Patent Application
20070254091
The present invention relates to the application of coating material to medical devices.
Coatings are often applied to implantable medical devices to increase their effectiveness or safety. These coatings may provide a number of benefits including reducing the trauma suffered during the insertion procedure, facilitating the acceptance of the medical device into the target site, or improving the effectiveness of the device.
A coating that serves as a therapeutic agent is one such way in which the coating on a medical device can improve its effectiveness. This type of coating on the medical device allows for localized delivery of therapeutic agents at the site of implantation and avoids the problems of systemic drug administration, such as producing unwanted effects on parts of the body which are not being treated, or not being able to deliver a high enough concentration of therapeutic agent to the afflicted part of the body.
Expandable stents are one specific example of medical devices that can be coated. Expandable stents are tubular structures formed in a mesh-like pattern designed to support the inner walls of a lumen, such as a blood vessel. These stents are typically positioned within a lumen and then expanded to provide internal support for the lumen. Because the stent comes into direct contact with the inner walls of the lumen, stents have been coated with various compounds and therapeutics to enhance their effectiveness. The coating on these stents may contain a drug or biologically active material which is released in a controlled fashion (including long-term or sustained release) and delivered locally to the surrounding blood vessel.
Aside from facilitating localized drug delivery, the coating on a medical device can provide other beneficial surface properties. For example, medical devices are often coated with radiopaque materials to allow for fluoroscopic visualization during placement in the body. It is also useful to coat certain devices to enhance biocompatibility or to improve surface properties such as lubricity.
For small-sized medical devices, such as a coronary artery stent, conventional spray coating methods can be inefficient. The transfer efficiency is low and much of the coating solution is lost in excessive overspraying. One way in which a coating can be applied more efficiently is to electrostatically spray the coating substance onto the device. In this method, which is also known as electrospray or electrohydrodynamic spray (and used interchangeably with electrostatic spray herein), an electrical potential difference is generated between the coating material and the target with the resulting electrostatic forces causing the coating material to atomize into fine, highly charged droplets which are then driven by the electric field lines towards the oppositely-charged target. For example, U.S. Pat. No. 6,669,980 to Hansen (filed Sep. 18, 2001), which is incorporated by reference herein, describes an electrostatic spray coating method in which a medical device is coated by electrically charged droplets that are dispensed from a nozzle. The electrostatic spray coating method described by Hansen can provide up to 60% efficiency in coating a target medical device.
However, effective electrostatic spraying usually requires a coating solution with adequate electrical conductivity. Many solvents used in the coating fluid for medical devices are organic hydrocarbon solvents such as xylene, which may not be sufficiently conductive for conventional electrostatic spray techniques. Using such low electrically conductive solutions in conventional electrostatic spray techniques can produce unsteady spray plumes with non-uniform droplet sizes, which are not suitable for the process control needed in coating medical devices.
Therefore, there is a need for an electrostatic-assisted spray coating method and apparatus for coating medical devices with coating solutions of any electrical conductivity, including those having low electrical conductivity.
The present invention is directed to an electrostatic-assisted spray coating method and apparatus that satisfies this need. In one embodiment of the invention, a method is provided for electrostatic-assisted spray coating of a medical device in which a pressure atomizer is used to atomize the coating material.
In an alternate embodiment, a method is provided for electrostatic-assisted spray coating of a medical device in which a swirl atomizer is used to atomize the coating material.
In another alternate embodiment, a method is provided for electrostatic-assisted spray coating of a medical device in which an effervescent atomizer is used to atomize the coating material.
In yet another alternate embodiment, a method is provided for electrostatic-assisted spray coating of a medical device in which a vibrating atomizer is used to atomize the coating material.
In yet another alternate embodiment, a method is provided for electrostatic-assisted spray coating of a medical device in which a rotary atomizer is used to atomize the coating material.
In another embodiment of the present invention, a system is provided for electrostatic-assisted spray coating of a medical device in which a pressure atomizer is included in the system to atomize the coating material.
In an alternate embodiment, a system is provided for electrostatic-assisted spray coating of a medical device in which a swirl atomizer is included in the system to atomize the coating material.
In another alternate embodiment, a system is provided for electrostatic-assisted spray coating of a medical device in which an effervescent atomizer is included in the system to atomize the coating material.
