Title of Invention	AN IMPLANTABLE MEDICAL DEVICE AND A COATING FOR THE SAME
Abstract	An implantable medical device: comprising, a biocompatible film effective to provide an inert surface to be in contact with body tissue of a mammal upon implantation of said device in said mammal, said film comprising a polyfluoro copolymer comprising a polyfluoro copolymer comprising polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing said polyfluoro copolymer wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of second moiety are effective to provide said film with properties effective for use in coating said implantable medical device.

Title of Invention

AN IMPLANTABLE MEDICAL DEVICE AND A COATING FOR THE SAME

Abstract

An implantable medical device: comprising, a biocompatible film effective to provide an inert surface to be in contact with body tissue of a mammal upon implantation of said device in said mammal, said film comprising a polyfluoro copolymer comprising a polyfluoro copolymer comprising polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing said polyfluoro copolymer wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of second moiety are effective to provide said film with properties effective for use in coating said implantable medical device.

Full Text	COATINGS FOR MEDICAL DEVICES This patent application is a continuation-in-part of pending United States Patent Application Serial No. 09/675,882, filed on September 29, 2000. FIELD OF THE INVENTION The invention relates to the use of polyfluoro copolymers as coatings for implantable surgical medical devices. BACKGROUND OF THE INVENTION Implantable medical devices are used in various medical procedures- Such devices include, without limitation, stents, catheters, sutureis, meshes, vascular grafts, shunts and filters for removing emboli. Stents, which generally are open tubular structures, have become increasingly important in medical procedures to restore the function of body lumens. Stents now are commonly used in translumenial procedures such as angioplasty to restore adequate blood flow to the heart and other organs. However, deployment of stents may stimulate foreign body reactions thereto that result in thrombosis or restenosis. To avoid these complications, a variety of stent coatings and compositions have been proposed to reduce the incidence of these complications. The coatings may be capable themselves of reducing the stimulus the stent provides to the injured lumen wall, thus reducing the tendency towards thrombosis or restenosis. Alternately, the coating may deliver a pharmaceutical/therapeutic agent or drug to the lumen that reduces smooth muscle tissue proliferation or restenosis. The reported mechanism for delivery of the agent has been via diffusion of the agent through either the bulk polymer, or through pores that are created in the polymer structure, or by erosion of a biodegradable coating. Both bioabsorbable and biostable compositions have been reported as coatings for stents. They generally have been polymeric coatings that either encapsulate a pharmaceutical/therapeutic agent or drug, e.g. taxol, rapamycin, etc., or bind such an agent to the surface, e.g. heparin-coated stents. These coatings are applied to the stent in a number of ways, including, though not limited to, dip, spray, or spin coating processes. One class of biostable materials that has been reported as coatings for stents is polyfluoro homopolymers. Polytetrafluoroethylene (PTFE) homopolymers have been used as implants for many years. These homopolymers are not soluble in any solvent at reasonable temperatures and therefore are difficult, to coat onto small medical devices while maintaining important features of the devices (e.g. slots in stents). Stents with coatings made from polyvinylideneflouride, homopolymers and containing pharmaceutical/therapeutic agents or drugs for release have been suggested. However, like most crystalline polyfluoro homopolymers, they are difficult to apply as high quality films onto surfaces without subjecting them to relatively high temperatures, e.g. greater than about 125-200°C, that correspond to the melting temperature of the polymer. It would be advantageous to develop coatings for implantable medical devices that will reduce thrombosis, restenosis, or other adverse reactions, that may include, but do not require, the use of pharmaceutical or therapeutic agents or drugs to achieve such affects, and that possess physical and mechanical properties effective for use in such devices, even when such coated devices are subjected to relatively low maximum temperatures. SUMMARY OF THE INVENTION The present invention includes biocompatible coatings and films for use on implantable medical devices and medical devices comprising such coatings and films applied to a surface thereof that is to be in contact with body- tissue of a mammal. The biocompatible; film provides an inert surface to be in contact with body tissue of a mammal upon implantation of the device in the mammal. The coating and film comprise a film-forming polyfluoro copolymer comprising the polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride (VDF) and tetrafluoroethylene (TFE), and the polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing the polyflouro copolymer, said second moiety being capable of providing toughness or elastomeric properties to the polyfluoro copolymer, wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of said second moiety are effective to provide the coating and film produced therefrom with properties effective for use in coating implantable medical devices. BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES Figure 1 indicates the fraction of drug released as a function of time from coatings of the present invention over which no topcoat has been disposed. Figure 2 indicates the fraction of drug released as a function of time from coatings of the present invention including a topcoat disposed thereon. Figure 3 indicates the fraction of drug released as a function of time from coatings of the present invention over which no topcoat has been disposed. Figure 4 indicates in vivo stent release kinetics of rapamycin from poly(VDF/HFP). DETAILED DESCRIPTION OF THE INVENTION The present invention provides polymeric coatings comprising a polyfluoro copolymer and implantable medical devices, e.g. stents, coated with a film of the polyfluoro polymeric coating in amounts effective to reduce thrombosis and/or restenosis when such stents are used in, e.g. angioplasty procedures. As used herein, polyfluoro copolymers means those copolymers comprising the polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, the polymerized residue of a second moiety other than the first moiety and which is copolymerized with the first moiety to produce the polyfluoro copolymer, said second moiety being capable of providing toughness or elastomeric properties to the polyfluoro copolymer, wherein the relative amounts of the polymerized residue of the first moiety and the polymerized residue of the second moiety are effective to provide coatings and films made from such polyfluoro copolymers with properties effective for use in coating implantable medical devices. In certain embodiments, the invention provides an inert, low surface energy coating for medical devices that are implanted into the body of a mammal and later retrieved therefrom. The low surface energy coating makes wetting of the device surface and protein deposition thereon difficult, which could prolong the time for encapsulation in the body, after which time the device could be removed easily. In certain embodiments of the invention, although not necessary, the coatings may comprise pharmaceutical or therapeutic agents in amounts effective for achieving desired purposes, e.g. for reducing thrombosis or restenosis, and stents coated with such coatings may provide sustained release of the agents. Films prepared from certain polyfluoro copolymer coatings of the present invention provide the physical and mechanical properties required of conventional coated medical devices, even where maximum temperatures to which the device, coatings and films are exposed are limited to relatively low temperatures, e.g. less than about 100°C, preferably at about ambient temperatures. This is particularly important when using the coating/film to deliver pharmaceutical/therapeutic agent or drugs that are heat sensitive, or when applying the coating onto temperature- sensitive devices such as, but not limited to, catheters. When maximum exposure temperature is not an issue, e.g. where heat-stable agents such as itraconazole are incorporated into the coatings, higher melting thermoplastic polyfluoro copolymers may be used and, if very high elongation and adhesion is required, elastomers may be used. If desired or required, the polyfluoro elastomers may be crosslinked by standard methods described in, e.g. Modern Fluoropolymers, J. Shires editor, John Wiley & Sons, New York, 1997, pp. 77-87. The present invention comprises polyfluoro copolymers that provide improved biocompatible coatings for medical devices. These coatings provide inert surfaces to be in contact with body tissue of a mammal, e.g. a human, sufficient to reduce thrombosis, or restenosis, or other undesirable reactions. While most reported coatings made from polyfluoro homopolymers are insoluble and/or require high heat, e.g. greater than about 125°C, to obtain films with adequate physical and mechanical properties for use on implantable devices, e.g. stents, or are not particularly tough or elastomeric, films prepared from the polyfluoro copolymer coatings of the present invention provide adequate adhesion, toughness or elasticity, and resistance to cracking when formed on medical devices claimed herein. In certain embodiments, this is the case even where the coated devices are subjected to relatively low maximum temperatures, e.g. less than about 100°C, preferably less than about 65°C, and more preferably about 60°C or less. In such cases, preferred polyfluoro copolymers may comprise the polymerized residue of from about 65 to about 55 weight percent polymerized residue of the first moiety, e.g. VDF, and from about 35 to about 45 weight percent polymerized residue of the second moiety, e.g. hexafluoropropylene. In certain embodiments, such polyfluoro copolymers will be crystalline, although amorphous copolymers of similar composition also are employed. The polyfluoro copolymers used for coatings according to the present invention must be film-forming polymers that have molecular weight high enough so as not to be waxy or tacky. The polymers and films formed therefrom must adhere to the stent and not be readily deformable after deposition on the stent as to be able to be displaced by hemodynamic stresses. The polymer molecular weight must be high enough to provide sufficient toughness so that films comprising the polymers will not be rubbed off during handling or deployment of the stent. In certain embodiments the coating will not crack where expansion of the stent or other medical devices, such as vena cava filters, occurs. The flow point of the polymer used in the present invention should be above 40°C, preferably above about 4 5°C, more preferably above 50°C and most preferably above 55°C. Coatings of the present invention comprise polyfluoro copolymers, as defined hereinabove. The second moiety copolymerized with the first moiety to prepare the polyfluoro copolymer may be selected from those biocompatible monomers that would provide biocompatible polymers acceptable for implantation in a mammal, while maintaining sufficient elastomeric film properties for use on medical devices claimed herein. Such monomers include, without limitation, hexafluoropropylene (HFP), tetrafluoroethylene (TFE), VDF, 1- hydropentafluoropropylene, perfluoro(methyl vinyl ether), chlorotrifluoroethylene (CTFE), pentafluoropropene, trifluoroethylene, hexafluoroacetone and hexafluoroisobutylene. Polyfluoro copolymers used in the; present invention typically comprise vinylidinefluoride copolymerized with HFP, in the weight ratio of from about 50 to about 92 weight percent vinylidinefluoride to about 50 to about 8 weight percent HFP. Preferably, polyfluoro copolymers used in the present invention comprise from about 50 to about 85 weight percent VDF copolymerized with from about 50 to about 15 weight percent HFP. More preferably, the polyfluoro copolymers will comprise from about 55 to about 70 weight percent VDF copolymerized with from about 45 to about 3 0 weight percent HFP. Even more preferably, polyfluoro copolymers comprise from about 55 to about 65 weight percent VDF copolymerized with from about 45 to about 35 weight percent HFP. Such polyfluoro copolymers are soluble, in varying degrees, in solvents such as dimethylacetamide (DMAc), tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide and n-methyl pyrrolidone. Some are soluble in methylethylketone (MEK), acetone, methanol and other solvents commonly used in applying coatings to conventional implantable medical devices. Conventional polyfluoro homopolymers are crystalline and difficult to apply as high quality films onto metal surfaces without exposing the coatings to relatively high temperatures that correspond to the melting temperature (Tm) of the polymer. The elevated temperature serves to provide films prepared from such PVDF homopolymer coatings that exhibit sufficient adhesion of the film to the device, while preferably maintaining sufficient flexability to resist film cracking upon expansion/contraction of the coated medical device. Certain films and coatings according to the present invention provide these same physical and mechanical properties, or essentially the same properties, even when the maximum temperatures to which the coatings and films are exposed is less than about 100°C, and preferably less than about 65°C. This is particularly important when the coatings/films comprise pharmaceutical or therapeutic agents or drugs that are heat sensitive, e.g. subject to chemical or physical degradation or other heat-induced negative affects, or when coating heat sensitive substrates of medical devices, e.g. subject to heat- induced compositional or structural degradation. Depending on the particular device upon which the coatings and films of the present invention are to be applied and the particular use/result required of the device, polyfluoro copolymers used to prepare such devices may be crystalline, semi-crystalline or amorphous. Where devices have no restrictions or limitations with respect to exposure of same to elevated temperatures, e.g. 100°C or higher, crystalline polyfluoro copolymers may be employed. Crystalline polyfluoro copolymers tend to resist the tendency to flow under applied stress or gravity when exposed to temperatures above their glass transition (Tg) temperatures. Crystalline polyfluoro copolymers provide tougher coatings and films than their fully amorphous counterparts. In addition, crystalline polymers are more lubricious and more easily handled through crimping and transfer processes used to mount self-expanding stents, e.g. nitinol stents. Semi-crystalline and amorphous polyfluoro copolymers are advantageous where exposure to elevated temperatures is an issue, e.g. where heat-sensitive pharmaceutical or therapeutic agents are incorporated into the coatings and films, or where device design, structure and/or use preclude exposure to such elevated temperatures. Semi- crystalline polyfluoro copolymer elastomers comprising relatively high levels, e.g. from about 3 0 to about 45 weight percent of the second moiety, e.g. HFP, copolymerized with the first moiety, e.g. VDF, have the advantage of reduced coefficient of friction and self- blocking relative to amorphous polyfluoro copolymer elastomers. Such characteristics can be of significant value when processing, packaging and delivering medical devices coated with such polyfluoro copolymers. In addition, such polyfluoro copolymer elastomers comprising such relatively