US 8119151 B2
The present invention is directed to methods, systems, devices, and kits for coating portions of a medical device or other work piece as well as to medical devices that have themselves been coated in accord with the invention. Under methods of the invention, portions of a medical device may be selectively coated. The method may include providing a medical device, an applicator, and a spreader. A layer of coating having a thickness may then be applied to a target surface of the medical device with the applicator. When the coating is applied, the spreader can be positioned in contact with the coating to reduce the coating thickness by spreading the coating over a larger surface area of the target surface.
1. A method for selectively coating portions of a medical device comprising:
providing a medical device, an applicator, and a spreader that is either a roller or a blade;
applying a layer of coating having a thickness to an accessible surface of the medical device with the applicator, the applied coating masking a surface area of the medical device;
positioning the spreader in contact with the applied coating; and
reducing the coating thickness from a first thickness to a second thickness by spreading the coating over a surface area of the target surface larger than the surface area masked when the coating is first applied.
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19. A method for coating an outer surface of a stent comprising:
providing a stent including a strut having an outer surface with a width;
providing an applicator; providing a spreader;
applying a bead of coating including a therapeutic agent, the coating having a thickness and covering a portion of the outer surface of the strut;
spreading the applied coating with the spreader, the spreader reducing the thickness of the applied coating during spreading, and spreading the coating over a larger portion of the outer surface of the strut during spreading, wherein the spreader is sized to have about the same width as the width of the outer surface of the strut.
The present application claims priority to U.S. provisional application Ser. No. 60/912,939, filed Apr. 20, 2007, the disclosure of which is incorporated herein by reference in its entirety.
The present invention generally relates to methods for selectively coating medical devices. More specifically, the present invention relates to medical devices, such as expandable stents, self-expanding stents, and vena-cava filters, and methods for coating these devices, wherein a coating is applied to the medical device and then spread on one or more accessible surfaces of the device.
Coating medical devices is an often repeated procedure in contemporary manufacturing. Medical devices may be coated by methods that include spray coating, dip coating and roll coating. During each of these procedures coating is applied to the medical device and is then allowed to dry or cure prior to the medical device being used for an intended purpose.
When the medical device is formed partially or completely out of lattice struts or some other open framework, each of the faces of these struts or framework may be exposed to coating during the coating methods listed above.
In some cases, when the medical device being coated is a stent, all faces of the struts that comprise the stent may be coated when using the coating systems identified above. For example, when dip coating is used, each face of the stent struts will be exposed to the coating and thereby coated. This coating will remain when the stent is removed from the dip and will dry on surfaces of the struts without further intervention. Coating may even remain in the spaces between the struts after the coating has been applied to the workpiece. This phenomenon is sometimes called “webbing.” Here, not only are the individual struts covered, but some or all of the spaces between the struts are spanned by the coating as well.
The present invention is directed to methods, systems, devices, and kits, wherein a coating is applied to an accessible surface of a medical device and then subsequently spread. The coating may be spread to other areas of the medical device not in contact with the coating when it is first applied. The coating may also be spread to reduce the thickness of the coating on the medical device and to change its coverage area. The coating may be spread for other reasons. The coating may be applied by various applicators and it may be spread by various spreaders as well. The applicators employed may include hand-held devices and computer controlled devices. Likewise, the spreaders may themselves be hand-operated and may also be more automated. The coating being applied may include a therapeutic agent and it may be applied directly to the medical device as well to a coating already present on a medical device. Portions of the coating may be dried during the coating process while other portions remain wet or not dried.
The invention may be embodied through numerous devices, systems, methods, and kits. The following detailed description, which, when taken in conjunction with the annexed drawings, discloses examples of the invention. Other embodiments, which incorporate some or all of the features as taught herein, mixing and drawing from the various descriptions, are also possible.
Referring to the drawings, which form a part of this disclosure:
The present invention regards coating one or more accessible surfaces of a medical device while not coating other surfaces of the medical device. In some embodiments this may include coating the outside or side surfaces of the medical device while not coating the inside surfaces of the medical device. In some instances this may include coating the inside surfaces of the device. By selectively coating in this fashion the amount of coating resident on the medical device may be reduced. This can be useful when the amount of coating is metered or otherwise is of interest. For example, if the medical device is a stent and the coating contains therapeutic agent a reduction in coating may allow the therapeutic agent, to be delivered in a more targeted fashion after the stent is implanted at a target site. The controlled application of therapeutic may also improve the efficiency of the process and reduce the amount of lost or wasted therapeutic.
The selective coating of a medical device may be accomplished with an applicator and spreader. An applicator may apply a layer of coating onto an accessible surface of a strut of a lattice portion of a stent. During or after the coating is the applied, a spreader, such as a roller, may be used to spread the coating on the accessible surfaces of the stent. The spreader may remove coating during this process and may also be in communication with a coating reservoir to deliver additional coating if desired. Each of the medical device, the applicator, and the spreader may be movable relative to each other to facilitate the coating of one or more surfaces of the work piece.
