Patent Application
20070196451
The present invention relates to the delivery of a patch, graft, implant, therapeutic agent, or other material to a target site of an organic vessel.
The delivery of therapeutic agents to diseased muscle or other tissue is an important, often repeated, procedure in the practice of modem medicine. Therapeutic agents, including therapeutic drugs and genetic material, may be used to treat, regenerate, or otherwise affect the muscle surface or the interior of the muscle itself. Such therapy can promote revascularization and create new formation of muscle, such as the myocardium of the heart. For example, many of the treatments for a failing heart due to congestive heart failure entail the delivery of therapeutic agents, growth factors, nucleic acids, gene transfection agents, or cellular transplants, e.g. fetal cardiomyocytes, allogeneic cardiomyocytes, allogeneic or autologous myocytes, and other potentially pluripotential cells from autologous or allogeneic bone marrow or stem cells.
Current methods for delivering therapeutic agents to muscle, such as the heart muscle, entail injecting directly into the muscle a genetic cell or therapeutic drug. Delivery of therapeutic agents has been proposed or achieved using medical devices such as catheters, needle devices and various coated implantable devices such as stents. The cells and agents can be injected directly or can be formulated into gels, sealants, or microparticles for injection.
Certain areas of the body, such as between an organ and the surrounding membrane, present particular difficulties for effective implantation of a patch, implant or graft, or application of therapeutic agents, due to the restricted space involved. For example, the region between the pericardium and the myocardium of the heart is particularly space-limited and difficult to reach and treat using traditional catheters such as balloon-type catheters. The application of a patch to tissue by a balloon catheter generally requires a catheter with an expanded diameter at least equal to the width of the patch, and a catheter with a length at least equal to the length of the patch. Thus, it is difficult to place a patch of a large size in confined, space-limited locations for treatment with balloon-type catheters, and the overall efficacy of a therapy may be reduced.
Accordingly, there is a need for a system to allow placement of patches, grafts, implants and therapeutic agents in space-limited and sensitive areas. Further, there is a need for a system that allows the insertion and placement of relatively large patches, grafts and implants using small profile medical delivery devices.
The present invention relates to a system for the delivery of therapeutic agent in a confined space, wherein the system requires little space for delivery of the therapeutic agent.
In one embodiment of the present invention, a system for delivering therapeutic agent in a confined space is provided, wherein the system comprises a rolled delivery mechanism at the end of a catheter, endoscope, thorascope, or other device. A sheet comprising a patch, therapeutic agent, gel, or other device or substance may be disposed on the rolled portion, for example on one side of the rolled portion, such that the device or substance to be deposited may be rolled in place with the rolled portion of the rolled delivery mechanism, and placed on the surface of a muscle, organ, or other tissue when the rolled portion is unrolled. The rolled portion may be unrolled via fluid pressure, application of heat, mechanical means, or other methods. As the rolled delivery mechanism is unrolled, pressure from the mechanism may cause the therapeutic agent, patch, or graft to be delivered to the desired location.
In an alternative embodiment of the present invention, the rolled delivery mechanism itself may be a patch or graft that is to applied to the desired location, such that the rolled delivery mechanism, patch or graft detaches from the catheter, endoscope, thorascope or other device after the rolled delivery mechanism is unrolled. The detached rolled delivery mechanism remains at the target tissue site acting as the patch or graft after the catheter, thorascope or endoscope is removed.
In alternative embodiments of the present invention, a system for delivering therapeutic agent in a confined space is provided, wherein a rolled delivery mechanism is disposed on the end of a catheter, endoscope, thorascope, or other device, and the rolled delivery mechanism is covered by a sheath. The sheath may facilitate delivery of the rolled delivery mechanism to the targeted tissue site, and may constrain the rolled delivery mechanism. The rolled delivery mechanism may comprise a patch or other therapeutic agent to be delivered to tissue. The rolled delivery mechanism may be disposed within the sheath, such that the longitudinal axis of the rolled portion is perpendicular to the longitudinal axis of the catheter or other device. The rolled delivery mechanism may also be disposed within the sheath such that its longitudinal axis is parallel to the longitudinal axis of the catheter or other device.
In another alternative embodiment, the patch, graft, or other device to be delivered to tissue may be folded when rolled within the rolled delivery mechanism, such that when the delivery mechanism is unrolled the patch may unroll and further unfold in order to be placed in a confined region, thereby permitting a patch having a large width to be delivered to the target site.
In another alternative embodiment, the patch, graft, or other device to be delivered to tissue may comprise a metal or shape-memory material. When the delivery mechanism is unrolled, the patch may assume a pre-defined shape.
In some embodiments of the invention, a system for delivery of a therapeutic agent in a confined space is provided, wherein a rolled delivery mechanism is disposed on the end of a catheter or other device, wherein the delivery mechanism comprises a patch containing a therapeutic agent. The delivery mechanism may be unrolled, for example with fluid pressure, application of heat, mechanical means, or other methods.
In some embodiments of the invention, a delivery mechanism is provided that expands primarily in a single dimension. Other delivery methods, such as balloon-type catheters, require expansion in several dimensions and therefore cannot be used to deliver therapeutic agents to confined areas of the body, or to deliver large patches to tissue without requiring a large-sized catheter or delivery device. The present invention therefore provides a way to deliver a therapeutic agent to confined spaces such as between an organ and the surrounding membrane, and along the outside or inside surface of organs and other structures. It is therefore advantageous, for example, in the treatment of infarction, ulcers, and wounds, and as part of cancer therapies. The patch may also be used to deliver therapeutic agent, allowing therapeutic agents to be administered to the interior and the surface of a muscle or other tissue.