high content of the second moiety serves to control the solubility of certain agents, e.g. Sirolimus, in the polymer and therefore controls permeability of the agent through the matrix. Polyfluoro copolymers utilized in the present inventions may be prepared by various known polymerization methods. For example, high pressure, free-radical, semi- continuous emulsion polymerization techniques such as those disclosed in Fluoroelastomers-dependence of relaxation phenomena on composition, POLYMER 3O, 2180, 1989, by Ajroldi, et al, may be employed to prepare amorphous polyfluoro copolymers, some of which may be elastomers. In addition, free-radical batch emulsion polymerization techniques disclosed herein may be used to obtain polymers that are semi-crystalline, even where relatively high levels of the second moiety, e.g. greater than about 19-20 mole percent (equivalent to about 36-37 weight percent), are included. One embodiment of the invention comprises stents coated with a film of a polyfluoro copolymer according to the present invention. Conventional stents are used in translumenial procedures such as angioplasty to restore adequate blood flow to the heart and other organs. They generally are cylindrical and perforated with passages that are slots, ovoid, circular or the like shape. Stents also may be composed of helically wound or serpentine wire structures in which the spaces between the wires form passages. Stents may be flat perforated structures that are subsequently rolled to form tubular or cylindrical structures that are woven, wrapped, drilled, etched or cut to form passages. Examples of stents that may be advantageously coated by polyfluoro copolymers of the present invention include, but are not limited to, stents described in U.S. Patent Nos. 4,733,665; 4,800,882; 4,886,062, 5,514,154, and 6,190,403, the contents each of which is incorporated herein in its entirety as if set forth herein. These stents can be made of biocompatible materials, including biostable and bioabsorbable materials. Suitable biocompatible metals include, but are not limited to, stainless steel, tantalum, titanium alloys (including nitinol), and cobalt alloys (including cobalt- chromium-nickel alloys) . Suitable nonmetallic biocompatible materials include, but are not limited to, polyamides, polyolefins (i.e. polypropylene, polyethylene etc.), nonabsorbable polyesters (i.e. polyethylene terephthalate), and bioabsorbable aliphatic polyesters (i.e. homopolymers and copolymers of lactic acid, glycolic acid, lactide, glycolide, para-dioxanone, trimethylene carbonate, s-caprolactone, and blends thereof). The film-forming biocompatible polymer coatings generally are applied to the stent in order to reduce local turbulence in blood flow through the stent, as well as adverse tissue reactions. The coatings and films formed therefrom also may be used to administer a pharmaceutically active material to the site of the stent placement. Generally, the amount of polymer coating to be applied to the stent will vary depending on, among other possible parameters, the particular polyfluoro copolymer used to prepare the coating, the stent design and the desired effect of the coating. Generally, the coated stent will comprise from about 0.1 to about 15 weight percent of the coating, preferably from about 0.4 to about 10 weight percent. The polyfluoro copolymer coatings may be applied in one or more coating steps, depending on the amount of polyfluoro copolymer to be applied. Different polyfluoro copolymers may be used for different layers in the stent coating. In fact, in certain embodiments, it is highly advantageous to use a diluted first coating solution comprising a polyfluoro copolymer as a primer to promote adhesion of a subsequent polyfluoro copolymer coating layer that may contain pharmaceutically active materials. The individual coatings may be prepared from different polyfluoro copolymers. Additionally, a top coating can be applied to delay- release of the pharmaceutical agent, or they could be used as the matrix for the delivery of a different pharmaceutically active material. Layering of coatings can be used to stage release of the drug or to control release of different agents placed in different layers. Blends of polyfluoro copolymers also may be used to control the release rate of different agents or to provide desirable balance of coating properties, i.e. elasticity, toughness, etc., and drug delivery characteristics, e.g. release profile. Polyfluoro copolymers with different solubilities in solvents can be used to build up different polymer layers that may be used to deliver different drugs or to control the release profile of a drug. For example, polyfluoro copolymers comprising 85.5/14.5 (wt/wt) of poly(VDF/HFP) and 60.6/39.4 (wt/wt) of poly(VDF/HFP) are both soluble in DMAc. However, only the 60.6/39.4 poly (VDF/HFP) polyfluoro copolytner is soluble in methanol. So, a first layer of the 85.5/14.5 poly(VDF/HFP) polyfluoro copolymer comprising a drug could be over- coated with a topcoat of the 60.6/3 9.4 poly(VDF/HFP) polyfluoro copolymer made with the methanol solvent. The top coating can be used to delay the drug deliver of the drug contained in the first layer. Alternatively, the second layer could contain a different drug to provide for sequential drug delivery. Multiple layers of different drugs could be provided by alternating layers of first one polyfluoro copolymer, then the other. As will be readily appreciated by those skilled in the art numerous layering approaches can be used to provide the desired drug delivery. The coatings can be used to deliver therapeutic and pharmaceutic agents such as, but not limited to: antiproliferative/antimitotic agents including natural products such as vinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L- asparagine and deprives cells which don't have the capacity to synthesize their own asparagine); antiproliferative/antimitotic alkylating agents such as nitrogen mustards(mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes - dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2- chlorodeoxyadenosine{cladribine}); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e.estrogen); Anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); antiinflammatory: such as adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6α- methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives i.e. aspirin; para-aminophenol derivatives i.e. acetominophen; Indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac) , arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate) ; itnmunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); Angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); nitric oxide donors; cell cycle inhibitors; mTOR inhibitors; growth factor signal transduction knase inhibitors; anti- sense oligonucleotide; prodrug molecules; and combinations thereof. Coatings may be formulated by mixing one or more therapeutic agents with the coating polyfluoro copolymers in a coating mixture. The therapeutic agent may be present as a liquid, a finely divided solid, or any other appropriate physical form. Optionally, the coating mixture may include one or more additives, e.g., nontoxic auxiliary substances such as diluents, carriers, excipients, stabilizers or the like. Other suitable additives may be formulated with the polymer and pharmaceutically active agent or compound. For example, a hydrophilic polymer may be added to a biocompatible hydrophobic coating to modify the release profile, or a hydrophobic polymer may be added to a hydrophilic coating to modify the release profile. One example would be adding a hydrophilic polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, carboxylmethyl cellulose, and hydroxymethyl cellulose to a polyfluoro copolymer coating to modify the release profile. Appropriate relative amounts can be determined by monitoring the in vitro and/or in vivo release profiles for the therapeutic agents. The best conditions for the coating application are when the polyfluoro copolymer and pharmaceutic agent have a common solvent. This provides a wet coating that is a true solution. Less desirable, yet still, usable, are coatings that contain the pharmaceutical agent as a solid dispersion in a solution of the polymer in solvent. Under the dispersion conditions, care must be taken to ensure that the particle size of the dispersed pharmaceutical powder, both the primary powder size and its aggregates and agglomerates, is small enough not to cause an irregular coating surface or to clog the slots of the stent that need to remain essentially free of coating. In cases where a dispersion is applied to the stent and the smoothness of the coating film surface requires improvement, or to be ensured that all particles of the drug are fully encapsulated in the polymer, or in cases where the release rate of the drug is to be slowed, a clear (polyfluoro copolymer only) topcoat of the same polyfluoro copolymer used to provide sustained release of the drug or another polyfluoro copolymer that further restricts the diffusion of the drug out of the coating can be applied. The topcoat can be applied by dip coating with mandrel to clear the slots, referred to herein as the dip and wipe method. This method is disclosed in United States Patent 6,153,252, the contents of which are incorporated herein in their entirety. Other methods for applying the topcoat include spin coating and spray coating. Dip coating of the top coat can be problematic if the drug is very soluble in the coating solvent, which swells the polyfluoro copolymer, and the clear coating solution acts as a zero concentration sink and redissolves previously deposited drug. The time spent in the dip bath may need to be limited so that the drug is not extracted out into the drug-free bath. Drying should be rapid so that the previously deposited drug does not completely diffuse into the topcoat. The amount of therapeutic agent will be dependent upon the particular drug employed and medical condition being treated. Typically, the amount of drug represents about 0.001% to about 70%, more typically about 0.001% to about 60%. The quantity and type of polyfluoro copolymers employed in the coating film containing the pharmaceutic agent will vary depending on the release profile desired and the amount of drug employed. The product may contain blends of the same or different polyfluoro copolymers having different molecular weights to provide the desired release profile or consistency to a given formulation. Polyfluoro copolymers may release dispersed drug by diffusion. This can result in prolonged delivery (over, say 1 to 2,000 hours, preferably 2 to 800 hours) of effective amounts (say, 0.001 μg/cm2-min to 100 μg/cm2-min) of the drug. The dosage can be tailored to the subject being treated, the severity of the affliction, the judgment of the prescribing physician, and the like. Individual formulations of drugs and polyfluoro copolymers may be tested in appropriate in vitro and in vivo models to achieve the desired drug release profiles. For example, a drug could be formulated with a polyfluoro copolymer, or blend of polyfluoro copolymers, coated onto a stent and placed in an agitated or circulating fluid system, e.g. 25% ethanol in water. Samples of the circulating fluid could be taken to determine the release profile (such as by HPLC, UV analysis or use of radiotagged molecules). The release of a pharmaceutical compound from a stent coating into the interior wall of a lumen could be modeled in appropriate animal system. The drug release profiles could then be monitored by appropriate means such as, by taking samples at specific times and assaying the samples for drug concentration (using HPLC to detect drug concentration). Thrombus formation can be modeled in animal models using the 111 In-platelet imaging methods described by Hanson and Harker, Proc. Natl. Acad. Sci. USA 85:3184-3188 (1988). Following this or similar procedures, those skilled in the art will be able to formulate a variety of stent coating formulations. While not a requirement of the present invention, the coatings and films may be crosslinked once applied to the medical devices. Crosslinking may be affected by any of the known crosslinking mechanisms, such as chemical, heat or light. In addition, crosslinking initiators and promoters may be used where applicable and appropriate. In those embodiments utilizing crosslinked films comprising pharmaceutical agents, curing may affect the rate at which the drug diffuses from the coating. Crosslinked polyfluoro copolymers films and coatings of the present invention also may be used without drug to modify the surface of implantable medical devices. Examples: Example 1: A poly(VDF) homopolymer (Solef 10 0 8 from Solvay Advanced Polymers, Houston, TX, Tm about 175°C) and polyfluoro copolymers of poly(VDF/HFP), 92/8 and 91/9 weight percent VDF/HFP, respectively, as determined by F19 NMR (eg: Solef 11010 and 11008, Solvay Advanced Polymers, Houston, TX, Tm about 15 9°C and 160°C, respectively) were examined as potential coatings for stents. These polymers are soluble in solvents such as, but not limited to, DMAc, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP), tetrahydrofuran (THF) and acetone. Polymer coatings were prepared by dissolving the polymers in acetone, at 5 weight percent as a primer, or by dissolving the polymer in 50/50 DMAc/acetone, at 30 weight percent as a topcoat. Coatings that were applied to the stents by dipping and dried at 60°C in air for several hours, followed by 60°C for 3 hours in a Hg vacuum, resulted in white foamy films. As applied, these films adhered poorly to the stent and flaked off, indicating they were too brittle. When stents coated in this manner were heated above 175°C, i.e. above the melting temperature of the polymer, a clear, adherent film was formed. Such coatings require high temperatures, e.g. above the melting temperature of the polymer, to achieve high quality films. Example 2: A polyfluoro copolymer (Solef 21508) comprising 85.5 weight percent VDF copolymerized with 14.5 weight, percent HFP, as determined by F19 NMR, was evaluated. This copolymer is less crystalline than the polyfluoro homopolymer and copolymers described in Example 1. It also has a lower melting point reported to be about 133°C. Once again, a coating comprising about 2 0 weight percent of the polyfluoro copolymer was applied from a polymer solution in 50/50 DMAc/MEK. After drying (in air) at 6 0°C for several hours, followed by 6 0°C for 3 hours in a This eliminated the need for a high temperature heat treatment to achieve high quality films. Coatings were smoother and more adherent than those of Example 1. Some coated stents that underwent expansion show some degree of adhesion loss and "tenting" as the film pulls away from the metal. Where necessary, modification of coatings containing such copolymers may be made, e.g. by addition of plasticizers or the like to the coating compositions. Films prepared from such coatings may be used to coat stents or other medical devices, particularly where those devices are not susceptible to expansion to the degree of the stents. The coating process above was repeated, this time with a coating comprising the 85.5/14.6 (wt/wt) (VDF/HFP) and about thirty (3 0) weight percent of rapamycin (Wyeth- Ayerst Laboratories, Philadelphia, PA), based on total weight of coating solids. Clear films that would occasionally crack or peel upon expansion of the coated stents resulted. It is believed that inclusion of plasticizers and the like in the coating composition will result in coatings and films for use on stents and other medical devices that are not susceptible to such cracking and peeling. Example 3: Polyfluoro copolymers of still higher HFP content then were examined. This series of polymers were not semi-crystalline, but rather are marketed as elastomers. One such copolymer is Fluorel FC-2261Q (from Dyneon, a 3M- Hoechst Enterprise, Oakdale, MN), a 60.6/39.4 (wt/wt) copolymer of VDF/HFP. Although this