In yet another alternate embodiment, a system is provided for electrostatic-assisted spray coating of a medical device in which a vibrating atomizer is included in the system to atomize the coating material.
In yet another alternate embodiment, a system is provided for electrostatic-assisted spray coating of a medical device in which a rotary atomizer is included in the system to atomize the coating material.
A conventional electrostatic spray apparatus is illustrated in
However, effective atomization of coating material using electrostatic forces requires the use of a coating material of sufficient electrical conductivity. Where the conductivity of the coating material is low and electrostatic atomization of the coating material is ineffective, atomization of the coating material may be enhanced by other means. For example, U.S. patent application Ser. No. 10/774,483 (filed by Worsham et al. on Feb. 10, 2004), whose entire disclosure is incorporated by reference herein, discloses an electrostatic spray coating apparatus that uses pressurized gas to enhance atomization of the charged coating fluid as the fluid emerges from the fluid nozzle orifice.
In the present invention, the system includes any type of gas-less atomizer, such as a pressure, swirl, vibrating, or rotary atomizer as described in more detail below, in which the coating material is not entrained into jets of gas. Alternatively, as also described in more detail below, the system may include an effervescent atomizer to assist in atomization of the coating material.
One of ordinary skill in the art would appreciate that enhancing atomization by using an atomizer in association with an electrostatic sprayer will allow coating material of any electrical conductivity to be used, including those having low electrical conductivity, such as a xylene solution, which has a conductivity of less than 10−14 S/cm, or a methyl ethyl ketone (MEK) solution, which has a conductivity of less than 10−7 S/cm.
In a first embodiment of the present invention illustrated in
The target holder 56 may hold the medical device by any number of means, such as the stent holders described in U.S. patent application Ser. No. 10/198,094, whose entire disclosure is incorporated by reference herein. In addition to holding the medical device 54 in a position suitable for coating applications, the medical device holder 56 can also function as an electrode maintaining the medical device 54 at a first electrical potential. In certain embodiments, the medical device holder 56 functions as the electrode to maintain the medical device 54 at a first electrical potential while minimizing masking of the medical device 54 to allow for greater coating coverage. However, in another embodiment, the medical device 54 itself can be electrically connected at a first potential without using the holder 56 as an electrode.
In this first embodiment, the nozzle assembly 80 includes a coating material supply line 22 that supplies coating material to the nozzle body 78 and an electrode 23, which is connected to a voltage source 50 by an electrically conducting cable 24. A second electric potential is conducted to the electrode 23, which then electrically charges the coating material. The nozzle assembly 80 also includes a high pressure fluid atomizer 40 that is well known in the art. The pressure atomizer 40 has a fluid passageway 42 in communication with the fluid in the nozzle body 78 and a nozzle exit orifice 30 of very small diameter ranging from 0.001 inches to 0.015 inches. The ejection of fluid from the small orifice 30 under high pressure causes the fluid to atomize into small droplets 52. Because the droplets 52 are electrically charged, they repel each other and are driven by electrical field lines towards the oppositely charged medical device 54. One of skill in the art will appreciate that there are other designs for pressure atomizers which atomize fluid by ejecting the fluid through a small orifice under high pressure. For example, the pressure atomizer 40 can be used in conjunction with a plunger-type apparatus (not shown) that can increase the pressure of the coating material within the nozzle body 78.
One of ordinary skill in the art would understand that the necessary voltage potential difference between the electrode 23 and the medical device 54 will vary depending upon the size of the medical device 54, distance between the exit orifice 30 of the nozzle body 78 and the medical device 54, and electrical conductivity of the coating material. However, a potential difference between the electrode 23 and the medical device 54 in the range of 2,000 volts to 40,000 volts should be sufficient for efficient transfer of the coating material to the target medical device.
The nozzle body 78 may be made of an electrically conductive material such as stainless steel or an electrically insulative material. The electrically conducting cable 24 may be affixed to the electrode (or nozzle body) by an electrically conductive coupling, or by any other electrically conductive means that are well known to one of ordinary skill in the art, such as soldering, welding or securing with a fastener. Alternatively, if the nozzle body 78 is made of an electrically conductive material, the nozzle body 78 may serve as the electrode to electrically charge the coating material contained in the nozzle body 78, and no separate electrode 23 is necessary. An electrically conductive nozzle body 78 may be electrically connected via an electrically conducting cable to a voltage source 50.
