Patent Application
20070191816
The present invention relates to an apparatus and method for releasing one or more therapeutic agents from a medical device.
U.S. Pat. Nos. 5,797,898, 6,123,861, 6,491,666 and 6,537,256, to Santini Jr. et al., herein incorporated by reference in their entirety, disclose a microchip drug delivery device that provides active timed release of a drug. The microchips control both the rate and time of release of multiple chemical substances and allow for the release of a wide variety of molecules in either a continuous or pulsatile manner. A material that is impermeable to the drugs or other molecules to be delivered and the surrounding fluids is used as the substrate. Reservoirs are etched into the substrate using either chemical (wet) etching or ion beam (dry) etching techniques well known in the field of microfabrication. The molecules to be delivered are inserted into the reservoirs by injection or spin coating methods in their pure form or in a release system. The physical properties of the release system control the rate of release of the molecules. The reservoirs can contain multiple drugs or other molecules in variable dosages. The filled reservoirs can be capped with materials that either degrade or allow the molecules to diffuse passively out of the reservoir over time or materials that oxidize and dissolve upon application of an electric potential. Release from an active device can be controlled by a preprogrammed microprocessor, remote control, or by biosensors.
Microchip devices have numerous in vitro and in vivo applications. The microchip can be used in vitro to deliver small, controlled amounts of chemical reagents or other molecules to solutions or reaction mixtures at precisely controlled times and rates. Analytical chemistry and medical diagnostics are examples of fields where the microchip delivery device can be used. The microchip can be used in vivo as a drug delivery device. The microchip can be implanted into a patient, either by surgical techniques or by injection. The microchip provides delivery of drugs to animals or persons who are unable to remember or be ambulatory enough to take medication. The microchip further provides delivery of many different drugs at varying rates and at varying times of delivery.
The microchip may also be incorporated into a medical implant, such as catheters, guide wires, balloons, filters (e.g., vena cava filters), stents, stent grafts, vascular grafts, intraluminal paving systems, implants and other devices. Such medical devices are implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, and the like. Medical implants are used for a number of medical purposes, including the reinforcement of recently re-enlarged lumens, the replacement of ruptured vessels, and the treatment of disease such as vascular disease by local pharmacotherapy, i.e., delivering therapeutic drug doses to target tissues while minimizing systemic side effects.
There is a need, however, for a power source capable of powering the above-described microchips without interfering with functioning of the device. Santini Jr. et al. disclose a power source connected to the microchip device itself. However, location of the power source on the microchip device necessarily increases the size of the microchip and requires that the power source be coated or otherwise protected from the environment which the microchip is exposed. Further, location of the power source on a device, such as a medical implant, incorporating the microchip may interfere with the functioning of the medical implant, etc.
The present invention relates to a device including at least one reservoir, fillable with a material, such as a therapeutic agent, and sealed by a cover. The reservoir is openable, so as to release the material, for example, by (i) disintegration of the cover, (ii) movement of the cover to an open position, and/or (iii) a change of composition or properties of the cover allowing the material to pass therethrough. The power required to open the reservoir is provided, consistent with Faraday's law, by a current induced in a coil associated with the device by a change in magnetic flux in the area of the device.
An exemplary embodiment of the present invention includes at least one reservoir fillable with a material, such as a therapeutic agent, a cover configured to seal the at least one reservoir in a first state and to allow the material to exit the at least one reservoir in a second state, and at least one coil. The cover is configured such that it transitions between the first and second states when the coil is exposed to a magnetic flux. The magnetic flux may have a radio frequency and may be time varying.
The cover in the second state may (i) be at least partially disintegrated, (ii) completely cover the reservoir but allow the material to pass directly through it, (iii) be shifted away from or towards the reservoir so as to unseal the reservoir, and/or (iv) be fully intact but have at least one smaller dimension than in the first state.
The coil may be connected across the cover such that a current induced in the coil by the magnetic flux passes through the cover. The current may be rectified to produce a DC current through the cover.