copolymer has a Tg well below room temperature (Tg about -20°C), it is not tacky at room temperature or even at 60°C. This polymer has no detectable crystallinity when measured by Differential Scanning Calorimetry (DSC) or by wide angle X-ray diffraction. Films formed on stents as described above were non-tacky, clear, and expanded without incident when the stents were expanded. The coating process above was repeated, this time with coatings comprising the 60.6/39.4 (wt/wt) poly(VDF/HFP) and about nine (9), thirty (30) and fifty (50) weight percent of rapamycin , based on total weight of coating solids, respectively. Coatings comprising about 9 and 30 weight percent rapamycin provided white, adherent, tough films that expanded without incident on the stent. Inclusion of 50% drug, in the same manner, resulted in some loss of adhesion upon expansion. Changes in the comonomer composition of the polyfluoro copolymer also can affect the nature of the solid state coating, once dried. For example, the semi-crystalline copolymer, Solef 21508, containing 85.5% VDF polymerized with 14.5% by weight HFP forms homogeneous solutions with about 3 0% rapamycin (drug weight divided by total solids weight, e.g. drug plus copolymer) in DMAc and 50/50 DMAc/MEK. When the film is dried (60°C/16 hours followed by 60°C/3 hours in vacuum of 10 0 mm Hg) a clear coating, indicating a solid solution of the drug in the polymer, is obtained. Conversely, when an amorphous copolymer, Fluorel FC-2261Q, of poly(VDF/HFP) at 60.6/39.5 (wt/wt) forms a similar 30% solution of rapamycin in DMAc/MEK and is similarly dried, a white film, indicating phase separation of the drug and the polymer, is obtained. This second drug containing film is much slower to release the drug into an in vitro test solution of 25% ethanol in water than is the former clear film of crystalline Solef 21508. X-ray analysis of both films indicates that the drug is present in a non-crystalline form. Poor or very low solubility of the drug in the high HFP-containing copolymer results in slow permeation of the drug through the thin coating film. Permeability is the product of diffusion rate of the diffusing species (in this case the drug) through the film (the copolymer) and the solubility of the drug in the film. Example 4: In vitro release results of rapamycin from coating. Figure 1 is a plot of data for the 85.5/14.5 VDF/HFP polyfluoro copolymer, indicating fraction of drug released as a function of time, with no topcoat. Figure 2 is a plot of data for the same polyfluoro copolymer over which a topcoat has been disposed, indicating that most effect on release rate is with a clear topcoat. As shown therein, TC150 refers to a device comprising 150 micrograms of topcoat, TC235 refers to 23 5 micrograms of topcoat, etc. The stents before top coating had an average of 750 micrograms of coating containing 30% rapamycin ( based on drug/[drug + polymer]) Figure 3 is a plot for the 60.6/39.4 VDF/HFP polyfluoro copolymer, indicating fraction of drug released as a function of time, showing significant control of release rate from the coating without the use of a topcoat. Release is controlled by loading of drug in the film. Example 5: in vivo stent release kinetics of rapamycin from poly(VDF/HFP). Nine (9) New Zealand white rabbits (2.5-3.0 kg) on a normal diet were given aspirin 24 hours prior to surgery, again just prior to surgery and for the remainder of the study. At the time of surgery, animals were premedicated with Acepromazine (0.1-0.2 mg/kg) and anesthetized with a Ketamine/Xylazine mixture (4 0 mg/kg and 5 mg/kg, respectively). Animals were given a single intraprocedural dose of heparin (150 IU/kg, i.v.) Arteriectomy of the right common carotid artery was performed and 5 F catheter introducer (Cordis, Inc.) placed in the vessel and anchored with ligatures. Iodine contrast agent was injected to visualize the right common carotid artery, brachlocephalic trunk and aortic arch. A steerable guide wire (0.014 inch/180 cm,, Cordis, Inc.) was inserted via the introducer and advanced sequentially into each iliac artery to a location where the artery possesses a diameter closest to 2 mm using the cingiographic mapping done previously. Two stents coated with a film made from poly(VDF/HFP) : (60.6/39.4) , with about 30% rapamycin ( based on drug/ [drug + polymer] ) were deployed in each animal where feasible, one in each iliac artery, using 3.0 mm balloon and inflation to 8-10 ATM for 30 seconds followed after a 1 minute interval by a second inflation to 8-10 ATM for 30 seconds. Follow-up angiogiraphs visualizing both iliac arteries are obtained to confirm correct deployment position of the stent. At the end of procedure, the carotid artery was ligated and the skin is closed with 3/0 vicryl suture using a one layered interrupted closure. Animals were given butoropanol (0.4 mg/kg, s.c.) and gentamycin (4 mg/kg, i.m.). Following recovery, the animals were returned to their cages and allowed free access to food and water. Due to early deaths and surgical difficulties, 2 animals were not used in this analysis. Stented vessels were removed from the remaining 7 animals at the following time points: 1 vessel (1 animal) at 10 inain post implant; 6 vessels (3 animals) between 45 min and 2 h post-implant (average, 1.2 hours); 2 vessels (2 animals) at 3 d post implant; and 2 vessels (1 animal) at 7 d post-implant. In one animal at 2 hours, the stent was retrieved from the aorta rather than the iliac artery. Upon removal, arteries were carefully trimmed at both the proximal and distal ends of the stent. Vessels were then carefully dissected free of the stent, flushed to remove any residual blood, and both stent and vessel frozen immediately, wrapped separately in foil, labeled and kept frozen at -8 0 °C. When all samples had been collected, vessels and stents were frozen, transported and subsequently analyzed for rapamycin in tissue. Results are shown in Figure 4. Example 6: Purifying the polymer. The Fluorel FC-2261Q copolymer was dissolved in MEK at about 10 weight percent and was washed in a 50/50 mixture of ethanol/water. The (ethanol/water): MEK solution ratio = about 14:1. The polymer precipitated out and was separated from the solvent phase by centrifugation. The polymer again was dissolved in MEK and the washing procedure repeated. The polymer was dried after each washing step at 60°C in a vacuum oven ( Example 7: In vivo testing of coated stents in porcine coronary arteries. CrossFlex® stents (available from Cordis, a Johnson & Johnson Company) were coated with the "as received" Fluorel FC-2261Q PVDF copolymer and with the purified polyfluoro copolymer of example 6, using the dip and wipe approach. The coated stents were sterilized using ethylene oxide and a standard cycle. The coated stents and bare metal stents (controls) were implanted in porcine coronary arteries, where they remained for 28 days. Angiography was performed on the pigs at implantation and at 28 days. Angiography indicated that the control uncoated stent exhibited about 21 percent restenosis. The polyfluoro copolymer "as received" exhibited about 26% restenosis (equivalent to the control) and the washed copolymer exhibited about 12.5% restenosis. Histology results reported neointimal area at 28 days to be 2.89±0.2, 3.57±0.4 and 2.75+0.3, respectively, for the bare metal control, the unpurified copolymer and the purified copolymer. Example 8: Utilizing the following high pressure, free-radical batch emulsion polymerization technique, a series of semi- crystalline, poly(VDF/HFP) copolymer elastomers was prepared. The VDF and HFP monomers were premixed under pressure in a pressure vessel. HPLC-grade water, surfactant and initiator were mixed outside of a 2 liter Zipperclave® reactor (Autoclave Engineers, Erie, PA) and then charged to the reactor, which then was sealed. The premixed monomers then were transferred under nitrogen pressure to the reactor. While stirring, the reactor was raised to the desired temperature and held for a predetermined period of time. The reactor then was cooled and residual monomer vented. The resultant polymer latex was removed from the reactor and coagulated or crashed by adding dilute hydrochloric acid, followed by aqueous sodium chloride. The resulting polymer was washed extensively with water and dried. The polyfluoro copolymers then were compared with respect to kinetic coefficient of friction of a film prepared therefrom to the kinetic coefficient of friction of a film prepared from a commercial amorphous polyfluoro copolymer comprising 59.5 weight percent VDF copolymerized with 40.5 weight percent HFP utilizing the following procedure. A 57.2 mm wide by 140.0 mm long polymer film was cast on a 101.6 mm wide by 203.2 mm long aluminum panel (Q- panel, anodized finish, A-48). A silicone rubber gasket was placed on the aluminum panel and clamped using binder clips. The mold was leveled in a fume hood using a bubble level. Approximate 5.0 g of 10.0% polymer solution in methyl ethyl ketone was poured into the mold slowly. The film was dried at room temperature for 3 days followed by 3 hours at 23°C and 50% R.H. prior to testing. The kinetic coefficient of friction of the polymer film was measured in accordance with the method described in ASTM D 1894 -00, "Static and Kinetic Coefficients of Friction of Plastic Film and Sheeting", Method C. A 46.5 g Teflon block, 25.4 mm wide by 41.3 mm long by 19.1 mm thick, with an eye screw fastened in one end was used as a sled. The surface of the sled that contacted to the film was polished using 500-grit sandpaper. The Teflon sled was attached to a flexible beaded chain and pulled using an Instron tensile tester at a rate of 150 mm/min., at 23°C and 50% R.H. Five measurements was made on each film sample. The thickness of the film was measured using a digital thickness gauge. The kinetic coefficient test results are given in Table I. The maximum kinetic coefficient of friction of five measurements of each film were averaged and reported. The Differential Scanning Calorimetry (DSC) data were obtained on the following polymers using vacuum dried films in a TA Instruments Model 2 92 0 Modulated DSC in standard (non-modulated) DSC mode. The samples were quenched to -80°C and heated at 10°C/min to 275°C in nitrogen. The data are reported as AH (J/g) for endothermic, melting events above glass transition temperature (Tg). WE CLAIM: 1. An implantable medical device: comprising, a biocompatible film effective to provide an inert surface to be in contact with body tissue of a mammal upon implantation of said device in said mammal, said film comprising a polyfluoro copolymer comprising a polyfluoro copolymer comprising polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing said polyfluoro copolymer wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of second moiety are effective to provide said film with properties effective for use in coating said implantable medical device. 2. The device as claimed in claim 1, wherein said polyfluoro copolymer comprises from about 50 to about 92 weight percent of said polymerized residue of said first moiety copolymerized with from about 50 to about 8 weight percent of said polymerized of said second moiety. 3. The device as claimed in claim 1, wherein said polyfluoro copolymer comprises from about 50 to about 85 weight percent of polymerized residue of vinylidenefluoride copolymerized with from about 50 to about 15 weight percent of said polymerized residue of said second moiety. 4. The device as claimed in claim 1, wherein said copolymer comprises from about 55 to about 65 weight percent of said polymerized residue of said vinylidenefluoride copolymerized with from about 45 to about 35 weight percent of said polymerized residue of said second moiety. 5. The device as claimed in claim 1, wherein said second moiety is selected from the group consisting of hexafluoropropylene, tetrafluoroethylene, vinylidenefluoride, 1 -hydropentafluoropropylene, perfluoro(methyl vinyl ether), chlorotrifluoroethylene, pentafluoropropene, trifluoroethylene, hexafluoroacetone and hexafluoroisobutylene. 6. The device as claimed in claim 4, wherein said second moiety is hexafluoropropylene. 7. The implantable medical device as claimed in claim 1, wherein said film further comprises effective amounts of a therapeutic and/or pharmaceutical agent. 8. The implantable device as claimed in claim 1, wherein said polyfluoro copolymer is effective to provide said film with properties effective for use in coating said implantable medical device when said coated device is subjected to a maximum temperature of less than about 100°C. 9. A biocompatible coating for use on implantable medical devices: said coating comprising, a polyfluoro copolymer comprising polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing said polyfluoro copolymer, wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of said second moiety are effective to provide said coating with properties effective to provide said coating with properties effective for use in coating implantable medical devices; and a solvent in which said polyfluoro copolymer is substantially soluble. 10.The coating as claimed in claim 9, wherein said polyfluoro copolymer comprises from about 50 to about 92 weight percent of said polymerized residue of said first moiety copolymerized with from about 50 to about 8 weight percent of said polymerized of said second moiety. 11.The coating as claimed in claim 9, wherein said polyfluoro copolymer comprises from about 50 to about 85 weight percent of polymerized residue of vinylidenefluoride copolymerized with from about 50 to about 15 weight percent of said polymerized residue of said second moiety. 12.The coating as claimed in claim 9, wherein said copolymer comprises, from about 55 to about 65 weight percent of said polymerized residue of said vinylidenefluoride copolymerized with from about 45 to about 35 weight percent of said polymerized residue of said second moiety. 13.The coating as claimed in claim 9, wherein said second moiety is selected from the group consisting of hexafluoropropylene, tetrafluoroethylene, vinylidenefluoride, 1 -hydropentafluoropropylene, perfluoro (methyl vinyl ether), chlorotrifluoroethylene, pentafluoropropene, trifluoroethylene, hexafluoroacetone and hexafluoroisobutylene. 14.The coating as claimed in claim 12, wherein said second moiety is hexafluoropropylene. 15.The coating as claimed in claim 9, further comprising effective amounts of a therapeutic and/or pharmaceutical agent. 16.The coating as claimed in claim 9, wherein said polyfluoro copolymer is effective to provide said film with properties effective for use in coating said implantable medical device when said coated device is subjected to a maximum temperature of less than about 100°C. 17. The coating as claimed in claim 9, wherein said solvent is selected from the group consisting of dimethylacetamide, N, N- dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, methylethylketone, methanol and acetone. 18. A film prepared from the coating as claimed in claim 9. 19. The film prepared from the coating as claimed in claim 15. 20. The film as claimed in claim 18, wherein the polyfluoro copolymer is crosslinked. 21. The film as claimed in claim 19, wherein the polyfluoro copolymer is crosslinked. An implantable medical device: comprising, a biocompatible film effective to provide an inert surface to be in contact with body tissue of a mammal upon implantation of said device in said mammal, said film comprising a polyfluoro copolymer comprising a polyfluoro copolymer comprising polymerized residue of a first moiety selected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than said first moiety and which is copolymerized with said first moiety, thereby producing said polyfluoro copolymer wherein the relative amounts of said polymerized residue of said first moiety and said polymerized residue of second moiety are effective to provide said film with properties effective for use in coating said implantable medical device.

