Abstract:
A system for coating implantable medical devices, such as stents, and a method of coating stents using the system is also disclosed. The system includes a barrier or barriers for isolating an area of the stent on which a composition for coating a stent is applied. Two coating compositions can be applied simultaneously to a stent by separate nozzles on different sides of a barrier. Cross-contamination of the compositions is prevented by the barrier.

Description:
This application is a continuation of U.S. patent application Ser. No. 10/266,479, filed Oct. 8, 2002 now U.S. Pat. No. 7,335,265, the entire disclosure of which is incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to systems for coating implantable medical devices, such as stents. 
     2. Description of the Background 
       FIG. 1  illustrates a conventional stent  10 , which includes connected struts  12  forming a tubular expandable body. Stent  10  functions as a scaffolding structure for physically holding open the wall of a blood vessel or other bodily lumen. Stent  10  is capable of being compressed, so that stent  10  can be inserted through small lumens via catheters, and then expanded to a larger diameter once it is at the desired location. Mechanical intervention via stents has reduced the rate of restenosis as compared to balloon angioplasty; restenosis, however, is still a significant problem. Moreover, treating restenosis in stented vessels can be challenging, as clinical options are more limited as compared to lesions that were treated solely with a balloon. 
     In order to more effectively treat restenosis, stent implantation procedures are being supplemented with a pharmaceutical regimen. Systemic administration of drugs for the treatment of restenosis can produce adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results. 
     Being made of metal, stents need to be modified so as to provide a suitable means of locally delivering a drug. A polymeric coated stent has proved to be a very effective way of allowing a stent to locally deliver a drug. A solution of a polymer dissolved in a solvent and a therapeutic substance added thereto is applied to the stent. The composition is applied to the stent by spraying the composition on the stent or immersing the stent in the composition. Once the solvent evaporates, a polymeric coating impregnated with a therapeutic substance remains on the surface of the stent. The coating provides for a sustained release of the therapeutic substance at the treatment site. 
     To the extent that the mechanical functionality of stents has been optimized, continued improvements can be made to the coating of the stent. A coating design is needed that is capable of releasing more than one therapeutic substance to the treatment site. Accordingly, conditions other than restenosis, such as excessive inflammation or thrombosis, can also be addressed. Moreover, the coating should be capable of releasing a single drug or more than one drug at different release rates. For example, a coating should be capable of releasing a steroidal anti-inflammatory substance immediately subsequent to the stent implantation and releasing a drug for inhibiting migration and proliferation of vascular smooth muscle cells at a slower release rate for a prolonged duration of time. Accordingly, a more customized treatment regimen for the patient can be provided. The present invention provides an apparatus that can produce a coating that addresses these needs and provides other improved coating designs for drug eluting vascular stents. 
     SUMMARY 
     The present invention is generally directed to a system for coating a stent. In aspects of the present invention, the system comprises a nozzle adapted to deliver a coating substance, and a barrier located at a position relative to the nozzle. The barrier has a first surface to face one end of the stent, a second surface to face an opposing end of the stent, a through hole extending through the first and second surfaces, the through hole having a size that allows the stent to extend through the barrier. When the stent extends through the barrier, the barrier shields a first area of the stent to which the coating substance is not be applied and does not shield a second area of the stent to which the first coating substance is to be applied. 
     In further aspects, the system further comprises a second nozzle adapted to deliver a second coating substance. The second nozzle located at a position relative to the barrier that allows application of the second coating substance from the second nozzle to the first area of the stent but not the second area of the stent. In detailed aspects, the through hole in the barrier is sized to prevent or significantly minimize cross-contamination of the coating substance from the nozzle and the second coating substance from the second nozzle. 
     In other aspects of the present invention, the system comprises a barrier having a first surface facing a first direction, a second surface facing a second direction opposite the first direction, a through hole extending through the first and second surfaces, the through hole sized to allow a stent to pass through the barrier such that a first portion of the stent extends in the first direction away from the first surface and a second portion of the stent extends in the second direction away from the second surface. The system also comprises a nozzle adapted to deliver a coating substance, the nozzle located at the first surface side of the barrier for application of the coating substance to the first portion of the stent such that the barrier prevents or reduces application of the coating substance from the nozzle to the second portion of the stent. 
     In further aspects, the system further comprises a second nozzle located at the second surface side of the barrier for application of a second coating substance to the second portion of the stent such that the barrier prevents or reduces application of the second coating substance from the second nozzle to the first portion of the stent. In detailed aspects, the through hole in the barrier is sized to prevent cross-contamination of the coating substance from the nozzle and the second coating substance from the second nozzle. 
