artisan can appreciate that the ratio of therapeutic agent ions can be controlled, for example, by initially dissolving a greater concentration of therapeutic agent into the electrolytic solution 31. [0032] The parameters of the voltage source may also be adjusted to control the amount of therapeutic agent deposited on the medical device. For example, as noted above, an example of one suitable range, among others, is between 0 mV and (-)800 mV. [0033] In accordance with other embodiments of the invention, two or more therapeutic agents may be used. For example, two or more therapeutic agents may be dissolved and ionized in the electrolytic solution 31. In addition, multiple coatings of therapeutic agent may be delivered to the medical device 20. 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 or polymer- free 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. Any suitable method of choosing the type, thickness and other properties of the polymer and/or therapeutic agent to create different release kinetics is possible. [0034] Also in accordance with embodiments of the invention, 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, lattices, etc. Further, the solvents used 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.

[0035] FIGS. 2 and 3 show alternative aspects of the invention in which the system is used to load porous regions of the medical device with therapeutic agent. For example, in FIG. 2, a medical device 220 having a porous layer 223 is shown. Alternatively, in FIG. 3, the entire medical device 320 is porous. In this example, the medical device may be loaded with two therapeutic agents 21, 324 via electrochemical deposition. Due to the large surface area of the porous structure, large amounts of therapeutic agent can be drawn into the pores, and a larger concentration of therapeutic agent can be applied.

[0036] The porous regions of the medical device 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 amount of therapeutic agent which can be loaded onto the porous layer is much greater than the amount of therapeutic agent that can be loaded onto a flat surface. This is because the pores not only add more surface area upon which to load the therapeutic agent, but also because the volume of the pores can be filled with the therapeutic agent. In some instances, the surface area/porosity of a nanoporous medical device may be ten times that of a non-porous medical device. For example, if 20 micrograms/cm² of paclitaxel can be coated on a smooth surface of a non- porous medical device from a 0.75 micrograms/ml (~0.9 uM) solution, then 200 micrograms/cm² of paclitaxel can be loaded into a porous medical device. [0037] Porous medical devices or layers of porous material deposited on medical devices may be made from a powdered material such as powdered metal or polymer. The medical devices may be formed of any therapeutic-compatible powdered metals such as stainless steel. Other suitable metals include, but are not limited to, spring steel, nitinol and titanium as well as any other therapeutic-compatible metal which may become available in powdered form in the future. Suitable metals typically should not produce toxic reactions or act as carcinogens. The medical devices of the present invention may also be prepared with different pore sizes and may be prepared having a range of porosities allowing for the production of medical devices with differing therapeutic agent delivery characteristics. The voids and interstices of the porous regions have various sizes, and may have dimensions in a nanometer scale and a micrometer scale. These voids and interstices may be homogenous in size or non-homogeneous in size.

[0038] As shown in FIGS. 2-3, one porous region may be provided, or, alternatively, the medical device may contain two or more porous regions. The first porous region may be characterized by a first porosity and first mean pore size configured to receive certain quantities and types of therapeutic agent while the second porous region may be characterized by a second porosity and a second mean pore size configured to receive different quantities and types of therapeutic agent. Thus, one therapeutic agent may be loaded into the pores of the first porous region and a second therapeutic agent may be loaded into the pores of the second porous region. The same therapeutic agent may also be loaded into both the first and the second porous regions.

[0039] Since the rate of drug elution from a porous matrix may be determined by the pore size in the matrix, it may be preferred that the pores are relatively small, for example, as stated herein, in the micrometer or nanometer scale. Smaller size pores may enable sustained therapeutic agent delivery over a reasonable timescale, for example, about three months. In order to provide enough therapeutic agent to have a therapeutic effect, it may be preferred that all available spaces in the porous layers are loaded with therapeutic agent. [0040] FIG. 4 shows a flow chart including method steps that may be employed with embodiments of the present invention to apply therapeutic agent to at least a portion of a medical device. In the example of FIG. 4, Step 1 may include providing a medical device. Step 2 may include providing an electrode. Step 3 may include immersing the medical device and the electrode within an electrolytic solution including a therapeutic agent. Step 4 may include introducing a voltage source to polarize the electrode. Step 5 may include transferring electrons from the electrode to ionize the therapeutic agent. Step 6 may include electrochemically delivering the ionized therapeutic agent to the medical device. [0041] In alternative embodiments, not shown, the sequence of steps may be reordered and steps may be added or removed. The steps may also be modified. The steps may also be repeated in continuous fashion.