Full Text

COATINGS FOR MEDICAL DEVICES
This patent application is a continuation-in-part of
pending United States Patent Application Serial No.
09/675,882, filed on September 29, 2000.
FIELD OF THE INVENTION
The invention relates to the use of polyfluoro
copolymers as coatings for implantable surgical medical
devices.
BACKGROUND OF THE INVENTION
Implantable medical devices are used in various
medical procedures- Such devices include, without
limitation, stents, catheters, sutureis, meshes, vascular
grafts, shunts and filters for removing emboli.
Stents, which generally are open tubular structures,
have become increasingly important in medical procedures
to restore the function of body lumens. Stents now are
commonly used in translumenial procedures such as
angioplasty to restore adequate blood flow to the heart
and other organs. However, deployment of stents may
stimulate foreign body reactions thereto that result in
thrombosis or restenosis.
To avoid these complications, a variety of stent
coatings and compositions have been proposed to reduce the
incidence of these complications. The coatings may be
capable themselves of reducing the stimulus the stent
provides to the injured lumen wall, thus reducing the
tendency towards thrombosis or restenosis. Alternately,
the coating may deliver a pharmaceutical/therapeutic agent
or drug to the lumen that reduces smooth muscle tissue
proliferation or restenosis. The reported mechanism for
delivery of the agent has been via diffusion of the agent

through either the bulk polymer, or through pores that are
created in the polymer structure, or by erosion of a
biodegradable coating.
Both bioabsorbable and biostable compositions have
been reported as coatings for stents. They generally have
been polymeric coatings that either encapsulate a
pharmaceutical/therapeutic agent or drug, e.g. taxol,
rapamycin, etc., or bind such an agent to the surface,
e.g. heparin-coated stents. These coatings are applied to
the stent in a number of ways, including, though not
limited to, dip, spray, or spin coating processes.
One class of biostable materials that has been
reported as coatings for stents is polyfluoro
homopolymers. Polytetrafluoroethylene (PTFE) homopolymers
have been used as implants for many years. These
homopolymers are not soluble in any solvent at reasonable
temperatures and therefore are difficult, to coat onto
small medical devices while maintaining important features
of the devices (e.g. slots in stents).
Stents with coatings made from polyvinylideneflouride,
homopolymers and containing pharmaceutical/therapeutic
agents or drugs for release have been suggested. However,
like most crystalline polyfluoro homopolymers, they are
difficult to apply as high quality films onto surfaces
without subjecting them to relatively high temperatures,
e.g. greater than about 125-200°C, that correspond to the
melting temperature of the polymer.
It would be advantageous to develop coatings for
implantable medical devices that will reduce thrombosis,
restenosis, or other adverse reactions, that may include,
but do not require, the use of pharmaceutical or
therapeutic agents or drugs to achieve such affects, and
that possess physical and mechanical properties effective

for use in such devices, even when such coated devices are
subjected to relatively low maximum temperatures.
SUMMARY OF THE INVENTION
The present invention includes biocompatible coatings
and films for use on implantable medical devices and
medical devices comprising such coatings and films applied
to a surface thereof that is to be in contact with body-
tissue of a mammal. The biocompatible; film provides an
inert surface to be in contact with body tissue of a mammal
upon implantation of the device in the mammal. The coating
and film comprise a film-forming polyfluoro copolymer
comprising the polymerized residue of a first moiety
selected from the group consisting of vinylidenefluoride
(VDF) and tetrafluoroethylene (TFE), and the polymerized
residue of a second moiety other than said first moiety and
which is copolymerized with said first moiety, thereby
producing the polyflouro copolymer, said second moiety
being capable of providing toughness or elastomeric
properties to the polyfluoro copolymer, wherein the
relative amounts of said polymerized residue of said first
moiety and said polymerized residue of said second moiety
are effective to provide the coating and film produced
therefrom with properties effective for use in coating
implantable medical devices.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
Figure 1 indicates the fraction of drug released as a
function of time from coatings of the present invention
over which no topcoat has been disposed.
Figure 2 indicates the fraction of drug released as a
function of time from coatings of the present invention
including a topcoat disposed thereon.

