Patent Grant
8173200
The present invention generally relates to the application of therapeutic agents to a medical device, such as a stent.
The positioning and deployment of medical devices within a target site of a patient is a common procedure of contemporary medicine. These devices, which may be implantable stents, chronic rhythm management leads, neuromodulation devices, implants, grafts, defibrillators, filters, catheters and other devices that may be deployed for short or sustained periods of time, may be used for many medical purposes. These can include the reinforcement of recently re-enlarged lumens, the replacement of ruptured vessels, and the treatment of disease, such as vascular disease by local pharmacotherapy, e.g., delivering therapeutic agent doses to target tissues while minimizing systemic side effects. The targeted delivery areas may include body lumens such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, and the like.
Coatings may be applied to the surfaces of these medical devices to increase their effectiveness. 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, and improving the post-procedure effectiveness of the device.
Coated medical devices may also provide for the localized delivery of therapeutic agents to target locations within the body. Such localized drug delivery avoids the problems of systemic drug administration, such as producing unwanted effects on parts of the body which are not to be treated, or not being able to deliver a high enough concentration of therapeutic agent to the afflicted part of the body. Localized drug delivery may be achieved, for example, by coating the entire outer surface of the medical device or just those portions of the medical device that directly contact the desired treatment site, such as the inner vessel wall. This drug delivery may be intended for short and/or sustained periods of time.
The present invention generally relates to the application of coating materials, including coating materials containing a therapeutic agent, to medical devices.
In accordance with certain embodiments of the present invention, an implantable medical device may be provided. This device may be expandable from an unexpanded position to an expanded position and may be carried on or supported by a delivery device such as an elongated catheter.
The medical device may be coated on one or more surfaces and this coating may contain a therapeutic agent. The therapeutic agent may be applied to or coated on the device in a selective manner such that it only covers portions of the device, has higher concentrations in some zones of the device than in others, and/or is positioned at different or selected depths of a coating of the device. Other selected deposition features may be used as well. This selective application of the therapeutic agent may be accomplished with precision dispensing devices as well as with the use of solvents.
In accordance with certain embodiments of the present invention, a method of coating an implantable medical device may include providing an implantable medical device, applying a polymer base coating to the medical device, and directing a first solution including therapeutic agent and solvent through the nozzle onto a target zone of the polymer base coating to penetrate the polymer base coating. The solution may be directed at the target zone until a predetermined concentration of the therapeutic agent can be integrated within the polymer base coating.
Also in accordance with certain embodiments of the present invention, a method of coating an implantable medical device may include providing an implantable medical device, positioning a delivery device having first, second, and third or more nozzles proximate to the medical device, applying a polymer base coating through the first nozzle to the medical device, and directing a first solution including therapeutic agent and solvent through the second nozzle onto a target zone of the polymer base coating to penetrate the polymer base coating. The solution may be directed at the target zone until a predetermined concentration of the therapeutic agent can be integrated within the polymer base coating.
Still in accordance with certain embodiments of the present invention, a method of coating a stent may comprise providing a stent having a lattice comprised of a plurality of struts, each strut having an inner surface, an outer surface, and a plurality of cut faces, applying a polymer base coating onto a target portion of the lattice portion, and directing a solution including therapeutic agent and solvent towards at least one first target zone of the polymer base coating to penetrate the polymer base coating. The solution may be directed at the first target zone until a predetermined concentration of the therapeutic agent can be integrated within the polymer base coating.
The invention may be embodied in numerous devices and through numerous methods and systems. The following detailed description, taken in conjunction with the annexed drawings, discloses examples of the invention. Other embodiments, which incorporate some, all or more of the features as taught herein, are also possible.