A system for coating an accessible outer surface 104 of a strut 102 of a lattice portion of a stent in accord with the present invention is shown in
Although in the preceding examples, the applicators 106 are shown connected to a machine tool 114 component, the applicators 106 may also be hand-held.
The spreader 108 shown in
As seen in
Various dispensing process parameters may also be controlled to extend control over the thickness and position of the coating 110 placed on the medical device. For example, coating solution viscosity and the amount of pressure the spreader applies can each be varied to adjust the resulting thickness and position of coating 110, 112 resident on the medical device after it has been applied and spread.
As is evident in
Although the previous example shows a lathe, any suitable machine tool 216 may be used. A machine tool 216 may include any powered mechanical device used to fabricate or assemble components, such as metal stock. For example, a milling machine may also be used.
In accord with the embodiments of the invention, the machine tool 216 may be operated by computer numerical control (CNC). CNC refers to a computer 222 controller system which reads G-code instructions which drive the machine tool. The controller system is programmable with instructions or other retained data which may be unique to each medical device 224 to be coated and may account for the unique external pattern and precise dimensions of each medical device 224 to be coated. The controller system may also hold unique instruction sets for many different medical devices 224.
A medical device 224, such as stent in this embodiment, may be rotated by the machine tool 216 to expose different sides of the medical device 224 to the applicator 206. As described herein, the applicator 206 may also be moved in the x, y, and z directions. Consequently, through the coordinated movement of the medical device 224 and/or the applicator 206, in conjunction with the displacement of coating, all target portions of the medical device 224 may be exposed to and coated by the applicator 206.
The medical implants themselves may be self-expanding, mechanically expandable, or hybrid implants which may have both self-expanding and mechanically expandable characteristics. Mechanical or expandable medical devices may aid in traversing the narrower peripheral arteries and allow for expansion to the appropriate size/geometry when the targeted vessel lumen is reached.
Another step in a method embodying the invention may include drying the medical device during the coating process or after the coating process is complete. For example, as shown in
In the example of
In all of the embodiments described, the applicators may be positioned on or with respect to any suitable machine tool, and, may also be hand held. Furthermore, although the preceding examples illustrate various applicators, the embodiments of the present invention are not limited thereto and alternative applicators may also fall within the scope of the invention.
In this example, the plate 838 and reducing orifice 840 may move along the stent in a longitudinal direction, however, any suitable arrangement may be used. For example, the stent 824 may be moved through a stationary reducing orifice 840. As the reducing orifice 840 moves over the stent 824, the thickness of the coating 810 reduces slightly. As each portion of the stent 824 exits the reducing orifice 840, pressure is applied to the coating 810 and the coating thickness of the stent 824 may be reduced a predetermined distance. Since the target surface of the coating 810 may be held in about the same radial position relative to the reducing orifice 840, the reducing orifice 840 may eliminate irregularities that may arise when coating the target surface of the stent 824. For instance, variations forming on the target surface may be reduced.
In all of the embodiments described, the spreader may be positioned on or with respect to any suitable machine tool, and, may also be hand-held. Furthermore, although the previous examples illustrate various spreaders, the embodiments of the present invention are not limited thereto and alternative spreaders may also fall within the scope of the invention.
While various embodiments have been described, other embodiments are plausible. It should be understood that the foregoing descriptions of various examples of the applicator and spreader are not intended to be limiting, and any number of modifications, combinations, and alternatives of the examples may be employed to facilitate the effectiveness of the coating of target surfaces of a medical device.
The coating, in accord with the embodiments of the present invention, may comprise a polymeric and or therapeutic agent formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. A suitable list of drugs and/or polymer combinations is listed below. The term “therapeutic agent” as used herein includes one or more “therapeutic agents” or “drugs.” The terms “therapeutic agents” or “drugs” can be used interchangeably herein and include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), viruses (such as adenovirus, adenoassociated virus, retrovirus, lentivirus and α-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences.
Specific examples of therapeutic agents used in conjunction with the present invention include, for example, pharmaceutically active compounds, proteins, cells, oligonucleotides, ribozymes, anti-sense oligonucleotides, DNA compacting agents, gene/vector systems (i.e., any vehicle that allows for the uptake and expression of nucleic acids), nucleic acids (including, for example, recombinant nucleic acids; naked DNA, cDNA, RNA; genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector and which further may have attached peptide targeting sequences; antisense nucleic acid (RNA or DNA); and DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences (“MTS”) and herpes simplex virus-1 (“VP22”)), and viral, liposomes and cationic and anionic polymers and neutral polymers that are selected from a number of types depending on the desired application. Non-limiting examples of virus vectors or vectors derived from viral sources include adenoviral vectors, herpes simplex vectors, papilloma vectors, adeno-associated vectors, retroviral vectors, and the like. Non-limiting examples of biologically active solutes include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPACK (dextrophenylalanine proline arginine chloromethylketone); antioxidants such as probucol and retinoic acid; angiogenic and anti-angiogenic agents and factors; anti-proliferative agents such as enoxaprin, angiopeptin, rapamycin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, acetyl salicylic acid, and mesalamine; calcium entry blockers such as verapamil, diltiazem and nifedipine; antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors; antimicrobials such as triclosan, cephalosporins, aminoglycosides, and nitrofurantoin; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, Warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet factors; vascular cell growth promoters such as growth factors, growth factor receptor antagonists, transcriptional activators, and translational promoters; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; survival genes which protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; and combinations thereof. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogeneic), genetically engineered if desired to deliver proteins of interest at the insertion site. Any modifications are routinely made by one skilled in the art.