Figure 3 indicates the fraction of drug released as a
function of time from coatings of the present invention
over which no topcoat has been disposed.
Figure 4 indicates in vivo stent release kinetics of
rapamycin from poly(VDF/HFP).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides polymeric coatings
comprising a polyfluoro copolymer and implantable medical
devices, e.g. stents, coated with a film of the polyfluoro
polymeric coating in amounts effective to reduce
thrombosis and/or restenosis when such stents are used in,
e.g. angioplasty procedures. As used herein, polyfluoro
copolymers means those copolymers comprising the
polymerized residue of a first moiety selected from the
group consisting of vinylidenefluoride and
tetrafluoroethylene, the polymerized residue of a second
moiety other than the first moiety and which is
copolymerized with the first moiety to produce the
polyfluoro copolymer, said second moiety being capable of
providing toughness or elastomeric properties to the
polyfluoro copolymer, wherein the relative amounts of the
polymerized residue of the first moiety and the polymerized
residue of the second moiety are effective to provide
coatings and films made from such polyfluoro copolymers
with properties effective for use in coating implantable
medical devices.
In certain embodiments, the invention provides an
inert, low surface energy coating for medical devices that
are implanted into the body of a mammal and later
retrieved therefrom. The low surface energy coating makes
wetting of the device surface and protein deposition
thereon difficult, which could prolong the time for

encapsulation in the body, after which time the device
could be removed easily.
In certain embodiments of the invention, although not
necessary, the coatings may comprise pharmaceutical or
therapeutic agents in amounts effective for achieving
desired purposes, e.g. for reducing thrombosis or
restenosis, and stents coated with such coatings may
provide sustained release of the agents. Films prepared
from certain polyfluoro copolymer coatings of the present
invention provide the physical and mechanical properties
required of conventional coated medical devices, even
where maximum temperatures to which the device, coatings
and films are exposed are limited to relatively low
temperatures, e.g. less than about 100°C, preferably at
about ambient temperatures. This is particularly important
when using the coating/film to deliver
pharmaceutical/therapeutic agent or drugs that are heat
sensitive, or when applying the coating onto temperature-
sensitive devices such as, but not limited to, catheters.
When maximum exposure temperature is not an issue, e.g.
where heat-stable agents such as itraconazole are
incorporated into the coatings, higher melting
thermoplastic polyfluoro copolymers may be used and, if
very high elongation and adhesion is required, elastomers
may be used. If desired or required, the polyfluoro
elastomers may be crosslinked by standard methods
described in, e.g. Modern Fluoropolymers, J. Shires
editor, John Wiley & Sons, New York, 1997, pp. 77-87.
The present invention comprises polyfluoro copolymers
that provide improved biocompatible coatings for medical
devices. These coatings provide inert surfaces to be in
contact with body tissue of a mammal, e.g. a human,
sufficient to reduce thrombosis, or restenosis, or other
undesirable reactions. While most reported coatings made

from polyfluoro homopolymers are insoluble and/or require
high heat, e.g. greater than about 125°C, to obtain films
with adequate physical and mechanical properties for use
on implantable devices, e.g. stents, or are not
particularly tough or elastomeric, films prepared from the
polyfluoro copolymer coatings of the present invention
provide adequate adhesion, toughness or elasticity, and
resistance to cracking when formed on medical devices
claimed herein. In certain embodiments, this is the case
even where the coated devices are subjected to relatively
low maximum temperatures, e.g. less than about 100°C,
preferably less than about 65°C, and more preferably about
60°C or less. In such cases, preferred polyfluoro
copolymers may comprise the polymerized residue of from
about 65 to about 55 weight percent polymerized residue of
the first moiety, e.g. VDF, and from about 35 to about 45
weight percent polymerized residue of the second moiety,
e.g. hexafluoropropylene. In certain embodiments, such
polyfluoro copolymers will be crystalline, although
amorphous copolymers of similar composition also are
employed.
The polyfluoro copolymers used for coatings according
to the present invention must be film-forming polymers
that have molecular weight high enough so as not to be
waxy or tacky. The polymers and films formed therefrom
must adhere to the stent and not be readily deformable
after deposition on the stent as to be able to be
displaced by hemodynamic stresses. The polymer molecular
weight must be high enough to provide sufficient toughness
so that films comprising the polymers will not be rubbed
off during handling or deployment of the stent. In
certain embodiments the coating will not crack where
expansion of the stent or other medical devices, such as

vena cava filters, occurs. The flow point of the polymer
used in the present invention should be above 40°C,
preferably above about 4 5°C, more preferably above 50°C
and most preferably above 55°C.
Coatings of the present invention comprise polyfluoro
copolymers, as defined hereinabove. The second moiety
copolymerized with the first moiety to prepare the
polyfluoro copolymer may be selected from those
biocompatible monomers that would provide biocompatible
polymers acceptable for implantation in a mammal, while
maintaining sufficient elastomeric film properties for use
on medical devices claimed herein. Such monomers include,
without limitation, hexafluoropropylene (HFP),
tetrafluoroethylene (TFE), VDF, 1-
hydropentafluoropropylene, perfluoro(methyl vinyl ether),
chlorotrifluoroethylene (CTFE), pentafluoropropene,
trifluoroethylene, hexafluoroacetone and
hexafluoroisobutylene.
Polyfluoro copolymers used in the; present invention
typically comprise vinylidinefluoride copolymerized with
HFP, in the weight ratio of from about 50 to about 92
weight percent vinylidinefluoride to about 50 to about 8
weight percent HFP. Preferably, polyfluoro copolymers
used in the present invention comprise from about 50 to
about 85 weight percent VDF copolymerized with from about
50 to about 15 weight percent HFP. More preferably, the
polyfluoro copolymers will comprise from about 55 to about
70 weight percent VDF copolymerized with from about 45 to
about 3 0 weight percent HFP. Even more preferably,
polyfluoro copolymers comprise from about 55 to about 65
weight percent VDF copolymerized with from about 45 to
about 35 weight percent HFP. Such polyfluoro copolymers
are soluble, in varying degrees, in solvents such as
dimethylacetamide (DMAc), tetrahydrofuran, dimethyl

formamide, dimethyl sulfoxide and n-methyl pyrrolidone.
Some are soluble in methylethylketone (MEK), acetone,
methanol and other solvents commonly used in applying
coatings to conventional implantable medical devices.
Conventional polyfluoro homopolymers are crystalline
and difficult to apply as high quality films onto metal
surfaces without exposing the coatings to relatively high
temperatures that correspond to the melting temperature
(Tm) of the polymer. The elevated temperature serves to
provide films prepared from such PVDF homopolymer coatings
that exhibit sufficient adhesion of the film to the
device, while preferably maintaining sufficient
flexability to resist film cracking upon
expansion/contraction of the coated medical device.
Certain films and coatings according to the present
invention provide these same physical and mechanical
properties, or essentially the same properties, even when
the maximum temperatures to which the coatings and films
are exposed is less than about 100°C, and preferably less
than about 65°C. This is particularly important when the
coatings/films comprise pharmaceutical or therapeutic
agents or drugs that are heat sensitive, e.g. subject to
chemical or physical degradation or other heat-induced
negative affects, or when coating heat sensitive
substrates of medical devices, e.g. subject to heat-
induced compositional or structural degradation.
Depending on the particular device upon which the
coatings and films of the present invention are to be
applied and the particular use/result required of the
device, polyfluoro copolymers used to prepare such devices
may be crystalline, semi-crystalline or amorphous.
Where devices have no restrictions or limitations
with respect to exposure of same to elevated temperatures,

e.g. 100°C or higher, crystalline polyfluoro copolymers
may be employed. Crystalline polyfluoro copolymers tend to
resist the tendency to flow under applied stress or
gravity when exposed to temperatures above their glass
transition (Tg) temperatures. Crystalline polyfluoro
copolymers provide tougher coatings and films than their
fully amorphous counterparts. In addition, crystalline
polymers are more lubricious and more easily handled
through crimping and transfer processes used to mount
self-expanding stents, e.g. nitinol stents.
Semi-crystalline and amorphous polyfluoro copolymers
are advantageous where exposure to elevated temperatures
is an issue, e.g. where heat-sensitive pharmaceutical or
therapeutic agents are incorporated into the coatings and
films, or where device design, structure and/or use
preclude exposure to such elevated temperatures. Semi-
crystalline polyfluoro copolymer elastomers comprising
relatively high levels, e.g. from about 3 0 to about 45
weight percent of the second moiety, e.g. HFP,
copolymerized with the first moiety, e.g. VDF, have the
advantage of reduced coefficient of friction and self-
blocking relative to amorphous polyfluoro copolymer
elastomers. Such characteristics can be of significant
value when processing, packaging and delivering medical
devices coated with such polyfluoro copolymers. In
addition, such polyfluoro copolymer elastomers comprising
such relatively high content of the second moiety serves
to control the solubility of certain agents, e.g.
Sirolimus, in the polymer and therefore controls
permeability of the agent through the matrix.
Polyfluoro copolymers utilized in the present
inventions may be prepared by various known polymerization
methods. For example, high pressure, free-radical, semi-

