Abstract:
An implantable medical device includes a substrate, a drug-impregnated layer deposited over the substrate, and a barrier layer at least partially covering the drug-impregnated layer. The barrier layer may be a biodegradable metal, biodegradable metal oxide, or biodegradable metal alloy, such as, magnesium, a magnesium oxide or a magnesium alloy. The drug-impregnated layer includes a therapeutic substance, such as, antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, fibrinolytic, thrombin inhibitor, antimitotic, antiallergic, and antiproliferative substances.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to implantable medical devices that release a drug, in particular, stents that provide in situ controlled release delivery of a therapeutic substance. 
       BACKGROUND OF THE INVENTION 
       [0002]    Cardiovascular disease, specifically atherosclerosis, remains a leading cause of death in developed countries. Atherosclerosis is a multifactorial disease that results in a narrowing, or stenosis, of a vessel lumen. Briefly, pathologic inflammatory responses resulting from vascular endothelium injury causes monocytes and vascular smooth muscle cells (VSMCs) to migrate from the sub endothelium and into the arterial wall&#39;s intimal layer. There the VSMC proliferate and lay down an extracellular matrix causing vascular wall thickening and reduced vessel patency. 
         [0003]    Cardiovascular disease caused by stenotic coronary arteries is commonly treated using either coronary artery by-pass graft (CABG) surgery or angioplasty. Angioplasty is a percutaneous procedure wherein a balloon catheter is inserted into the coronary artery and advanced until the vascular stenosis is reached. The balloon is then inflated, restoring arterial patency. A variation in the angioplasty procedure may include arterial stent deployment. Briefly, after arterial patency has been restored, the balloon is deflated and a vascular stent is inserted into the vessel lumen at the stenosis site. After expansion of the stent, the catheter is then removed from the coronary artery and the deployed stent remains implanted to prevent the newly opened artery from constricting spontaneously. An alternative procedure, which is sometimes referred to as primary stenting, involves stent deployment without prior balloon angioplasty, wherein the expansion of the stent against the arterial wall is sufficient to open the artery and restore arterial patency. However, balloon catheterization and/or stent deployment can result in vascular injury ultimately leading to VSMC proliferation and neointimal formation within the previously opened artery. This biological process whereby a previously opened artery becomes re-occluded is referred to as restenosis. 
         [0004]    Treating restenosis requires additional, generally more invasive, procedures including CABG surgery in severe cases. Consequently, methods for preventing restenosis, or treating incipient forms, are being aggressively pursued. One possible method for preventing restenosis is the administration of anti-inflammatory compounds that block local invasion/activation of monocytes thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration. Other potentially anti-restenotic compounds include antiproliferative agents, such as chemotherapeutics, which include rapamycin and paclitaxel. Other classes of drugs such as anti-thrombotics, anti-oxidants, platelet aggregation inhibitors and cytostatic agents have also been suggested for anti-restenotic use. 
         [0005]    However, many of these drugs, particularly anti-inflammatory and antiproliferative compounds, can be toxic when administered systemically in anti-restenotic-effective amounts. Accordingly, local delivery is a preferred method of treatment since smaller amounts of medication are administered in comparison to systemic dosages and the medication may be concentrated at a specific treatment site. Local delivery thus produces fewer side effects and achieves more effective results. 
         [0006]    A common technique for local delivery of drugs involves coating a stent or graft with a polymeric material which, in turn, is impregnated with a drug or a combination of drugs. Once the stent or graft is implanted within a lumen of the cardiovascular system, the drug(s) is released from the polymer for treatment of the local tissues. The drug(s) is released into the lumen by a process of diffusion through the polymer layer for biostable polymers, and/or as the polymer material degrades for biodegradable polymers. 
         [0007]    In attempts to control the rate of elution of a drug from the drug impregnated polymeric material, barrier layers have been provided. Barrier layers have generally been another layer of polymeric material. By providing an extra layer of polymeric material, it is thought that the elution rate can be controlled because the barrier layer adds material and distance through which the drug must diffuse to be released. However, test data has shown that the use of a polymeric barrier layer does not significantly slow elution. 
         [0008]    U.S. Pat. No. 6,716,444 discloses a stent including a drug-impregnated polymeric layer over a substrate material, and further including a metallic barrier layer or cap coat. However, the metallic barrier layer of U.S. Pat. No. 6,716,444 is not biodegradable. Using a non-biodegradable metallic barrier or cap layer with a biodegradable base polymer is not desirable because as the drug-impregnated polymer degrades, the non-biodegradable metallic barrier or cap layer may fracture or collapse. The fracture or deformation of the metallic cap layer may then cause tissue inflammation or other complications at the artery wall. 