Referring to the drawings, which form a part of this disclosure:
a-b show the coronary stent of
a-c are enlarged cross-sectional side-views of the struts of
a shows the microinjection dispensing device of
b shows the drop-on-demand dispensing device of
a-b show coated coronary stent struts as may be employed in accordance with certain embodiments of the present invention;
a-b show enlarged views of portions of a coated lattice portion of a coronary stent coated with the device
a-b show stent struts coated with the device of
The present invention generally relates to the selective application of therapeutic agents to a medical device. This may include applying therapeutic agent to medical devices such as implantable stents, chronic rhythm management leads, neuromodulation devices, implants, grafts, defibrillators, filters, and catheters.
Certain embodiments of the present invention regard the application of therapeutic agents in at least a two-step process so that various therapeutic agent distribution patterns may be achieved independently of the medical device geometry.
For example, in a conventional coating application for a stent, a polymer, therapeutic agent, and solvent are uniformly applied at the same time over the length the stent. Consequently, in the conventional stent coating process, therapeutic agent distribution patterns may be substantially dictated by stent geometry. However, as therapeutic agent delivery and dosage become increasingly important with drug eluting stents, there is a developing need for coating processes which optimize therapeutic agent delivery irrespective of stent geometry.
To address this need for improved coating processes for medical devices, certain embodiments of the present invention may utilize at least a two-step coating process for applying therapeutic agents. In the first step, a polymer base coating can be applied. Then, in at least a second separate step, at least one therapeutic agent and solvent solution can be applied selectively over the length of the medical device utilizing a targeted delivery device (e.g., a drop-on-demand device) to achieve a desired therapeutic agent distribution pattern. It is noted, in other embodiments, the base coating may include therapeutic agent.
In addition, the solvent may be selected such that the therapeutic agent may be completely soluble and the base polymer can be partially or fully soluble. Coating process parameters (e.g., droplet size, nozzle distance, etc.) and solvent solution selection may then be used to control the depth of penetration of the therapeutic agent into the polymer base coating. The therapeutic agent distribution pattern may control the rate, duration, and dosage of therapeutic agent release.
Also in accordance with certain embodiments of the present invention, therapeutic agent may be increased in specialized regions of the medical device geometry (e.g., apices of a stent) or decreased in others (e.g., segments of a stent). Likewise, different types and combinations of therapeutic agents may be applied over the length of the medical device.
When the stent 100 is expanded, the distance between adjacent apices increases. For example, as seen in
The medical implant may be made from a variety of materials, including bio-ceramics, ceramics, plastics and metals. In addition, while the device shown in these initial figures is a stent, many other devices may be coated in accordance with the invention. For example, as stated herein above, other medical devices that may be coated include cardiac rhythm management leads, neuromodulation devices, implants, grafts, defibrillators, filters, catheters, and other devices used in connection with coating materials including therapeutic agent.
a-c are enlarged side cross-sectional views of the struts of the stent of
The struts 104 in
As also can be seen in
In these examples, the base coating 320 containing therapeutic agent A may completely dissolve within the solution including solvent and therapeutic agent A. Accordingly, therapeutic agent A can penetrate the entire thickness of base coating 320 and may be highly concentrated through the entire thickness. In contrast, the second coating 322 may only partially dissolve within the solution including solvent and therapeutic agent B. Therefore, therapeutic agent B, in these examples, may not penetrate the entire thickness of the second coating 322 and can be concentrated near the free surfaces (e.g., the sides opposite to the medical device-base coating interface or the base coating-second coating interface) of the base and second coatings 320, 322.
c shows still another example in which only therapeutic agent A is located in the base coating 320. In this example, therapeutic agent B is not provided at all in the base coating 320.
It is contemplated that in other embodiments of the invention other arrangements for base and second coatings 320, 322, as well as therapeutic agent concentrations, are possible.