continuous emulsion polymerization techniques such as
those disclosed in Fluoroelastomers-dependence of
relaxation phenomena on composition, POLYMER 3O, 2180,
1989, by Ajroldi, et al, may be employed to prepare
amorphous polyfluoro copolymers, some of which may be
elastomers. In addition, free-radical batch emulsion
polymerization techniques disclosed herein may be used to
obtain polymers that are semi-crystalline, even where
relatively high levels of the second moiety, e.g. greater
than about 19-20 mole percent (equivalent to about 36-37
weight percent), are included.
One embodiment of the invention comprises stents
coated with a film of a polyfluoro copolymer according to
the present invention. Conventional stents are used in
translumenial procedures such as angioplasty to restore
adequate blood flow to the heart and other organs. They
generally are cylindrical and perforated with passages
that are slots, ovoid, circular or the like shape. Stents
also may be composed of helically wound or serpentine wire
structures in which the spaces between the wires form
passages. Stents may be flat perforated structures that
are subsequently rolled to form tubular or cylindrical
structures that are woven, wrapped, drilled, etched or cut
to form passages. Examples of stents that may be
advantageously coated by polyfluoro copolymers of the
present invention include, but are not limited to, stents
described in U.S. Patent Nos. 4,733,665; 4,800,882;
4,886,062, 5,514,154, and 6,190,403, the contents each of
which is incorporated herein in its entirety as if set
forth herein. These stents can be made of biocompatible
materials, including biostable and bioabsorbable
materials. Suitable biocompatible metals include, but are
not limited to, stainless steel, tantalum, titanium alloys
(including nitinol), and cobalt alloys (including cobalt-

chromium-nickel alloys) . Suitable nonmetallic
biocompatible materials include, but are not limited to,
polyamides, polyolefins (i.e. polypropylene, polyethylene
etc.), nonabsorbable polyesters (i.e. polyethylene
terephthalate), and bioabsorbable aliphatic polyesters
(i.e. homopolymers and copolymers of lactic acid, glycolic
acid, lactide, glycolide, para-dioxanone, trimethylene
carbonate, s-caprolactone, and blends thereof).
The film-forming biocompatible polymer coatings
generally are applied to the stent in order to reduce
local turbulence in blood flow through the stent, as well
as adverse tissue reactions. The coatings and films
formed therefrom also may be used to administer a
pharmaceutically active material to the site of the stent
placement. Generally, the amount of polymer coating to be
applied to the stent will vary depending on, among other
possible parameters, the particular polyfluoro copolymer
used to prepare the coating, the stent design and the
desired effect of the coating. Generally, the coated
stent will comprise from about 0.1 to about 15 weight
percent of the coating, preferably from about 0.4 to about
10 weight percent. The polyfluoro copolymer coatings may
be applied in one or more coating steps, depending on the
amount of polyfluoro copolymer to be applied. Different
polyfluoro copolymers may be used for different layers in
the stent coating. In fact, in certain embodiments, it is
highly advantageous to use a diluted first coating
solution comprising a polyfluoro copolymer as a primer to
promote adhesion of a subsequent polyfluoro copolymer
coating layer that may contain pharmaceutically active
materials. The individual coatings may be prepared from
different polyfluoro copolymers.

Additionally, a top coating can be applied to delay-
release of the pharmaceutical agent, or they could be used
as the matrix for the delivery of a different
pharmaceutically active material. Layering of coatings
can be used to stage release of the drug or to control
release of different agents placed in different layers.
Blends of polyfluoro copolymers also may be used to
control the release rate of different agents or to provide
desirable balance of coating properties, i.e. elasticity,
toughness, etc., and drug delivery characteristics, e.g.
release profile. Polyfluoro copolymers with different
solubilities in solvents can be used to build up different
polymer layers that may be used to deliver different drugs
or to control the release profile of a drug. For example,
polyfluoro copolymers comprising 85.5/14.5 (wt/wt) of
poly(VDF/HFP) and 60.6/39.4 (wt/wt) of poly(VDF/HFP) are
both soluble in DMAc. However, only the 60.6/39.4
poly (VDF/HFP) polyfluoro copolytner is soluble in methanol.
So, a first layer of the 85.5/14.5 poly(VDF/HFP)
polyfluoro copolymer comprising a drug could be over-
coated with a topcoat of the 60.6/3 9.4 poly(VDF/HFP)
polyfluoro copolymer made with the methanol solvent. The
top coating can be used to delay the drug deliver of the
drug contained in the first layer. Alternatively, the
second layer could contain a different drug to provide for
sequential drug delivery. Multiple layers of different
drugs could be provided by alternating layers of first one
polyfluoro copolymer, then the other. As will be readily
appreciated by those skilled in the art numerous layering
approaches can be used to provide the desired drug
delivery.
The coatings can be used to deliver therapeutic and
pharmaceutic agents such as, but not limited to:
antiproliferative/antimitotic agents including natural

products such as vinca alkaloids (i.e. vinblastine,
vincristine, and vinorelbine), paclitaxel,
epidipodophyllotoxins (i.e. etoposide, teniposide),
antibiotics (dactinomycin (actinomycin D) daunorubicin,
doxorubicin and idarubicin), anthracyclines, mitoxantrone,
bleomycins, plicamycin (mithramycin) and mitomycin,
enzymes (L-asparaginase which systemically metabolizes L-
asparagine and deprives cells which don't have the
capacity to synthesize their own asparagine);
antiproliferative/antimitotic alkylating agents such as
nitrogen mustards(mechlorethamine, cyclophosphamide and
analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and
analogs, streptozocin),trazenes - dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as
folic acid analogs (methotrexate), pyrimidine analogs
(fluorouracil, floxuridine, and cytarabine), purine
analogs and related inhibitors (mercaptopurine,
thioguanine, pentostatin and 2-
chlorodeoxyadenosine{cladribine}); platinum coordination
complexes (cisplatin, carboplatin), procarbazine,
hydroxyurea, mitotane, aminoglutethimide; hormones
(i.e.estrogen); Anticoagulants (heparin, synthetic
heparin salts and other inhibitors of thrombin);
fibrinolytic agents (such as tissue plasminogen activator,
streptokinase and urokinase), aspirin, dipyridamole,
ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory (breveldin); antiinflammatory: such as
adrenocortical steroids (cortisol, cortisone,
fludrocortisone, prednisone, prednisolone, 6α-
methylprednisolone, triamcinolone, betamethasone, and
dexamethasone), non-steroidal agents (salicylic acid

derivatives i.e. aspirin; para-aminophenol derivatives
i.e. acetominophen; Indole and indene acetic acids
(indomethacin, sulindac, and etodalac), heteroaryl acetic
acids (tolmetin, diclofenac, and ketorolac) , arylpropionic
acids (ibuprofen and derivatives), anthranilic acids
(mefenamic acid, and meclofenamic acid), enolic acids
(piroxicam, tenoxicam, phenylbutazone, and
oxyphenthatrazone), nabumetone, gold compounds (auranofin,
aurothioglucose, gold sodium thiomalate) ;
itnmunosuppressives: (cyclosporine, tacrolimus (FK-506),
sirolimus (rapamycin), azathioprine, mycophenolate
mofetil); Angiogenic agents: vascular endothelial growth
factor (VEGF), fibroblast growth factor (FGF); nitric
oxide donors; cell cycle inhibitors; mTOR inhibitors;
growth factor signal transduction knase inhibitors; anti-
sense oligonucleotide; prodrug molecules; and combinations
thereof.
Coatings may be formulated by mixing one or more
therapeutic agents with the coating polyfluoro copolymers
in a coating mixture. The therapeutic agent may be present
as a liquid, a finely divided solid, or any other
appropriate physical form. Optionally, the coating mixture
may include one or more additives, e.g., nontoxic auxiliary
substances such as diluents, carriers, excipients,
stabilizers or the like. Other suitable additives may be
formulated with the polymer and pharmaceutically active
agent or compound. For example, a hydrophilic polymer may
be added to a biocompatible hydrophobic coating to modify
the release profile, or a hydrophobic polymer may be added
to a hydrophilic coating to modify the release profile.
One example would be adding a hydrophilic polymer selected
from the group consisting of polyethylene oxide, polyvinyl
pyrrolidone, polyethylene glycol, carboxylmethyl cellulose,
and hydroxymethyl cellulose to a polyfluoro copolymer

coating to modify the release profile. Appropriate
relative amounts can be determined by monitoring the in
vitro and/or in vivo release profiles for the therapeutic
agents.
The best conditions for the coating application are
when the polyfluoro copolymer and pharmaceutic agent have
a common solvent. This provides a wet coating that is a
true solution. Less desirable, yet still, usable, are
coatings that contain the pharmaceutical agent as a solid
dispersion in a solution of the polymer in solvent. Under
the dispersion conditions, care must be taken to ensure
that the particle size of the dispersed pharmaceutical
powder, both the primary powder size and its aggregates
and agglomerates, is small enough not to cause an
irregular coating surface or to clog the slots of the
stent that need to remain essentially free of coating. In
cases where a dispersion is applied to the stent and the
smoothness of the coating film surface requires
improvement, or to be ensured that all particles of the
drug are fully encapsulated in the polymer, or in cases
where the release rate of the drug is to be slowed, a
clear (polyfluoro copolymer only) topcoat of the same
polyfluoro copolymer used to provide sustained release of
the drug or another polyfluoro copolymer that further
restricts the diffusion of the drug out of the coating can
be applied. The topcoat can be applied by dip coating with
mandrel to clear the slots, referred to herein as the dip
and wipe method. This method is disclosed in United States
Patent 6,153,252, the contents of which are incorporated
herein in their entirety. Other methods for applying the
topcoat include spin coating and spray coating. Dip
coating of the top coat can be problematic if the drug is
very soluble in the coating solvent, which swells the
polyfluoro copolymer, and the clear coating solution acts

as a zero concentration sink and redissolves previously
deposited drug. The time spent in the dip bath may need
to be limited so that the drug is not extracted out into
the drug-free bath. Drying should be rapid so that the
previously deposited drug does not completely diffuse into
the topcoat.
The amount of therapeutic agent will be dependent upon
the particular drug employed and medical condition being
treated. Typically, the amount of drug represents about
0.001% to about 70%, more typically about 0.001% to about
60%.
The quantity and type of polyfluoro copolymers
employed in the coating film containing the pharmaceutic
agent will vary depending on the release profile desired
and the amount of drug employed. The product may contain
blends of the same or different polyfluoro copolymers
having different molecular weights to provide the desired
release profile or consistency to a given formulation.
Polyfluoro copolymers may release dispersed drug by
diffusion. This can result in prolonged delivery (over,
say 1 to 2,000 hours, preferably 2 to 800 hours) of
effective amounts (say, 0.001 μg/cm2-min to 100 μg/cm2-min)
of the drug. The dosage can be tailored to the subject
being treated, the severity of the affliction, the judgment
of the prescribing physician, and the like. Individual
formulations of drugs and polyfluoro copolymers may be
tested in appropriate in vitro and in vivo models to
achieve the desired drug release profiles. For example, a
drug could be formulated with a polyfluoro copolymer, or
blend of polyfluoro copolymers, coated onto a stent and
placed in an agitated or circulating fluid system, e.g. 25%
ethanol in water. Samples of the circulating fluid could be
taken to determine the release profile (such as by HPLC, UV