         [0009]    Further, stent design is evolving to where a substrate material may be a biodegradable polymer or biodegradable metallic material. Accordingly, it would be desirable to have a biodegradable drug-impregnated layer and a biodegradable metallic barrier or cap layer such that the entire structure is biodegradable. 
       BRIEF SUMMARY OF THE INVENTION 
       [0010]    The present invention allows for a controlled rate of release of a drug or drugs from a polymer carried on an implantable medical device. The controlled rate of release allows localized drug delivery for extended periods, depending upon the application. This is especially useful in providing therapy to reduce or prevent cell proliferation, inflammation, or thrombosis in a localized area. 
         [0011]    An embodiment of an implantable medical device in accordance with the present invention includes a substrate, which may be, for example, a metal or polymeric stent or graft, among other possibilities. At least a portion of the substrate is coated with a first layer that includes one or more therapeutic substances in a polymer carrier. A barrier layer overlies the first layer. The barrier layer reduces the rate of release of the therapeutic substance from the polymer once the medical device has been placed into the patient&#39;s body, thereby allowing an extended period of localized drug delivery once the medical device is in situ. 
         [0012]    The barrier layer may be a biodegradable metal, biodegradable metal oxide, or biodegradable metal alloy and may have a thickness ranging from about 5 to about 100 nanometers. In various embodiments, a material of the barrier layer may be magnesium, a magnesium oxide or a magnesium alloy. 
         [0013]    The one or more drugs contained within the drug-impregnated polymer layer may include, but are not limited to, antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, fibrinolytic, thrombin inhibitor, antimitotic, antiallergic, and antiproliferative substances. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0014]    The foregoing and other features and advantages of the invention will be apparent from the following description of the invention as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated herein and form a part of the specification, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. The drawings are not to scale. 
           [0015]      FIG. 1  is a perspective view of an exemplary stent in accordance with an embodiment of the present invention. 
           [0016]      FIG. 2  illustrates a cross-sectional view taken along line A-A of  FIG. 1  of a stent strut. 
           [0017]      FIG. 3  illustrates a cross-sectional view taken along line A-A of  FIG. 1  of a stent strut in accordance with another embodiment of the present invention. 
           [0018]      FIG. 4  illustrates a cross-sectional view along line A-A of  FIG. 1  of a stent strut in accordance with another embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0019]    Specific embodiments of the present invention are now described with reference to the figures, where like reference numbers indicate identical or functionally similar elements. 
         [0020]    The present invention provides a stent or graft, which are often referred to as endoprostheses, with a drug-impregnated coating and a barrier or cap layer.  FIG. 1  illustrates an exemplary stent  10  in accordance with an embodiment of the present invention. Stent  10  is a patterned tubular device that includes a plurality of radially expandable cylindrical rings  12 . Cylindrical rings  12  are formed from struts  14  formed in a generally sinusoidal pattern including peaks  16 , valleys  18 , and generally straight segments  20  connecting peaks  16  and valleys  18 . Connecting links  22  connect adjacent cylindrical rings  12  together. In  FIG. 1 , connecting links  22  are shown as generally straight links connecting a peak  16  of one ring  12  to a valley  18  of an adjacent ring  12 . However, connecting links  22  may connect a peak  16  of one ring  12  to a peak  16  of an adjacent ring, or a valley  18  to a valley  18 , or a straight segment  20  to a straight segment  20 . Further, connecting links  22  may be curved. Connecting links  22  may also be excluded, with a peak  16  of one ring  12  being directly attached to a valley  18  of an adjacent ring  12 , such as by welding, soldering, or the manner in which stent  10  is formed, such as by etching the pattern from a flat sheet or a tube. It will be appreciated by one of ordinary skill in the art that stent  10  of  FIG. 1  is merely an exemplary stent and that stents of various forms and methods of fabrication can be used. For example, in a typical method of making a stent, a thin-walled, small diameter metallic tube is cut to produce the desired stent pattern, using methods such as laser cutting or chemical etching. The cut stent may then be descaled, polished, cleaned and rinsed. Some examples of methods of forming stents and structures for stents are shown in U.S. Pat. No. 4,733,665 to Palmaz, U.S. Pat. No. 4,800,882 to Gianturco, U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor, U.S. Pat. No. 5,292,331 to Boneau, U.S. Pat. No. 5,421,955 to Lau, U.S. Pat. No. 5,935,162 to Dang, U.S. Pat. No. 6,090,127 to Globerman, and U.S. Pat. No. 6,730,116 to Wolinsky et al., each of which is incorporated by reference herein in its entirety. 
