Abstract:
A method is provided for altering a drug release profile of a coating of a medical device by increasing a surface area of the coating of the medical device. The method may include indenting the coating using a crimping apparatus, a rolling apparatus, or a clamping device. The method may alternatively or additionally include changing a chemical composition of at least one coating component to increase a roughness of a texture of the coating, and/or drying or partially drying the coating before the coating impacts the medical device.

Description:
FIELD OF THE INVENTION 
     The present invention relates to the manufacturing of medical appliances. More particularly, the present invention relates to a method and device for deforming a coating on a medical appliance to alter a drug release profile. 
     BACKGROUND INFORMATION 
     Medical devices may be coated so that the surfaces of such devices have desired properties or effects. For example, it may be useful to coat medical devices to provide 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. Localized drug delivery may avoid some of the problems of systemic drug administration, which may be accompanied by unwanted effects on parts of the body which are not to be treated. Additionally, treatment of the afflicted part of the body may require a high concentration of therapeutic agent that may not be achievable by systemic administration. Localized drug delivery may be achieved, for example, by coating balloon catheters, stents and the like with the therapeutic agent to be locally delivered. The coating on medical devices may provide for controlled release, which may include long-term or sustained release, of a bioactive material. 
     Aside from facilitating localized drug delivery, medical devices may be coated with materials to provide beneficial surface properties. For example, medical devices are often coated with radiopaque 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. 
     The type, thickness and other properties of the polymer and/or therapeutic agent may be chosen to create different release kinetics. Coatings may be applied to medical devices by processes such as dipping, spraying, vapor deposition, plasma polymerization, and electrodeposition. Although these processes may be used to produce satisfactory coatings, they are all subject to a drawback. After the coating process, stents may need to endure further handling as part of the manufacturing process. For instance, stents may need to be crimped onto a balloon. This further handling may cause deformities in the coating. Additionally, the drying process, or even the coating process itself, may lead to uneven coating and/or an uneven coating surface. An uneven coating surface may lead to a less predictable Kinetic Drug Release (KDR), which may lead to an individual stent or a batch of stents (or other medical devices) failing quality control. A non-uniform or uneven coating may lead to the unit failing KDR, drug uniformity and coating thickness specifications. 
     Therefore, an uneven coating surface has traditionally been an unwanted, though often inevitable, result of the manufacturing process. There is, therefore, a need for a cost-effective method of coating devices that results in uniform, defect-free coatings and uniform drug doses per unit device. The method would allow for better control of the sensitivity of the bioactive material and would also reduce variations in the coating properties between medical devices. 
     To alter the KDR profile of a Drug Eluting (DE) product, typically either the formulation of the drug/carrier or application of an overcoat is required. Each of these methods involves altering the chemistry and potentially impacting the efficacy/bio-compatibility of the product. 
     SUMMARY 
     A method is provided for altering a drug release profile of a coating of a medical device. The method includes: determining the drug release profile of the coating of the medical device; determining an increased surface area necessary to alter the drug release profile to an altered drug release profile; and increasing a surface area of the coating of the medical device to obtain the altered drug release profile. 
     The method may further include determining a surface area of the coating of the medical device. In the method, the increasing of the surface area of the coating of the medical device may include indenting the coating. In the method, the indenting of the coating may include pressing the medical device, rolling the medical device, and/or crimping the medical device. In the method, the indenting of the coating may include creating angular indentations, rounded dimples, curved impressions, and/or linear edges. 
     In the method, a size of an indentation of the coating may be increased. In the method, a depth of an indentation of the coating may be increased. In the method, a spacing between indentations of the coating may be decreased. In the method, the indenting of the coating may include creating random indentations and/or regularly patterned indentations. 
     A method is provided for improving a drug release profile of a coating of a medical device. The method includes: determining an expected drug release profile of the coating of the medical device using first process parameters of a coating method; determining an increased surface area necessary to obtain an improved drug release profile; and altering the first process parameters to second process parameters of the coating method to achieve the increased surface area. Additionally, deforming the surface may ameliorate any changes to the drug release profile due to handling of the part during post-coating. The surface of the part may be made consistently inconsistent such that changes occurring during manipulations post-coating do not effect the drug release profile. 