[0042] While various embodiments have been described, other embodiments are possible. It should be understood that the foregoing descriptions of the various examples of the electrochemical deposition system are not intended to be limiting, and any number of modifications, combinations, and alternatives of the examples may be employed to facilitate the effectiveness of delivering therapeutic agent to the medical devices. [0043] The coating, in accordance with the embodiments of the present invention, may comprise a polymeric and or therapeutic agent formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. A suitable list of drugs and/or polymer combinations is listed below. The term "therapeutic agent" as used herein includes one or more "therapeutic agents" or "drugs." The terms "therapeutic agents" or "drugs " can be used interchangeably herein and include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), viruses (such as adenovirus, adenoassociated virus, retrovirus, lentivirus and α-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences.

[0044] Specific examples of therapeutic agents that may be used in conjunction with the present invention include, for example, pharmaceutically active compounds, proteins, cells, oligonucleotides, ribozymes, anti-sense oligonucleotides, DNA compacting agents, gene/vector systems (i.e., any vehicle that allows for the uptake and expression of nucleic acids), nucleic acids (including, for example, recombinant nucleic acids; naked DNA, cDNA, RNA; genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector and which further may have attached peptide targeting sequences; antisense nucleic acid (RNA or DNA); and DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences ("MTS") and herpes simplex virus- 1 ("VP22")), and viral liposomes and cationic and anionic polymers and neutral polymers that are selected from a number of types depending on the desired application. Non-limiting examples of virus vectors or vectors derived from viral sources include adenoviral vectors, herpes simplex vectors, papilloma vectors, adeno-associated vectors, retroviral vectors, and the like. Non- limiting examples of biologically active solutes include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPACK (dextrophenylalanine proline arginine chloromethylketone); antioxidants such as probucol and retinoic acid; angiogenic and anti- angiogenic agents and factors; anti-proliferative agents such as enoxaprin, angiopeptin, rapamycin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylic acid, and mesalamine; calcium entry blockers such as verapamil, diltiazem and nifedipine; antineoplastic / antiproliferative / anti-mitotic agents such as paclitaxel, 5- fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors; antimicrobials such as triclosan, cephalosporins, aminoglycosides, and nitrofurantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, a YIGSR 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 inhibitors and tick antiplatelet factors; vascular cell growth promoters such as growth factors, growth factor receptor antagonists, transcriptional activators, and translational promoters; 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 endogenous vascoactive mechanisms; survival genes which protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; and combinations thereof. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogeneic), genetically engineered if desired to deliver proteins of interest at the insertion site. Any modifications are routinely made by one skilled in the art.

[0045] Polynucleotide sequences that may be useful in practice of the invention include DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides can also code for therapeutic proteins or polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic proteins and polypeptides include as a primary example, those proteins or polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body. In addition, the polypeptides or proteins that can be injected, or whose DNA can be incorporated, include without limitation, angiogenic factors and other molecules competent to induce angiogenesis, including acidic and basic fibroblast growth factors, vascular endothelial growth factor, hif-1, 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; growth factors; cell cycle inhibitors including CDK inhibitors; anti-restenosis agents, including pl5, pl6, pl8, pl9, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase ("TK") and combinations thereof and other agents useful for interfering with cell proliferation, including agents for treating malignancies; and combinations thereof. Still other useful factors, which can be provided as polypeptides or as DNA encoding these polypeptides, include monocyte chemoattractant protein ("MCP-I"), and the family of bone morphogenic proteins ("BMPs"). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-I), BMP-8, BMP-9, BMP-IO, BMP-I l, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as homodimers, 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 "hedgehog" proteins, or the DNAs encoding them.

[0046] As stated above, coatings that may be used with the exemplary embodiments of the present invention may comprise a polymeric material/drug agent matrix formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. Curing of the mixture typically occurs in-situ. To facilitate curing, a cross-linking or curing agent may be added to the mixture prior to application thereof. Addition of the cross-linking or curing agent to the polymer/drug agent liquid mixture must not occur too far in advance of the application of the mixture in order to avoid over-curing of the mixture prior to application thereof. Curing may also occur in- situ by exposing the polymer/drug agent mixture, after application to the luminal surface, to radiation such as ultraviolet radiation or laser light, heat, or by contact with metabolic fluids such as water at the site where the mixture has been applied to the luminal surface. In coating systems employed in conjunction with the present invention, the polymeric material may be either bioabsorbable or biostable. Any of the polymers described herein that may be formulated as a liquid may be used to form the polymer/drug agent mixture. [0047] The polymer that may be used in the exemplary embodiments of the present invention is preferably capable of absorbing a substantial amount of drug solution. When applied as a coating on a medical device in accordanceance with the present invention, the dry polymer is typically on the order of from about 1 to about 50 microns thick. In the case of a balloon catheter, the thickness is preferably about 1 to 10 microns thick, and more preferably about 2 to 5 microns. Very thin polymer coatings, e.g., of about 0.2-0.3 microns and much thicker coatings, e.g., more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coating onto a medical device. Such multiple layers are of the same or different polymer materials. [0048] The polymer that may be used with the present invention may be hydrophilic or hydrophobic, and may be selected from the group consisting of polycarboxylic acids, cellulosic polymers, including cellulose acetate and cellulose nitrate, gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydrides including maleic anhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinyl aromatics, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters including polyethylene terephthalate, polyacrylamides, polyethers, polyether sulfone, polycarbonate, polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene, halogenated polyalkylenes including polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins, polypeptides, silicones, siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate and blends and copolymers thereof as well as other biodegradable, bioabsorbable and biostable polymers and copolymers.