     The features and advantages of the invention will be more readily understood from the following detailed description which should be read in conjunction with the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  illustrates a conventional stent; 
         FIG. 2  illustrates one embodiment of the coating apparatus of the present invention; 
         FIG. 3  illustrates a side view of one embodiment of the barrier used with the coating apparatus; and 
         FIGS. 4A to 4F  present various coating deposits that can be formed by the apparatus of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 2  illustrates one embodiment of a coating system  14  for depositing a coating on stent  10 . Although the present invention is described with reference to a stent, system  14  can also be used to coat a variety of other implantable medical devices, such as stent-grafts and grafts. Stent  10  can have any stent design and the structure is not limited to the illustration of  FIG. 1 . Stent  10  can be made from any suitable material, such as stainless steel. A mandrel  16  supports stent  10  during the coating process. Mandrel  16  includes two opposing conically shaped ends  18   a  and  18   b  that can penetrate at least partially within ends of stent  10 . A bar portion  20  extending through the longitudinal bore of stent  10  connects ends  18   a  and  18   b  to one another. The connection of bar  20  with ends  18   a  or  18   b  can be via a friction fit or a screw fit so that ends  18   a  and  18   b  are not only capable of disengaging from bar portion  20  but also are capable of being moved incrementally closer together for securely pinching stent  10 . Mandrel  16  can be coupled to a first motor assembly  22   a  for providing rotation motion to stent  10 . A second motor  22   b  can be optionally provided for moving stent  10  in a linear direction along rail  24 . 
     A set of nozzles  26  is provided for applying a coating composition to stent  10 . Although  FIG. 2  illustrates three nozzles, any suitable number of nozzles  26  can be used. Nozzles  26  can be, for example, model #780S external air mixing nozzles from EFD Inc., East Providence, R.I., or 8700-25, 8700-35, 8700-48, 8700-48H, or 8700-60 ultrasonic nozzles from Sono-Tek Corp., Milton, N.Y., that can be used in conjunction with an air focus shroud (not shown) to help direct the spray to the target, for example, the AccuMist system also from Sono-Tek Corp. Each nozzle  26  can have its own spray characteristics. 
     Nozzles  26  can eject a spray of a solution that spreads angularly as the spray moves away from nozzle  26 . As the cross-sectional area of the spray grows with respect to the distance away from nozzle  26 , the flux of the spray can be larger near the center of the cross-section of the spray and smaller near the edges of the cross-section of the spray, where the cross-section is taken perpendicular to the direction of the spray. The variability of the spray flux can produce a coating layer on stent  10  that is thicker directly under nozzle  26  and thinner further away from nozzle  26 . The uneven thickness of the layer can be minimized by making the spray angle wider. Nozzles  24  can be placed any suitable distance away stent  10  so that the application of the coating material is contained within the boundaries provided by barriers  28 . The selected distance, therefore, can be a function of a variety of factors, including spray characteristics of nozzle  26 , the viscosity of the composition, spray flux, and the like. The distance can be, for example, from about 3 cm to about 15 cm. 
     As further illustrated by  FIG. 2 , nozzles  26  are separated by barriers  28 . As illustrated by  FIG. 3 , barrier includes an opening  30  through which stent  10  is positioned. The size of opening  30  should be large enough to provide a suitable clearance between the outer surface of stent  10  and barrier  28 , but also small enough to prevent cross contamination of the coating substance from the adjacent spray nozzles  26 . The size of opening  30  will of course depend on the diameter of stent  10  as mounted on mandrel  16 . Barrier  28  can be made from 2 pieces, upper part  32   a  and lower part  32   b , which can be securely joined together. Barriers  28  can be made of any suitable material, for example, stainless steel. In one embodiment, barriers  28  can have pores  34  on the surface for preventing at least some of the coating composition from gathering and dripping on stent  10 . Alternatively, barriers  28  can be made from an absorbent material, such as a sponge, or the surface of barriers  28  can be coated with an absorbent material for preventing at least some of the composition from dripping onto stent  10 . The distance between barriers  28  can be adjusted so that nozzles  26  can cover any desired length of stent  10 . The distance could be adjusted during the application of the composition, or alternatively, the application of the composition can be terminated and then the distance adjusted. 