     In the method, the altering of the first process parameters to the second process parameters may further include changing a chemical composition of at least one coating component to increase a roughness of a texture of the coating. In the method, the altering of the first process parameters to the second process parameters may include drying the coating before the coating impacts the medical device. 
     In the method, the coating method may include a suspended air coating method and the altering of the first process parameters to the second process parameters may include increasing a number of further medical devices coated simultaneously with the medical device, increasing a force of air suspending the medical device, and/or increasing a time of suspending the medical device. 
     A device is provided for altering a drug release profile of a coating of a medical device. The device includes an arrangement adapted to hold the medical device and an arrangement adapted to indent a surface area of the coating. 
     In the device, the arrangement adapted to indent the surface of the coating may include a rolling apparatus. 
     In the device, the arrangement adapted to indent the surface of the coating may include a pressing apparatus. 
     In the device, the arrangement adapted to indent the surface of the coating may include a crimping apparatus. In the device, the arrangement adapted to indent the surface of the coating includes dimples. In the device, the dimples are arranged in a regular pattern on the arrangement adapted to indent the surface of the coating. 
     In the device, the arrangement adapted to hold the medical device includes a mandrel. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  illustrates an exemplary embodiment of a crimping device used to perform an exemplary method of the present invention with a stent being crimped. 
         FIG. 2  illustrates a close-up view of the crimping device shown in  FIG. 1  with a stent being crimped. 
         FIG. 3  illustrates an exemplary embodiment of a rolling device used to perform an exemplary method of the present invention with a stent being rolled. 
         FIG. 4  illustrates a close-up view of the rolling device shown in  FIG. 3  with a stent being rolled. 
         FIG. 5  illustrates an exemplary embodiment of a clamping device used to perform an exemplary method of the present invention with a stent being clamped. 
         FIG. 6  illustrates a close-up view of the clamping device shown in  FIG. 5  with a stent being clamped. 
         FIG. 7  illustrates a flowchart of an exemplary method of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     As medical devices and/or stents move toward thinner struts and/or reduced surface areas, controlling KDR through surface area changes may be valuable. Additionally, KDR for finished parts may be different from that of component parts due to disruption of the coating during handling. If the surface is dimpled prior to or subsequent to handling, the effects of handling may be reduced or eliminated. 
     According to an exemplary embodiment of the present invention, a method is provided for physically altering or deforming the surface of the drug eluting coating in a consistent manner to increase surface area and increase KDR to a desired level. This may be achieved by: post-processing (e.g., using a mechanical device to dimple the surface); choice of coating method (e.g., selecting a method that can consistently make the surface textured); and altering processing parameters to obtain a surface texture (e.g., applying parameters that result in a variable surface texture). 
     Each of these techniques may cause the surface area of the coating to be increased within a given range of variation. 
     Various improvements over conventional methods are possible using an exemplary method of the present invention. With post-processing, the same coated part may be altered in different ways to produce several different KDR profiles. Chemical components may remain unaltered while the surface area and KDR are altered. Subtle changes in KDR may be achieved readily through formulation/barrier layers. 
       FIG. 1  illustrates an exemplary embodiment of crimping device  10  performing a crimp on stent  11 . Stent  11  is held in mandrel  12  and is inserted into crimping device  10 . Stent  11  is arranged in constricting zone  13  of crimping device  10 . Crimping device  10  may then be operated to constrict around stent  11 , thereby crimping stent  11 . A pattern of projections on crimping device  10  may thereby be pressed into the surface of the coating of stent  11 . The indentations caused by the projections on crimping device  10  may increase the surface area of the coating of stent  11 , and may thereby increase the KDR profile of stent  11 . 