The medical device 54 may have an electrically conductive primer coating (such as silver, salt, or conductive polymers) applied to it before undergoing electrostatic spraying to enhance its electrostatic attraction for low electrically conductive coating materials. This primer coating may be particularly useful in applying the method and apparatus of the present invention to non-metallic or non-conducting medical devices.
In an alternate embodiment, as illustrated in
In another alternate embodiment, as illustrated in
In yet another alternate embodiment, as illustrated in
In yet another alternate embodiment, as illustrated in
The therapeutic agent may be any pharmaceutically acceptable agent such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof; antibiotics such as gentainycin, rifampin, iminocyclin, and ciprofolxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; angiotensin converting enzyme (ACE) inhibitors; beta-blockers; bAR kinase (bARKct) inhibitors; phospholamban inhibitors; protein-bound particle drugs such as ABRAXANE™; and any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include serca-2 protein, monocyte chemoattractant proteins (“MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homdimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation.
Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin−) cells including Lin−CD34−, Lin−CD34+, Lin−cKit+, mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts+5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells.
Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
Any of the above mentioned therapeutic agents may be incorporated into a polymeric coating on the medical device or applied onto a polymeric coating on a medical device. The polymers of the polymeric coatings may be biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polystrene; polyisobutylene copolymers, styrene-isobutylene block copolymers such as styrene-isobutylene-styrene tri-block copolymers (SIBS) and other block copolymers such as styrene-ethylene/butylene-styrene (SEBS); polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polyurethanes; polycarbonates, silicones; siloxane polymers; cellulosic polymers such as cellulose acetate; polymer dispersions such as polyurethane dispersions (BAYHDROL®); squalene emulsions; and mixtures and copolymers of any of the foregoing.
Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L,-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and arylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose, and hydroxypropylmethyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the foregoing. The biodegradable polymer may also be a surface erodable polymer such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc-calcium phosphate.
Such coatings used with the present invention may be formed by any method known to one in the art. For example, an initial polymer/solvent mixture can be formed and then the therapeutic agent added to the polymer/solvent mixture. Alternatively, the polymer, solvent, and therapeutic agent can be added simultaneously to form the mixture. The polymer/solvent/therapeutic agent mixture may be a dispersion, suspension or a solution. The therapeutic agent may also be mixed with the polymer in the absence of a solvent. The therapeutic agent may be dissolved in the polymer/solvent mixture or in the polymer to be in a true solution with the mixture or polymer, dispersed into fine or micronized particles in the mixture or polymer, suspended in the mixture or polymer based on its solubility profile, or combined with micelle-forming compounds such as surfactants or adsorbed onto small carrier particles to create a suspension in the mixture or polymer. The coating may comprise multiple polymers and/or multiple therapeutic agents.
The coating is typically from about 1 to about 50 microns thick. In the case of balloon catheters, the thickness is preferably from about 1 to about 10 microns, and more preferably from about 2 to about 5 microns. Very thin polymer coatings, such as about 0.2-0.3 microns and much thicker coatings, such as more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coatings onto the medical device. Such multiple layers may contain the same or different therapeutic agents and/or the same or different polymers. Methods of choosing the type, thickness and other properties of the polymer and/or therapeutic agent to create different release kinetics are well known to one in the art.
The medical device may also contain a radio-opacifying agent within its structure to facilitate viewing the medical device during insertion and at any point while the device is implanted. Non-limiting examples of radio-opacifying agents are bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.
While the present invention has been described with reference to what are presently considered to be preferred embodiments thereof, it is to be understood that the present invention is not limited to the disclosed embodiments or constructions. On the contrary, the present invention is intended to cover various modifications and equivalent arrangements. For example, the coating material may comprise a flowable solid material, such as a powder, in lieu of a fluid, as long as the flowable solid coating material can be reliably fed through the dispensing device and accept a charge imparted by the second potential. The present invention is also suitable for use in a high speed automated medical device coating apparatus. In as much as this invention references dispensed particles, these particles can be in the form of droplets with or without entrained solids at various levels of evaporation. Furthermore, these particles can be dispensed as a solution, a suspension, an emulsion, or any type flowable material as described above.
While the various elements of the disclosed invention are described and/or shown in various combinations and configurations, which are exemplary, other combinations and configurations, including more, less or only a single embodiment, are also within the spirit and scope of the present invention.