     In accordance with another embodiment, precision nozzles can be used, with or with out a barrier so as to only cover a selected length of stent with the coating composition. The coating sprayed by the precision nozzles can have a minimally varying diameter of the spray when the spray reaches stent  10 . The predictability of the spray&#39;s coverage enables the application of multiple coated regions without barriers. The precision nozzle can also create a spray with a substantially even flux distribution throughout the cross-section of the spray. Precision nozzles can be, for example, 8700-35, 8700-48, 8700-48H, or 8700-60 ultrasonic nozzles from Sono-Tek Corp., Milton, N.Y. 
     Coating system  14  can be used to deposit a variety of coating patterns onto stent  10 .  FIGS. 4A to 4F  illustrate several embodiments of coating patterns that can be produced.  FIG. 4A  illustrates stent surface  38  having an intermittent pattern of polymer layers  40  separated by bare stent regions  42 . Bare stent regions  42  are areas which were masked by barriers  28  during the coating process. The length of bare regions  42  between layers  40  has been exaggerated for illustrative purposes. Each of layers  40  can include a different polymer and optionally a therapeutic substance, which can also be different for each layer  40 . Each nozzle  26  can also deposit a different concentration of a therapeutic substance for each layer  40 . Accordingly, stent  10  will have different concentration of a therapeutic substance in different areas of stent  10 .  FIGS. 4B and 4C  illustrate layers  44  deposited over layers  40 . Each of layers  44  can include a different polymer and optionally a therapeutic substance, which can also be different for each layer  44 . By adjusting coating parameters, such as distance of nozzles  26  from stent  10 , the viscosity of the coating composition, etc., layers  44  can be deposited to extend beyond sidewalls of layers  40 . In accordance to yet another embodiment, as illustrated in  FIG. 4D , a topcoat layer  46  can be uniformly deposited over layers  40 . Topcoat layer  46  can serve as a rate-limiting barrier for the release of the drug. Accordingly, if layers  40  are each made from a different polymeric material and contain a different drug, stent  10  can release each of the different drugs at a different release rate for a prolonged duration of time. 
     As mentioned before, the positioning of barriers  28  can be adjusted to form any number of different coating patterns on stent  10 . For example,  FIG. 4E  illustrates layers  44  deposited in between layers  40 , in bare regions  42 . Again, layers  44  can be made from different polymeric materials and can optionally include the same or different therapeutic substances or combination of substances. Topcoat layer  46  can also be deposited over layers  40  and  44 .  FIG. 4F  illustrates that layers  44  can be of any suitable length and deposited on any selected region of stent  10  by adjusting the positioning of barriers  28 . As a result, customized release parameters for a variety of drugs can be achieved by producing coatings of unique layering patterns. 
     Representative examples of polymers that can be used to form the coating include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL); poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone; poly(lactide-co-glycolide); poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lactic acid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester urethane; poly(amino acids); cyanoacrylates; poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters) (e.g., PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules, such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; polyurethanes; silicones; polyesters; polyolefins; polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins; polyurethanes; rayon; rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose. 
     Representative examples of solvents can include N,N-dimethylacetamide (DMAC) having the formula CH 3 —CO—N(CH 3 ) 2 , N,N-dimethylformamide (DMFA) having the formula H—CO—N(CH 3 ) 2 , tetrahydrofuran (THF) having the formula C 4 H 8 O, dimethylsulfoxide (DMSO) having the formula (CH 3 ) 2 S═O, or trifluoro acetic anhydride (TFAA) having the formula (CF 3 —CO) 2 O. If multi-layered coatings are formed, the solvent of the top layer should not significantly dissolved the polymer of the underlying layer or extract the drug out from the underlying layer. 
     The therapeutic substance can be for inhibiting the activity of vascular smooth muscle cells. More specifically, the therapeutic substances can be aimed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells for the inhibition of restenosis. The therapeutic substances can also include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. For example, the therapeutic substances can be for enhancing wound healing in a vascular site or improving the structural and elastic properties of the vascular site. Examples of therapeutic substances include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich, Inc., Milwaukee, Wis.; or COSMEGEN available from Merck &amp; Co., Inc., Whitehouse Station, N.J.). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I 1 , actinomycin X 1 , and actinomycin C 1 . The active therapeutic substances can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. 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.). Examples of such antiplatelets, anticoagulants, antifibrins, 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 ä (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative therapeutic substances include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., Capoten® and Capozide® from Bristol-Myers Squibb Co.), cilazapril or lisinopril (e.g., Prinivil® and Prinzide® from Merck &amp; Co., Inc.), 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.), 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 therapeutic substance is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, dexamethasone and rapamycin. 
     While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.