Polynucleotide sequences useful in practice of the invention include DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides can also code for therapeutic proteins or polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic proteins and polypeptides include as a primary example, those proteins or polypeptides that can compensate for defective or deficient species in an animal, or those that act through toxic effects to limit or remove harmful cells from the body. In addition, the polypeptides or proteins that can be injected, or whose DNA can be incorporated, include without limitation, angiogenic factors and other molecules competent to induce angiogenesis, including acidic and basic fibroblast growth factors, vascular endothelial growth factor, hif-1, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor and insulin like growth factor; growth factors; cell cycle inhibitors including CDK inhibitors; anti-restenosis agents, including p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation, including agents for treating malignancies; and combinations thereof. Still other useful factors, which can be provided as polypeptides or as DNA encoding these polypeptides, include monocyte chemoattractant protein (“MCP-1”), and the family of bone morphogenic proteins (“BMPs”). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferred BMPs are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively or, in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedgehog” proteins, or the DNAs encoding them.
As stated above, coatings used with the exemplary embodiments of the present invention may comprise a polymeric material/drug agent matrix formed, for example, by admixing a drug agent with a liquid polymer, in the absence of a solvent, to form a liquid polymer/drug agent mixture. Curing of the mixture typically occurs in-situ. To facilitate curing, a cross-linking or curing agent may be added to the mixture prior to application thereof. Addition of the cross-linking or curing agent to the polymer/drug agent liquid mixture must not occur too far in advance of the application of the mixture in order to avoid over-curing of the mixture prior to application thereof. Curing may also occur in-situ by exposing the polymer/drug agent mixture, after application to the luminal surface, to radiation such as ultraviolet radiation or laser light, heat, or by contact with metabolic fluids such as water at the site where the mixture has been applied to the luminal surface. In coating systems employed in conjunction with the present invention, the polymeric material may be either bioabsorbable or biostable. Any of the polymers described herein that may be formulated as a liquid may be used to form the polymer/drug agent mixture.
The polymer used in the exemplary embodiments of the present invention is preferably capable of absorbing a substantial amount of drug solution. When applied as a coating on a medical device in accordance with the present invention, the dry polymer is typically on the order of from about 1 to about 50 microns thick. In the case of a balloon catheter, the thickness is preferably about 1 to 10 microns thick, and more preferably about 2 to 5 microns. Very thin polymer coatings, e.g., of about 0.2-0.3 microns and much thicker coatings, e.g., more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coating onto a medical device. Such multiple layers are of the same or different polymer materials.
The polymer of the present invention may be hydrophilic or hydrophobic, and may be selected from the group consisting of polycarboxylic acids, cellulosic polymers, including cellulose acetate and cellulose nitrate, gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydrides including maleic anhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinyl aromatics, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters including polyethylene terephthalate, polyacrylamides, polyethers, polyether sulfone, polycarbonate, polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene, halogenated polyalkylenes including polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins, polypeptides, silicones, siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate and blends and copolymers thereof as well as other biodegradable, bioabsorbable and biostable polymers and copolymers.
Coatings from polymer dispersions such as polyurethane dispersions (BAYHYDROL®, etc.) and acrylic latex dispersions are also within the scope of the present invention. The polymer may be a protein polymer, fibrin, collagen and derivatives thereof, polysaccharides such as celluloses, starches, dextrans, alginates and derivatives of these polysaccharides, an extracellular matrix component, hyaluronic acid, or another biologic agent or a suitable mixture of any of these, for example. In one embodiment of the invention, the preferred polymer is polyacrylic acid, available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205, the disclosure of which is hereby incorporated herein by reference. U.S. Pat. No. 5,091,205 describes medical devices coated with one or more polyisocyanates such that the devices become instantly lubricious when exposed to body fluids. In another preferred embodiment of the invention, the polymer is a copolymer of polylactic acid and polycaprolactone.
The examples described herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the exemplary embodiments of the present invention. Moreover, while certain features of the invention may be shown on only certain embodiments or configurations, these features may be exchanged, added, and removed from and between the various embodiments or configurations while remaining within the scope of the invention. Likewise, methods described and disclosed may also be performed in various sequences, with some or all of the disclosed steps being performed in a different order than described while still remaining within the spirit and scope of the present invention.