analysis or use of radiotagged molecules). The release of
a pharmaceutical compound from a stent coating into the
interior wall of a lumen could be modeled in appropriate
animal system. The drug release profiles could then be
monitored by appropriate means such as, by taking samples
at specific times and assaying the samples for drug
concentration (using HPLC to detect drug concentration).
Thrombus formation can be modeled in animal models using
the 111 In-platelet imaging methods described by Hanson and
Harker, Proc. Natl. Acad. Sci. USA 85:3184-3188 (1988).
Following this or similar procedures, those skilled in the
art will be able to formulate a variety of stent coating
formulations.
While not a requirement of the present invention, the
coatings and films may be crosslinked once applied to the
medical devices. Crosslinking may be affected by any of
the known crosslinking mechanisms, such as chemical, heat
or light. In addition, crosslinking initiators and
promoters may be used where applicable and appropriate. In
those embodiments utilizing crosslinked films comprising
pharmaceutical agents, curing may affect the rate at which
the drug diffuses from the coating. Crosslinked polyfluoro
copolymers films and coatings of the present invention also
may be used without drug to modify the surface of
implantable medical devices.
Examples:
Example 1:
A poly(VDF) homopolymer (Solef 10 0 8 from Solvay
Advanced Polymers, Houston, TX, Tm about 175°C) and
polyfluoro copolymers of poly(VDF/HFP), 92/8 and 91/9
weight percent VDF/HFP, respectively, as determined by F19
NMR (eg: Solef 11010 and 11008, Solvay Advanced Polymers,
Houston, TX, Tm about 15 9°C and 160°C, respectively) were

examined as potential coatings for stents. These polymers
are soluble in solvents such as, but not limited to, DMAc,
N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-
methylpyrrolidone (NMP), tetrahydrofuran (THF) and
acetone. Polymer coatings were prepared by dissolving the
polymers in acetone, at 5 weight percent as a primer, or
by dissolving the polymer in 50/50 DMAc/acetone, at 30
weight percent as a topcoat. Coatings that were applied
to the stents by dipping and dried at 60°C in air for
several hours, followed by 60°C for 3 hours in a Hg vacuum, resulted in white foamy films. As applied,
these films adhered poorly to the stent and flaked off,
indicating they were too brittle. When stents coated in
this manner were heated above 175°C, i.e. above the
melting temperature of the polymer, a clear, adherent film
was formed. Such coatings require high temperatures, e.g.
above the melting temperature of the polymer, to achieve
high quality films.
Example 2:
A polyfluoro copolymer (Solef 21508) comprising 85.5
weight percent VDF copolymerized with 14.5 weight, percent
HFP, as determined by F19 NMR, was evaluated. This
copolymer is less crystalline than the polyfluoro
homopolymer and copolymers described in Example 1. It
also has a lower melting point reported to be about 133°C.
Once again, a coating comprising about 2 0 weight percent
of the polyfluoro copolymer was applied from a polymer
solution in 50/50 DMAc/MEK. After drying (in air) at
6 0°C for several hours, followed by 6 0°C for 3 hours in a
This eliminated the need for a high temperature heat
treatment to achieve high quality films. Coatings were

smoother and more adherent than those of Example 1. Some
coated stents that underwent expansion show some degree of
adhesion loss and "tenting" as the film pulls away from
the metal. Where necessary, modification of coatings
containing such copolymers may be made, e.g. by addition
of plasticizers or the like to the coating compositions.
Films prepared from such coatings may be used to coat
stents or other medical devices, particularly where those
devices are not susceptible to expansion to the degree of
the stents.
The coating process above was repeated, this time
with a coating comprising the 85.5/14.6 (wt/wt) (VDF/HFP)
and about thirty (3 0) weight percent of rapamycin (Wyeth-
Ayerst Laboratories, Philadelphia, PA), based on total
weight of coating solids. Clear films that would
occasionally crack or peel upon expansion of the coated
stents resulted. It is believed that inclusion of
plasticizers and the like in the coating composition will
result in coatings and films for use on stents and other
medical devices that are not susceptible to such cracking
and peeling.
Example 3:
Polyfluoro copolymers of still higher HFP content
then were examined. This series of polymers were not
semi-crystalline, but rather are marketed as elastomers.
One such copolymer is Fluorel FC-2261Q (from Dyneon, a 3M-
Hoechst Enterprise, Oakdale, MN), a 60.6/39.4 (wt/wt)
copolymer of VDF/HFP. Although this copolymer has a Tg
well below room temperature (Tg about -20°C), it is not
tacky at room temperature or even at 60°C. This polymer
has no detectable crystallinity when measured by
Differential Scanning Calorimetry (DSC) or by wide angle

X-ray diffraction. Films formed on stents as described
above were non-tacky, clear, and expanded without incident
when the stents were expanded.
The coating process above was repeated, this time
with coatings comprising the 60.6/39.4 (wt/wt)
poly(VDF/HFP) and about nine (9), thirty (30) and fifty
(50) weight percent of rapamycin , based on total weight
of coating solids, respectively. Coatings comprising about
9 and 30 weight percent rapamycin provided white,
adherent, tough films that expanded without incident on
the stent. Inclusion of 50% drug, in the same manner,
resulted in some loss of adhesion upon expansion.
Changes in the comonomer composition of the polyfluoro
copolymer also can affect the nature of the solid state
coating, once dried. For example, the semi-crystalline
copolymer, Solef 21508, containing 85.5% VDF polymerized
with 14.5% by weight HFP forms homogeneous solutions with
about 3 0% rapamycin (drug weight divided by total solids
weight, e.g. drug plus copolymer) in DMAc and 50/50
DMAc/MEK. When the film is dried (60°C/16 hours followed by
60°C/3 hours in vacuum of 10 0 mm Hg) a clear coating,
indicating a solid solution of the drug in the polymer, is
obtained. Conversely, when an amorphous copolymer, Fluorel
FC-2261Q, of poly(VDF/HFP) at 60.6/39.5 (wt/wt) forms a
similar 30% solution of rapamycin in DMAc/MEK and is
similarly dried, a white film, indicating phase separation
of the drug and the polymer, is obtained. This second drug
containing film is much slower to release the drug into an
in vitro test solution of 25% ethanol in water than is the
former clear film of crystalline Solef 21508. X-ray
analysis of both films indicates that the drug is present
in a non-crystalline form. Poor or very low solubility of
the drug in the high HFP-containing copolymer results in

slow permeation of the drug through the thin coating film.
Permeability is the product of diffusion rate of the
diffusing species (in this case the drug) through the film
(the copolymer) and the solubility of the drug in the film.
Example 4: In vitro release results of rapamycin from
coating.
Figure 1 is a plot of data for the 85.5/14.5 VDF/HFP
polyfluoro copolymer, indicating fraction of drug released
as a function of time, with no topcoat. Figure 2 is a
plot of data for the same polyfluoro copolymer over which
a topcoat has been disposed, indicating that most effect
on release rate is with a clear topcoat. As shown
therein, TC150 refers to a device comprising 150
micrograms of topcoat, TC235 refers to 23 5 micrograms of
topcoat, etc. The stents before top coating had an
average of 750 micrograms of coating containing 30%
rapamycin ( based on drug/[drug + polymer]) Figure 3 is a
plot for the 60.6/39.4 VDF/HFP polyfluoro copolymer,
indicating fraction of drug released as a function of
time, showing significant control of release rate from the
coating without the use of a topcoat. Release is
controlled by loading of drug in the film.
Example 5: in vivo stent release kinetics of rapamycin
from poly(VDF/HFP).
Nine (9) New Zealand white rabbits (2.5-3.0 kg) on a
normal diet were given aspirin 24 hours prior to surgery,
again just prior to surgery and for the remainder of the
study. At the time of surgery, animals were premedicated
with Acepromazine (0.1-0.2 mg/kg) and anesthetized with a
Ketamine/Xylazine mixture (4 0 mg/kg and 5 mg/kg,

respectively). Animals were given a single
intraprocedural dose of heparin (150 IU/kg, i.v.)
Arteriectomy of the right common carotid artery was
performed and 5 F catheter introducer (Cordis, Inc.)
placed in the vessel and anchored with ligatures. Iodine
contrast agent was injected to visualize the right common
carotid artery, brachlocephalic trunk and aortic arch. A
steerable guide wire (0.014 inch/180 cm,, Cordis, Inc.) was
inserted via the introducer and advanced sequentially into
each iliac artery to a location where the artery possesses
a diameter closest to 2 mm using the cingiographic mapping
done previously. Two stents coated with a film made from
poly(VDF/HFP) : (60.6/39.4) , with about 30% rapamycin ( based
on drug/ [drug + polymer] ) were deployed in each animal
where feasible, one in each iliac artery, using 3.0 mm
balloon and inflation to 8-10 ATM for 30 seconds followed
after a 1 minute interval by a second inflation to 8-10
ATM for 30 seconds. Follow-up angiogiraphs visualizing
both iliac arteries are obtained to confirm correct
deployment position of the stent.
At the end of procedure, the carotid artery was
ligated and the skin is closed with 3/0 vicryl suture
using a one layered interrupted closure. Animals were
given butoropanol (0.4 mg/kg, s.c.) and gentamycin (4
mg/kg, i.m.). Following recovery, the animals were
returned to their cages and allowed free access to food
and water.
Due to early deaths and surgical difficulties, 2
animals were not used in this analysis. Stented vessels
were removed from the remaining 7 animals at the following
time points: 1 vessel (1 animal) at 10 inain post implant; 6
vessels (3 animals) between 45 min and 2 h post-implant
(average, 1.2 hours); 2 vessels (2 animals) at 3 d post
implant; and 2 vessels (1 animal) at 7 d post-implant. In

one animal at 2 hours, the stent was retrieved from the
aorta rather than the iliac artery. Upon removal,
arteries were carefully trimmed at both the proximal and
distal ends of the stent. Vessels were then carefully
dissected free of the stent, flushed to remove any
residual blood, and both stent and vessel frozen
immediately, wrapped separately in foil, labeled and kept
frozen at -8 0 °C. When all samples had been collected,
vessels and stents were frozen, transported and
subsequently analyzed for rapamycin in tissue. Results
are shown in Figure 4.
Example 6: Purifying the polymer.
The Fluorel FC-2261Q copolymer was dissolved in MEK at
about 10 weight percent and was washed in a 50/50 mixture
of ethanol/water. The (ethanol/water): MEK solution ratio =
about 14:1. The polymer precipitated out and was separated
from the solvent phase by centrifugation. The polymer
again was dissolved in MEK and the washing procedure
repeated. The polymer was dried after each washing step at
60°C in a vacuum oven ( Example 7: In vivo testing of coated stents in porcine
coronary arteries.
CrossFlex® stents (available from Cordis, a Johnson &
Johnson Company) were coated with the "as received" Fluorel
FC-2261Q PVDF copolymer and with the purified polyfluoro
copolymer of example 6, using the dip and wipe approach.
The coated stents were sterilized using ethylene oxide and
a standard cycle. The coated stents and bare metal stents

(controls) were implanted in porcine coronary arteries,
where they remained for 28 days.
Angiography was performed on the pigs at implantation
and at 28 days. Angiography indicated that the control
uncoated stent exhibited about 21 percent restenosis. The
polyfluoro copolymer "as received" exhibited about 26%
restenosis (equivalent to the control) and the washed
copolymer exhibited about 12.5% restenosis.
Histology results reported neointimal area at 28 days
to be 2.89±0.2, 3.57±0.4 and 2.75+0.3, respectively, for the
bare metal control, the unpurified copolymer and the
purified copolymer.
Example 8:
Utilizing the following high pressure, free-radical
batch emulsion polymerization technique, a series of semi-
crystalline, poly(VDF/HFP) copolymer elastomers was
prepared.
The VDF and HFP monomers were premixed under pressure
in a pressure vessel. HPLC-grade water, surfactant and
initiator were mixed outside of a 2 liter Zipperclave®
reactor (Autoclave Engineers, Erie, PA) and then charged to
the reactor, which then was sealed. The premixed monomers
then were transferred under nitrogen pressure to the
reactor. While stirring, the reactor was raised to the
desired temperature and held for a predetermined period of
time. The reactor then was cooled and residual monomer
vented. The resultant polymer latex was removed from the
reactor and coagulated or crashed by adding dilute
hydrochloric acid, followed by aqueous sodium chloride.