         [0021]      FIG. 2  is a cross-sectional view taken at A-A of  FIG. 1  through a portion of strut  14  of stent  10 . Strut  14  has a suitable thickness T that, typically, may be in the range of approximately 50 μm (0.002 inches) to 200 μm (0.008 inches). As shown in  FIG. 2 , strut  14  is formed of a substrate  24 , a drug-impregnated layer  26 , and a barrier layer  28 . Substrate  24  may be any material that is typically used for a stent, for example, stainless steel, “MP35N,” “MP20N,” nickel titanium alloys such as Nitinol, tantalum, platinum-iridium alloy, gold, magnesium, L605, or combinations thereof. “MP35N” and “MP20N” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Substrate  24  may alternatively be a polymeric material, such as poly(lactic acid), poly(glycolic acid), poly(dioxanone), poly(trimethylene carbonate), poly(ε-caprolactone), polyethylene, poly(etheretherketone), polyanhydrides, polyorthoesters, polyphosphazenes, or combinations thereof. 
         [0022]    Drug-impregnated layer  26  may be a therapeutic substance on substrate  24  or a polymer with a therapeutic substance  30  dispersed throughout the polymer. Typically, a solution of the polymeric material and one or more therapeutic substances are mixed, often with a solvent, and the polymer mixture is applied to stent  10 . Methods of applying the therapeutic substance or therapeutic substance and polymer mixture to strut  14  of stent  10  include, but are not limited to, immersion, spray-coating, sputtering, and gas-phase polymerization. Immersion, or dip-coating, entails submerging the entire stent  10 , or an entire section, e.g., cylindrical ring  12 , of stent  10 , in the mixture. Stent  10  is then dried, for instance in a vacuum or oven, to evaporate the solvent, leaving the therapeutic substance or therapeutic substance and polymer coating on the stent. Similarly, spray-coating requires enveloping the entire stent, or an entire section of the stent, in a large cloud of the mixture, and then allowing the solvent to evaporate, to leave the coating. Sputtering typically involves placing a polymeric coating material target in an environment, and applying energy to the target such that polymeric material is emitted from the target. The polymer emitted deposits onto the device, forming a coating. Similarly, gas phase polymerization typically entails applying energy to a monomer in the gas phase within a system set up such that the polymer formed is attracted to a stent, thereby creating a coating around the stent. Drug-impregnated layer  26  may be in the range of about 0.5 to about 10 microns in thickness. 
         [0023]    The polymer used for drug-impregnated layer  26  is preferably biodegradable. The term “biodegradable” as used in this application refers to materials that are capable of being completely degraded and/or eroded when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed and/or eliminated by the body. The processes of breaking down and eventual absorption and elimination of the material can be caused by, for example, hydrolysis, metabolic processes, bulk or surface erosion, and the like. For coating applications, it is understood that after the process of degradation, erosion, absorption, and/or resorption has been completed, no material will remain on the device. In some embodiments, very negligible traces or residue may be left behind. Whenever the terms “degradable” or “biodegradable” are used in this application, they are intended to broadly include biologically erodable, bioabsorbable, and bioresorbable materials as well as other types of materials that are broken down and/or eliminated by the body. Examples of biodegradable materials include but are not limited to polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolic acid-cotrimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly (amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates. 
         [0024]    Therapeutic substance  30  may include, but is not limited to, antineoplastic, antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antiproliferative, antibiotic, antioxidant, and antiallergic substances as well as combinations thereof. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g., TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxotere® from Aventis S. A., Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin® from Pharmacia &amp; Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™(Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include ABT-578 (a synthetic analog of rapamycin), angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g., Prinivil® and Prinzide® from Merck &amp; Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck &amp; Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents that may be used include nitric oxide, alpha-interferon, genetically engineered epithelial cells, and dexamethasone. In other examples, the therapeutic substance is a radioactive isotope for implantable device usage in radiotherapeutic procedures. Examples of radioactive isotopes include, but are not limited to, phosphorus (P 32 ), palladium (Pd 103 ), cesium (Cs 131 ), Iridium (I 192 ) and iodine (I 125 ). While the preventative and treatment properties of the foregoing therapeutic substances or agents are well-known to those of ordinary skill in the art, the substances or agents are provided by way of example and are not meant to be limiting. Other therapeutic substances are equally applicable for use with the disclosed methods and compositions. 
         [0025]    Barrier layer  28  acts to reduce the rate of delivery of therapeutic substance  30  to the internal target tissue area. Barrier layer  28  may be a biodegradable metal, biodegradable metal oxide or biodegradable metal alloy. In various embodiments, barrier layer  28  may be made from magnesium, iron, or an oxide or alloy of magnesium or iron. Several methods may be used to deposit barrier layer  28  on drug-impregnated layer  26 , such as sputtering, plasma deposition, reactive sputtering, physical vapor deposition, chemical vapor deposition, or cathodic arc vacuum deposition, depending on the specific material used for barrier layer  28 . Barrier layer  28  may have a thickness in the range from about 10 to about 100 nanometers. As shown in  FIG. 2 , drug-impregnated layer  26  and barrier layer  28  completely surround substrate  24 . 