The base and second coatings 320, 322 may be applied in accordance with the processes and methods of the present invention (e.g.,
a and 3c show that therapeutic agent B may be applied in a higher concentration on one end 106 of the stent than on the other end 108 of the stent. Likewise,
The coating device 426 may be connected to a processor 428 having storage media. The processor 428 may include software which determines the optimum distribution pattern, e.g., longitudinal and/or circumferential distribution of the coating solution 421 and therapeutic agent. The software may be used to avoid or create local regions of high or low drug concentration, to target steady state elution rates and/or concentration in the center of the therapeutic agent window. The software may also be used to store the characteristics of individual and/or groups of medical devices. For example, in
In
The dispensing device 426 may be connected to various machine tool components for positioning the device with respect to the target surface of a medical device. The medical device may also be connected to various machine tool components for positioning target surfaces of the device with respect to the dispensing device. For example, as shown in
In the alternative embodiment of
As seen in
The coatings 720, 721 may be applied in a variety of different ways. For instance, as seen in
As stated above, in this example, the leading nozzle 726a is applying the base coating 720. The trailing nozzle 726b is applying the coating solution 721 including therapeutic agent A and/or B. The coating solution 721, in this example, may be a therapeutic agent and solvent solution. The coating solution 721 may penetrate and dissolve the base coating 720 after being directed from the dispensing device 726. Any suitable solvent can be used, for example, suitable solvents include, but, are not limited to benzene, chloroform, dichloromethane, dimethylformamide (DMF), ethyl acetate, MEK, tetrahydroforum (THF), toluene, and xylene.
In any of the examples described, the coating parameters (e.g., nozzle distance, drying time, droplet size, etc.) and solvent selection may be varied to control depth of therapeutic agent penetration (linked to rate of release) and concentration of the therapeutic agent. Thus, the elution time and concentration of the therapeutic agent released to the localized area of the tissue may be improved. For example, the distance the nozzles 726a, b are located from the medical device and/or the time period between coating applications can be varied. Further, the size of the nozzle 726a, b orifice may be varied to change the droplet size (linked to rate of release). The coatings may be applied intermittently and/or multiple coatings may be applied in alternating fashion.
For instance, in some examples, percent solids in the therapeutic agent/solvent solution, droplet velocity (e.g., 0.5 to 6 m/s), droplet size (e.g., 15 to 40 micrometers diameter), and spacing (e.g., centered 5-80 micrometers apart) may be used to tailor the level of penetration of drug into the polymer base layer.
The solvent selection may be varied and can be selected such that the therapeutic agent can be completely soluble and the base coating 720 can be only partially soluble. The solvent selection may determine the outcome of depth of therapeutic agent penetration to control the rate, duration, and total dose of therapeutic agent released to a localized area of tissue of a patient. For example, the solvent selection may influence the penetration of coating.
As seen in
More specifically,
In another example shown in
b shows a coated strut with a conformal base coating 820 applied with the dispensing device of
a-b show enlarged views of portions (I and II of
a-b show struts 1304 that may be coated with the nozzles of
Also in these examples, it can be seen that concentration of therapeutic agent differs. In
The sequence of steps described herein may be reordered and steps may be added or removed. The steps may also be modified. Further, the steps may be repeated in continuous fashion.
While various embodiments have been described, other embodiments are plausible. It should be understood that the foregoing descriptions of various examples of the medical device and delivery devices 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 delivering therapeutic agent to a medical device.
The coating, in accordance with the certain 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, andenoassociated 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 agent 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 certain 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.
In accordance with the certain embodiments, the polymer used to coat the medical device is provided in the form of a coating on an expandable portion of a medical device. After applying the drug solution to the polymer and evaporating the volatile solvent from the polymer, the medical device is inserted into a body lumen where it is positioned to a target location. In the case of a balloon catheter, the expandable portion of the catheter is subsequently expanded to bring the drug-impregnated polymer coating into contact with the lumen wall. This enables administration of the drug to be site-specific, limiting the exposure of the rest of the body to the drug.
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 stent, 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 50 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.
The present application claims priority to U.S. provisional application Ser. No. 60/915,505 filed May 2, 2007, the disclosure of which is incorporated herein by reference in its entirety.
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