The device may include a substrate in which the at least one reservoir is formed.
The device may be a stent. The stent may have a coil configuration and at least a portion of the stent itself may form the coil that is used to transition the cover between the first and second states. Alternatively, the coil that is used to transition between the first and second states may be attached to a surface or a body of the stent, or wrapped around the stent.
The device may include another coil. The at least one coil and the other coil may be configured such that they each conduct a different level of current upon exposure to the same magnetic flux.
The device may include a second reservoir covered by a second cover configured to seal the second reservoir in a first state and to allow the material to exit the second reservoir in a second state. The first cover may be configured to transition between its first and second states when a first current passes through it, and the second cover may be configured to transition between its first and second states when a second current different from the first current passes through it. The second reservoir may be filled with a therapeutic agent different from the therapeutic agent in the first reservoir.
The device may include at least one switch configured to control electrical communication between the reservoir and the coil.
The device may include a controller configured to control the at least one switch, for example, made from a semi-conducting material.
The controller may have an input from another coil used to instruct the controller as to when to open and close the at least one switch.
The device may include a sleeve, for example, a polymeric sleeve, in which the least one reservoir is formed.
In an exemplary method of the present invention, the above described device may be used to control the release of a material from the device by exposing it to a magnetic flux, for example, a time varying magnetic flux.
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawing, which is given by way of illustration only and wherein:
The properties of the stent 10, e.g., number of coils, size of coils, conductivity, etc., may be specifically chosen so as to assure a predetermined level of current across the cover 16 upon exposure to a predetermined magnetic flux. For example, the stent 10 may be designed to avoid release of material 18 upon exposure to magnetic flux generally associated with noise, e.g., approximately 50 Hz. Stent 10 may also include a capacitor 15 connected across its ends, which may be used to control the resonant frequency of the stent 10. For example, the stent 10 may be tuned to 64 MHz emitted by an MRI machine and, thus, when exposed to electromagnetic radiation of this frequency will cause current to run across cover 16 and release the material 18. Conversely, the stent 10 may be designed with a resonant frequency unlike the electromagnetic frequencies emitted by an MRI machine (64 and 128 MHz) so as to avoid accidental release of material 18 by an MRI machine during a diagnostic scan.
In an exemplary method of operation, a patient having the stent 10 implanted in his or her body is exposed to a magnetic flux generated, for example, by an MRI machine. The magnetic flux may be generated, for example, by the electromagnetic radiation of radio frequency created by the MRI machine. The magnetic flux generates a current in the stent 10 thus triggering the release of the material 18, e.g., the therapeutic agent, in the reservoir 14. The therapeutic agent may be released, for example, to a vessel wall or into the blood stream of the patient. The magnetic flux may, for example, be time varying and at any frequency capable of generating a predetermined current in the stent 10.
Cover 16 may be made from any material capable of sealing the material 18 in reservoir 14 and capable of disintegrating upon exposure to a current developed in the stent 10 when the stent 10 is exposed to a predetermined magnetic flux. For example, the cover 16 may be made from a metal, such as copper, gold, silver, magnesium and/or zinc, or from a polymer. The cover 16 may also be made from an electro-activated polymer configured to change properties upon application of a current (rather than disintegrating) so as to allow the material 18 in reservoir 14 to pass directly through the cover 16. Examples of electro-activated polymers include polypyrole and Perfluorinated Ion exchange membrane metal composites (IPMC) using Nafion® film from DuPont.
In an exemplary embodiment, the substrate 12 or stent 10 may include a means for changing the temperature of material 18, such as a resistive heater or a cooler. For example, upon application of heat to the material 18, the material 18 may expand and, thereby, rupture cover 16 thus releasing material 18 from reservoir 14.
In an exemplary embodiment, the material 18 may be heated by heater 20 so as to cause diffusion of the material through cover 16 out of reservoir 14 without rupture of cover 16.