The resulting polymer was washed extensively with water and
dried.
The polyfluoro copolymers then were compared with
respect to kinetic coefficient of friction of a film
prepared therefrom to the kinetic coefficient of friction
of a film prepared from a commercial amorphous polyfluoro
copolymer comprising 59.5 weight percent VDF copolymerized
with 40.5 weight percent HFP utilizing the following
procedure.
A 57.2 mm wide by 140.0 mm long polymer film was cast
on a 101.6 mm wide by 203.2 mm long aluminum panel (Q-
panel, anodized finish, A-48). A silicone rubber gasket
was placed on the aluminum panel and clamped using binder
clips. The mold was leveled in a fume hood using a bubble
level. Approximate 5.0 g of 10.0% polymer solution in
methyl ethyl ketone was poured into the mold slowly. The
film was dried at room temperature for 3 days followed by
3 hours at 23°C and 50% R.H. prior to testing.
The kinetic coefficient of friction of the polymer
film was measured in accordance with the method described
in ASTM D 1894 -00, "Static and Kinetic Coefficients of
Friction of Plastic Film and Sheeting", Method C. A 46.5
g Teflon block, 25.4 mm wide by 41.3 mm long by 19.1 mm
thick, with an eye screw fastened in one end was used as a
sled. The surface of the sled that contacted to the film
was polished using 500-grit sandpaper. The Teflon sled was
attached to a flexible beaded chain and pulled using an
Instron tensile tester at a rate of 150 mm/min., at 23°C
and 50% R.H. Five measurements was made on each film
sample. The thickness of the film was measured using a
digital thickness gauge. The kinetic coefficient test
results are given in Table I. The maximum kinetic

coefficient of friction of five measurements of each film
were averaged and reported.
The Differential Scanning Calorimetry (DSC) data were
obtained on the following polymers using vacuum dried
films in a TA Instruments Model 2 92 0 Modulated DSC in
standard (non-modulated) DSC mode. The samples were
quenched to -80°C and heated at 10°C/min to 275°C in
nitrogen. The data are reported as AH (J/g) for
endothermic, melting events above glass transition
temperature (Tg).

WE CLAIM:
1. An implantable medical device: comprising,
a biocompatible film effective to provide an inert surface to be in
contact with body tissue of a mammal upon implantation of said
device in said mammal, said film comprising a polyfluoro copolymer
comprising a polyfluoro copolymer comprising polymerized residue
of a first moiety selected from the group consisting of
vinylidenefluoride and tetrafluoroethylene, and polymerized residue
of a second moiety other than said first moiety and which is
copolymerized with said first moiety, thereby producing said
polyfluoro copolymer wherein the relative amounts of said
polymerized residue of said first moiety and said polymerized residue
of second moiety are effective to provide said film with properties
effective for use in coating said implantable medical device.
2. The device as claimed in claim 1, wherein said polyfluoro copolymer
comprises from about 50 to about 92 weight percent of said
polymerized residue of said first moiety copolymerized with from
about 50 to about 8 weight percent of said polymerized of said second
moiety.

3. The device as claimed in claim 1, wherein said polyfluoro copolymer
comprises from about 50 to about 85 weight percent of polymerized
residue of vinylidenefluoride copolymerized with from about 50 to
about 15 weight percent of said polymerized residue of said second
moiety.
4. The device as claimed in claim 1, wherein said copolymer comprises
from about 55 to about 65 weight percent of said polymerized residue
of said vinylidenefluoride copolymerized with from about 45 to about
35 weight percent of said polymerized residue of said second moiety.
5. The device as claimed in claim 1, wherein said second moiety is
selected from the group consisting of hexafluoropropylene,
tetrafluoroethylene, vinylidenefluoride, 1 -hydropentafluoropropylene,
perfluoro(methyl vinyl ether), chlorotrifluoroethylene,
pentafluoropropene, trifluoroethylene, hexafluoroacetone and
hexafluoroisobutylene.

6. The device as claimed in claim 4, wherein said second moiety is
hexafluoropropylene.
7. The implantable medical device as claimed in claim 1, wherein said
film further comprises effective amounts of a therapeutic and/or
pharmaceutical agent.
8. The implantable device as claimed in claim 1, wherein said polyfluoro
copolymer is effective to provide said film with properties effective
for use in coating said implantable medical device when said coated
device is subjected to a maximum temperature of less than about
100°C.
9. A biocompatible coating for use on implantable medical devices: said
coating comprising,
a polyfluoro copolymer comprising polymerized residue of a first
moiety selected from the group consisting of vinylidenefluoride and
tetrafluoroethylene, and polymerized residue of a second moiety other
than said first moiety and which is copolymerized with said first
moiety, thereby producing said polyfluoro copolymer, wherein the

relative amounts of said polymerized residue of said first moiety and
said polymerized residue of said second moiety are effective to
provide said coating with properties effective to provide said coating
with properties effective for use in coating implantable medical
devices; and
a solvent in which said polyfluoro copolymer is substantially soluble.
10.The coating as claimed in claim 9, wherein said polyfluoro copolymer
comprises from about 50 to about 92 weight percent of said
polymerized residue of said first moiety copolymerized with from
about 50 to about 8 weight percent of said polymerized of said second
moiety.
11.The coating as claimed in claim 9, wherein said polyfluoro copolymer
comprises from about 50 to about 85 weight percent of polymerized
residue of vinylidenefluoride copolymerized with from about 50 to
about 15 weight percent of said polymerized residue of said second
moiety.

12.The coating as claimed in claim 9, wherein said copolymer comprises,
from about 55 to about 65 weight percent of said polymerized residue
of said vinylidenefluoride copolymerized with from about 45 to about
35 weight percent of said polymerized residue of said second moiety.
13.The coating as claimed in claim 9, wherein said second moiety is
selected from the group consisting of hexafluoropropylene,
tetrafluoroethylene, vinylidenefluoride, 1 -hydropentafluoropropylene,
perfluoro (methyl vinyl ether), chlorotrifluoroethylene,
pentafluoropropene, trifluoroethylene, hexafluoroacetone and
hexafluoroisobutylene.
14.The coating as claimed in claim 12, wherein said second moiety is
hexafluoropropylene.
15.The coating as claimed in claim 9, further comprising effective
amounts of a therapeutic and/or pharmaceutical agent.
16.The coating as claimed in claim 9, wherein said polyfluoro copolymer
is effective to provide said film with properties effective for use in
coating said implantable medical device when said coated device is
subjected to a maximum temperature of less than about 100°C.

17. The coating as claimed in claim 9, wherein said solvent is selected
from the group consisting of dimethylacetamide, N, N-
dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone,
tetrahydrofuran, methylethylketone, methanol and acetone.
18. A film prepared from the coating as claimed in claim 9.
19. The film prepared from the coating as claimed in claim 15.
20. The film as claimed in claim 18, wherein the polyfluoro copolymer is
crosslinked.
21. The film as claimed in claim 19, wherein the polyfluoro copolymer is
crosslinked.

An implantable medical device: comprising, a biocompatible film effective
to provide an inert surface to be in contact with body tissue of a mammal
upon implantation of said device in said mammal, said film comprising a
polyfluoro copolymer comprising a polyfluoro copolymer comprising
polymerized residue of a first moiety selected from the group consisting of
vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a
second moiety other than said first moiety and which is copolymerized with
said first moiety, thereby producing said polyfluoro copolymer wherein the
relative amounts of said polymerized residue of said first moiety and said
polymerized residue of second moiety are effective to provide said film with
properties effective for use in coating said implantable medical device.

Documents:

491-KOLNP-2003-FORM 15.pdf

491-KOLNP-2003-FORM-27.pdf

491-kolnp-2003-granted-abstract.pdf

491-kolnp-2003-granted-assignment.pdf

491-kolnp-2003-granted-claims.pdf

491-kolnp-2003-granted-correspondence.pdf

491-kolnp-2003-granted-description (complete).pdf

491-kolnp-2003-granted-drawings.pdf

491-kolnp-2003-granted-examination report.pdf

491-kolnp-2003-granted-form 1.pdf

491-kolnp-2003-granted-form 18.pdf

491-kolnp-2003-granted-form 2.pdf

491-kolnp-2003-granted-form 26.pdf

491-kolnp-2003-granted-form 3.pdf

491-kolnp-2003-granted-form 5.pdf

491-kolnp-2003-granted-reply to examination report.pdf

491-kolnp-2003-granted-specification.pdf

491-kolnp-2003-granted-translated copy of priority document.pdf

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Patent Number

226771

Indian Patent Application Number

491/KOLNP/2003

PG Journal Number

52/2008

Publication Date

26-Dec-2008

Grant Date

24-Dec-2008

Date of Filing

21-Apr-2003

Name of Patentee

ETHICON, INC.

Applicant Address

US ROUTE 22, SOMERVILLE, NJ

Inventors:

#	Inventor's Name	Inventor's Address
1	LLANOS, GERARD, H.	1514 MEGAN CIRCLE, STEWARTSVILLE NJ 08886
2	NARAYANAN, PALLASSANA.	3 SWEET BRIAR COURT, BELLE MEAD, NJ 08502
3	ROLLER, MARK, B.	9 QUINCE PLACE, NORTH BRUNSWICK NJ 08902
4	SCOPELIANOS, ANGELO.	7 JOHN STEVENS ROAD, WHITEHOUSE STATION, NJ 08889

PCT International Classification Number

A61L 31/10

PCT International Application Number

PCT/US01/30389

PCT International Filing date

2001-09-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	09/675,882	2000-09-29	U.S.A.
2	09/962,292	2001-09-25	U.S.A.