       FIG. 2  illustrates a close-up view of crimping device  10  shown in  FIG. 1  with stent  11  being held on mandrel  12  and being crimped. Iris elements  20  operate together to form constricting zone  13 . Each iris element  20  has a face  21  arranged towards an interior space which is adapted to accept stent  11  on mandrel  12 . Each face  21  of iris element  20  has pattern  22  arranged to provide relief and to create indentations on the surface of the coating of stent  11  when stent  11  is placed in crimping device  10  and iris elements  20  are moved radially inward. Pattern  22  in the exemplary embodiment shown in  FIG. 2  is composed of regularly arranged dimples  23 . Alternatively, any other shape may be used instead of or in addition to dimple  23 . Also, dimples  23  (or any other appropriate shape) may be arranged in a random or pseudo-random pattern on face  21 . 
     The operation of crimping device  10  may be part of the manufacturing process of stent  11 . In particular, crimping device  10  may be used to crimp stent  11  onto a balloon catheter or similar medical device. This crimping may induce a temporary or permanent deformation of stent  11  to secure stent  11  to the balloon. 
       FIG. 3  illustrates an exemplary embodiment of rolling device  30  used to perform an exemplary method of the present invention with stent  11  being rolled. Rolling device  30  includes upper plate  31  and lower plate  32 , though the plates may be interchangeable and may alternatively be oriented side by side or possibly in another configuration. Lower plate  32  includes pattern area  34  which includes dimples  35  arranged in a uniform pattern. Alternatively, pattern area  34  may include raised or indented elements in any other pattern, which may be uniform, random, or pseudo-random. Additionally, upper plate  31  may include a pattern area that may match pattern area  34  of lower plate  32  or may be a different pattern. Stent  11  may contact lower plate  32  at contact zone  33  that may cause dimples  35  of pattern area  34  to contact the coating of stent  11 . Dimples  35  may create indentations in the coating of stent  11  and may therefore increase the surface area of the coating of stent  11 , thereby altering (possibly increasing) the KDR profile of the drug in the coating of stent  11 . 
     Rolling device  30  may be operated by placing stent  11  on lower plate  32  and then bringing upper plate  31  into proximity with lower plate  32  so that upper plate  31  contacts stent  11 . Stent  11  may be placed in rolling device  30  before or after being crimped onto a balloon. By sandwiching stent  11  between lower plate  32  and upper plate  31 , stent  11  may be held securely in place. Lower plate  32  and upper plate  31  may be brought close enough to each other to hold stent  11  without deformation, with some deformation but without permanent deformation, or with permanent deformation. Lower plate  32  may be moved laterally with respect to upper plate  31  to cause stent  11  to roll between the plates. Alternatively upper plate  31  may be moved with respect to lower plate  32 , or both plates may be moved laterally and simultaneously in opposite directions. After contacting some or all of the surface of stent  11  with dimples  35  of pattern area  34 , the plates may be separated and stent  11  may be removed from between upper plate  31  and lower plate  32 . 
       FIG. 4  illustrates a close-up view of rolling device  30  shown in  FIG. 3  with stent  11  being rolled. Lower plate  32  is shown having pattern area  34  including dimples  35 . Stent  11  contacts lower plate  32  at contact zone  33 , thereby causing dimples  35  to contact the coating of stent  11  and to cause indentations in the surface of the coating of stent  11 . 
       FIG. 5  illustrates an exemplary embodiment of clamping device  50  used to perform an exemplary method of the present invention with stent  11  being clamped. Clamping device  50  includes upper clamp section  51  and lower clamp section  52 , which may be connected by hinge  57 . Upper clamp section  51  includes upper handle  53  and lower clamp section  52  includes lower handle  54 . Upper handle  53  and lower handle  54  may be operated manually or mechanically to move upper clamp section  51  and lower clamp section  52  towards and away from each other about the line defined by hinge  57 . Upper clamp section  51  may have upper clamping surface  55  and lower clamp section  52  may have lower clamping surface  56 . Upper clamping surface  55  and lower clamping surface  56  may be designed to accommodate stent  11  between their opposing surfaces with no force exerted on stent  11 , with some force exerted on stent  11  but not enough force to deform stent  11 , or with enough force to deform (either temporarily or permanently) stent  11 . Upper clamping surface  55  and/or lower clamping surface  56  may have pattern region  58  arranged thereon on all or part of their opposing surfaces. Pattern region  58  may include dimples  59  arranged in a uniform pattern, or may include other raised elements and/or depressions, in any other type of pattern. 