In an exemplary embodiment, the substrate 12 may be made from a piezoelectric material. Upon application of a current across the substrate 12, the substrate 12 may expand, for example, along the longitudinal axis of a stent strut, thereby pulling or tearing open the cover 16, which does not expand as a result of the generated current. The cover 16 maintains contact with the substrate 12 along the edges of the cover 16.
In an exemplary embodiment, cover 16 itself may be made from a piezoelectric material. As shown in
In an exemplary embodiment shown in
In an exemplary embodiment shown in
In an exemplary embodiment, the reservoir 14 may be embedded directly in a stent as opposed to in a substrate connected to the stent.
In an exemplary embodiment, rather than using or in addition to using the stent body as a current generating coil, one or more coils may be connected to or adhered to the stent. For example, as shown in
As shown in
In an exemplary embodiment, the release of material 18 from reservoir 14 may be further controlled by one or more switches, for example, made from a semi-conductor material. The switches may be used to eliminate the effects of random foreign radio wave sources.
The use of switches may be expanded to control additional reservoirs. As can be seen in an exemplary embodiment shown in
Switches 26a, 26b may be used, for example, to stagger the release of the material 18 from the reservoirs 14a, 14b (not shown). A staggered release may also be accomplished by using different primary coils for generating the current used to open the covers 16a, 16b. In such a case, different magnetic fluxes may be required to open each of the covers. Further, a staggered release may be accomplished by varying the material makeup of the covers such that they each require a different level of current, for example, to disintegrate or tear. In the case of the embodiment incorporating the heater 20, as shown in
In an exemplary embodiment of the present invention, rather than or in addition to having coils 30a and 30b, the controller 28 may be configured to detect modulation, such as amplitude modulation, of the first predetermined magnetic flux. The controller 28 may further be configured to open or close switch 26a so as to open or close cover 16a upon detection of a first modulation of the first predetermined magnetic flux. Similarly, controller 28 may be configured to open or close switch 26b so as to open or close cover 16b upon detection of a second modulation of the first predetermined magnetic flux, which may be different than the first modulation.
The present invention is not limited to stents. Further, the reservoirs may be filled with materials other than therapeutic agents. The reservoirs may be embedded in or connected to any device so long as the device permits access of the reservoir to the primary coil such that current generated in the primary coil passes through the reservoir or parts adjacent the reservoir used to open and close the reservoir. Non-limiting examples of medical devices according to the present invention include catheters, guide wires, balloons, filters (e.g., vena cava filters), stents, stent grafts, vascular grafts, intraluminal paving systems, and implants. Such medical devices may be implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, cartilage, eye, bone, and the like.
As indicated above, the reservoirs 14 may include a material 18, such as a drug. Further, medical devices according the present invention may also be coated with a drug. So as not to interfere with the opening of the covers, the coating may be performed in such a was so as to coat the entire body of the medical device except for the areas occupied by the reservoirs and their respective covers, etc.
The drug optionally stored in the reservoirs may be any pharmaceutically acceptable therapeutic agents such as non-genetic therapeutic agents, biomolecules, small molecules, 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, 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 gentamycin, rifampin, minocyclin, 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 a, 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.
The coating material of the medical device may include polymers, which may be biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polystrene; polyisobutylene copolymers and styrene-isobutylene block copolymers such as styrene-isobutylene-styrene tri-block copolymers (SIBS); 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.
Any of the above mentioned therapeutic agents may be used to fill the reservoirs, incorporated into a polymeric coating on the medical device or applied onto a polymeric coating on the medical device.
The material in the reservoirs of 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 material may comprise multiple polymers and/or multiple therapeutic agents.
Solvents may also be utilized in any order. For example, an initial polymer/solvent mixture can be formed and then the drug added to the polymer/solvent mixture. Alternatively, the polymer, solvent, and drug can be added simultaneously to form a mixture. Furthermore, multiple types of drug, polymers, and/or solvents may be utilized.
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.
The foregoing description and example have been set forth merely to illustrate the invention and are not intended as being limiting. Each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. None of the steps of the methods of the present invention are confined to any particular order of performance. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention are within the scope of the present invention.