         [0026]      FIG. 3  shows a cross-sectional view another embodiment of a strut  14 ′ of the stent  10  of  FIG. 1  taken along line A-A. Strut  14 ′ is similar to strut  14  of  FIG. 2  in that it includes a substrate  24 , a drug-impregnated layer  26 , and a barrier layer  28 . However, drug impregnated layer  26  and barrier layer  28  are disposed on only one surface of strut  14 ′, preferably an outwardly facing surface  32  of substrate  24 . As would be understood by one of ordinary skill in the art, drug-impregnated layer  26  and barrier layer  28  may cover other portions of substrate  24 . For example, drug-impregnated layer  26  and barrier payer  28  may cover the outer and inner surfaces of substrate  24 , but not the side surfaces, or may cover only the inner or outer surface, depending on the application. 
         [0027]      FIG. 4  shows a cross-sectional view of another of a strut  14 ″ of the stent  10  of  FIG. 1  taken along line A-A. Strut  14 ″ is similar to strut  14 ′ of  FIG. 3  in that it includes a substrate  24 , a drug-impregnated layer  26 , and a barrier layer  28 ′. However, barrier layer  28 ′ is not a continuous surface. Instead, barrier layer  28 ′ comprises a number of discrete deposits above drug-impregnated layer  26 , with the deposits separated by spaces  34 . In the embodiment illustrated in  FIG. 4 , the rate of drug delivery from drug-impregnated layer  26  to the target area is reduced because the surface area for therapeutic substance  30  to diffuse from drug-impregnated layer  26  is reduced. The majority of drug therapeutic substance  30  will diffuse at spaces  34 . Some of the therapeutic substance  30  will diffuse through barrier layer  28 ′, although at a slower rate than at spaces  34 . Further, some of the therapeutic substance  30  located in drug-impregnated layer  26  below barrier layer  28 ′ will migrate to the area of spaces  34  to be delivered to the target tissue area. As would be understood by one of ordinary skill in the art, the embodiment of  FIG. 4  may be modified such that drug-impregnated layer  26  and barrier layer  28 ′ cover all surfaces of strut  14 ″, similar to  FIG. 2 , or selected surfaces of strut  14 ″, as described above with respect to  FIG. 3 . 
         [0028]    The embodiment illustrated in  FIG. 4  may be achieved by performing deposition processes that deposit layers of material by way of nucleation, such as cathodic arc sputtering, reactive sputtering, thermal evaporation and electron beam (e-beam) evaporation. The embodiment illustrated in  FIG. 4  may also be achieved by depositing a continuous film, and then creating holes in that film. For example, a magnesium film can be deposited with differing amounts of grain structure. An etching chemical (e.g., typically mixtures of mineral acids) may be used to preferentially etch between grains and remove some of the magnesium film. Alternatively, a continuous film could be deposited, and holes made in that continuous film by, for example, ion milling, a laser, or electron beam machining. 
         [0029]    In an alternative method of tailoring the elution rate of the drug, similar to the embodiment of  FIG. 4 , the porosity of the barrier layer can be increased. In one method, wax or water soluble salt particles may be applied to the dried top surface of the drug-impregnated layer. The barrier layer is applied to the over the drug-impregnated layer. If salt particles are used, the salt can be washed away after the barrier layer is applied, thereby creating pores in the barrier layer. If wax particles are used, the wax particles may be left in place after application of the barrier layer. Upon deployment of the stent (expansion from it compressed configuration to its expanded configuration) the wax particles deform, thereby creating micro-cracks in the barrier layer. The micro-cracks alter the elution rate of the barrier layer. 
         [0030]    A cross-sectional view of connecting links  22  of stent  10  may be similar to struts  14 .  14 ′,  14 ″ or may be different. For example, a thickness of connecting links  22  may be different than strut  14  of cylindrical rings  12  to provide variable flexibility between the rings  12  and connecting links  22 . A specific choice of thickness for struts  14  and links  22  depends on several factors, including, but not limited to, the anatomy and size of the target lumen. Further, struts  14 ,  14 ′,  14 ″ may be coated as described above and links  22  may be uncoated. 
         [0031]    One of ordinary skill in the art will appreciate that, for all of the embodiments described herein, the thickness of barrier layer  28 ,  28 ′ may be varied, with a corresponding change in the drug release rate. Generally, the thicker the barrier, the greater the reduction in the drug release rate. 
         [0032]    While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of illustration and example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents. It will also be understood that each feature of each embodiment discussed herein, and of each reference cited herein, can be used in combination with the features of any other embodiment. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the detailed description. All patents and publications discussed herein are incorporated by reference herein in their entirety.