     Clamping device  50  may be operated by placing stent  11  (which may have been coated with a drug-eluting compound) between upper clamping surface  55  and lower clamping surface  56  while clamping device  50  is in an open configuration (i.e., upper clamp section  51  and lower clamp section  52  are separated). After inserting stent  11 , upper handle  53  and lower handle  54  may be operated manually or mechanically to move upper clamp section  51  and lower clamp section  52  towards each other, causing dimples  59  to indent the coating of stent  11 . Thereafter, upper handle  53  and lower handle  54  may be operated manually or mechanically to move upper clamp section  51  and lower clamp section  52  away from each other. Stent  11  may thereafter be removed from clamping device  50 . 
       FIG. 6  illustrates a close-up view of clamping device  50  shown in  FIG. 5  with stent  11  being clamped. Also shown are upper clamp section  51  and lower clamp section  52 . Upper clamping surface  55  of upper clamp section  51  and lower clamping surface  56  of lower clamp section  52  are also shown in  FIG. 6 . Pattern region  58  is arranged on lower clamping surface  56 , and a similar pattern is arranged on upper clamping surface  55 . Pattern region  58  includes dimples  59  arranged in a uniform pattern. Stent  11  contacts lower clamping surface  56  at contact region  60 . 
       FIG. 7  illustrates a flowchart of an exemplary method of the present invention. The flow in  FIG. 7  starts in start circle  70  and proceeds to action  71 , which indicates to determine a current KDR of a medical device. From action  71 , the flow proceeds to question  72 , which asks whether an increased KDR is desirable. If the answer to question  72  is affirmative, the flow proceeds to action  73 , which indicates to determine the amount of increased surface area necessary to increase the KDR sufficiently. From action  73 , the flow proceeds to action  74 , which indicates to indent the surface to increase the surface area. From action  74 , the flow proceeds to question  75 , which asks whether the indentations increased the surface area sufficiently to obtain the desired KDR. If the answer to question  75  is negative, the flow proceeds to action  73 . If the answer to question  75  is affirmative, the flow proceeds to end circle  76 . If the answer to question  72  is negative, the flow proceeds to end circle  76 . 
     Medical 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 localized delivery of therapeutic agents has been proposed or achieved using medical implants which both support a lumen within a patient&#39;s body and place appropriate coatings containing absorbable therapeutic agents at the implant location. Examples of such medical devices include catheters, guide wires, balloons, filters (e.g., vena cava filters), stents, stent grafts, vascular grafts, intraluminal paving systems, implants and other devices used in connection with drug-loaded polymer coatings. 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. 
     The therapeutic agent may be any pharmaceutically acceptable agent such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells. 
     Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such 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. 
     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. 
     Non-limiting examples of proteins include monocyte chemoattractant proteins (“MCP-1) and bone morphogenic proteins (“BMP&#39;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&#39;s 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 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. 
     Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD. 
     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. 
     Any of the therapeutic agents may be combined to the extent such combination is biologically compatible. 
     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 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. 
     Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyisobutylene copolymers and styrene-isobutylene-styrene block copolymers such as styrene-isobutylene-styrene tert-block copolymers (SIBS); 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. 
     In 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. 
     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. 
     The coating can be applied to the medical device by any known method in the art including dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition, air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle. 
     The coating is typically from about 1 to about 50 microns thick. In the case of balloon catheters, the thickness is preferably from about 1 to about 10 microns, and more preferably from about 2 to about 5 microns. Very thin polymer coatings, such as about 0.2-0.3 microns and much thicker coatings, such as more than 10 microns, are also possible. 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. 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. 
     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. 
     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, implants 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. 
     While the present invention has been described in connection with the foregoing representative embodiment, it should be readily apparent to those of ordinary skill in the art that the representative embodiment is exemplary in nature and is not to be construed as limiting the scope of protection for the invention as set forth in the appended claims.