[0049] Coatings from polymer dispersions such as polyurethane dispersions

(BAYHYDROL®, etc.) and acrylic latex dispersions also may be used with the present invention. The polymer may be a protein polymer, fibrin, collagen and derivatives thereof, polysaccharides such as celluloses, starches, dextrans, alginates and derivatives of these polysaccharides, an extracellular matrix component, hyaluronic acid, or another biologic agent or a suitable mixture of any of these, for example. In one embodiment, the preferred 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 hereby incorporated herein by reference. U.S. Patent No. 5,091,205 describes medical devices coated with one or more polyisocyanates such that the devices become instantly lubricious when exposed to body fluids. In another embodiment, the polymer is a copolymer of polylactic acid and polycaprolactone.

[0050] The examples described herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the exemplary embodiments of the present invention. Moreover, while certain features of the invention may be shown on only certain embodiments or configurations, these features may be exchanged, added, and removed from and between the various embodiments or configurations while remaining within the scope of the invention. Likewise, methods described and disclosed may also be performed in various sequences, with some or all of the disclosed steps being performed in a different order than described while still remaining within 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: transferring electrons from an electrode to ionize a therapeutic agent dissolved in an electrolytic solution; and electrochemically depositing the ionized therapeutic agent onto the medical device, thereby forming a coating with the therapeutic agent on the medical device.

2. The method of claim 1 further comprising dissolving a measured amount of therapeutic agent into the electrolytic solution.

3. The method of claim 1 further comprising dissolving a measured amount of at least a second therapeutic agent in the electrolytic solution.

4. The method of claim 1 wherein the step of transferring electrons comprises introducing a voltage source having a measured voltage.

5. The method of claim 4 wherein the voltage source polarizes the electrode.

6. The method of claim 1 further comprising charging the medical device with a charge opposite to that of the ionized therapeutic agent.

7. The method of claim 1 wherein the electrolytic solution is at least one of an aqueous based and alcohol based solution.

8. The method of claim 1 wherein the electrolytic solution is a phosphate buffer saline solution.

9. The method of claim 1 wherein the therapeutic agent is paclitaxel.

10. The method of claim 1 wherein the medical device is a stent.

11. A method for loading at least a portion of a medical device with a therapeutic agent comprising: transferring electrons from an electrode to ionize a therapeutic agent dissolved in an electrolytic solution; and electrochemically depositing the ionized therapeutic agent into at least one porous region of the medical device, thereby loading the at least one porous region with the therapeutic agent.

12. The method of claim 11 further comprising dissolving a measured amount of therapeutic agent in the electrolytic solution.

13. The method of claim 12 further comprising dissolving a measured amount of at least a second therapeutic agent in the electrolytic solution.

14. The method of claim 11 further comprising charging the medical device with a charge opposite to that of the ionized therapeutic agent.

15. The method of claim 11 wherein the at least one porous region is two porous regions.

16. The method of claim 11 wherein the at least one porous region is a porous coating.

17. The method of claim 11 wherein the medical device is porous.

18. A method for delivering a therapeutic agent to at least a portion of a medical device comprising: providing a medical device; providing an electrode; immersing the medical device and the electrode within an electrolytic solution including the therapeutic agent dissolved therein; introducing a voltage source to polarize the electrode; transferring electrons from the electrode to ionize the therapeutic agent in the electrolytic solution; and electrochemically delivering the ionized therapeutic agent to the medical device.

19. The method of claim 18 wherein the therapeutic agent is loaded into a porous region of the medical device.

20. The method of claim 19 wherein the porous region is a porous coating layer.

21. A system for coating at least a portion of a medical device comprising: a voltage source; an electrochemical cell including an electrolytic solution having a therapeutic agent dissolved therein; an electrode positioned within the electrolytic solution, the electrode connected to the voltage source and configured to transfer electrons to ionize the therapeutic agent; and a medical device connected to the voltage source and positioned within the electrolytic solution, wherein the ionized therapeutic agent is electrochemically deposited onto the medical device to form a coating with the therapeutic agent on the medical device when current is applied.

22. The method of claim 21 wherein the ionized therapeutic agent is electrochemically deposited onto a stent.

23. The method of claim 21 wherein the stent has a porous surface.