One of ordinary skill in the art would understand that catheter 130 may be introduced surgically or thorascopically to a treatment site (such as at the epicardial surface of the heart), or may be introduced interventionally to a treatment site (such as at the endocardial surface of the heart). One skilled in the art would appreciate that catheter 130 may be a thorascope or endoscope instead of a balloon catheter for non-interventional surgical procedures.
Referring to
Alternatively, as shown in
When delivery mechanism 100 is unrolled, a surface of sheet 150 may contact the tissue surface on which it is desired that sheet 150 be delivered. The sheet 150 may be pressed against the desired treatment site by the unrolling mechanism used to unroll delivery mechanism 100, for example due to fluid pressure or other mechanisms. The sheet 150 may be attached to the tissue. One of ordinary skill in the art would understand that there are a variety of means to attach the sheet to the tissue. For example, the sheet 150 may have an adhesive on the patch surface that contacts the tissue. In another embodiment, sheet 150 may be made from shape-memory material, such as Nitinol. When delivery mechanism 100 is unrolled and unconstrained, the memory material may allow sheet 150 to assume the desired shape. Shape-memory material allows an object to return to its initial shape by exposure to external conditions after being deformed to a different shape. For example, a shape-memory material may return to its initial shape when exposed to a minimum temperature. Such a configuration may allow sheet 150 to be given a form comprised of shape-memory material in order to fit sheet 150 to a specific treatment area. Similarly, delivery mechanism 100 may be made from shape memory material such that the material properties of the delivery mechanism will allow it to unroll. For example, in addition to the mechanisms described above to unroll the rolled delivery mechanism, the shape-memory material properties of the rolled delivery mechanism may also be used to unroll the delivery mechanism. One of ordinary skill in the art would understand, for example, that a hot fluid may be injected into a rolled delivery mechanism made from shape-memory material to unroll the delivery mechanism.
In another alternative embodiment, the sheet 150 to be delivered to tissue may be a patch or graft that is folded when rolled within the rolled delivery mechanism, such that when the delivery mechanism 100 is unrolled the patch may unroll and further unfold in order to be placed in a confined region, thereby permitting a patch having a large width to be delivered to the target site. The sheet 150 would be folded onto itself and then rolled up within the delivery mechanism 100 as the catheter 130 is advanced to the target area for delivery of the patch to the diseased muscle. Sheet 150 should be flexible enough such that the patch may stored in its folded position within the rolled delivery mechanism and catheter for delivery.
A person skilled in the pertinent art would also appreciate that the sheet or patch material may include any biostable biocompatible patch material, e.g., polypropylene meshes, metal alloy meshes, titanium metal alloy meshes, and solid metal or polymer disks of material. A patch can also be constructed of materials that have traditionally been used to patch septal defects and aneurysms of the heart, e.g. bovine or equine aldehyde fixed pericardium, polyester and polytetrafluorethylene fabrics, or expanded polytetrafluorethylene (ePTFE). Solid disks of material, e.g. a nonporous disk of plastic or polymer, may allow for attachment of the patch to the muscle surface through suturing or stapling. Nonporous solid disks can have holes used for attaching the patch. Porous disks may allow attachment of the patch with tissue adhesives.
In an alternate embodiment, the outer surface 111 of delivery mechanism 100, when unrolled, may be roughly flat or it may be rounded. The outer surface 111 may be slightly rounded in order to facilitate separation of a patch, graft, or other sheet from the outer surface 111 of the delivery mechanism at the intended treatment site. When delivery mechanism 100 is unrolled, sheet 150 may therefore be more easily removed from delivery mechanism 100. As delivery mechanism 100 is unrolled, the outer longitudinal edge of outer surface 111 may deform from substantially flat to rounded as it unrolls. This deformation may also be accomplished by other means, for example increasing fluid pressure after delivery mechanism 100 has unrolled. As delivery mechanism 100 is deformed, sheet 150 may peel off outer surface 111 and become secured to the intended delivery site.
One or more of the surfaces of sheet 150 and rolled delivery mechanism 100 may be coated with a non-adhesive material, such as Teflon®, in order to lessen bonding between the sheet 150 and the delivery mechanism 100 when rolled together, and will facilitate removal of sheet 150 from the delivery mechanism 100. To facilitate the securing of sheet 150 to a desired treatment location, the outer surface of the sheet 150 that contacts the tissue may be coated with an adhesive. Thus, in an alternate embodiment, the inner surface 110 may be coated with a non-adhesive material to prevent the outer surface of sheet 150 from adhering to the inner surface 110 when rolled together. Additionally or alternatively, outer surface 111 may also be coated with a non-adhesive material to facilitate separation of the sheet 150 from the delivery mechanism 100 once sheet 150 has been positioned and deployed at a treatment location.
A sheet 150 may further comprise a means of securing the sheet 150 to the delivery location. For example, it may comprise an adhesive applied to the outer surface of sheet 150 to adjoin the patch onto tissue. The means to secure sheet 150 may comprise a stake, barb, or other structure mounted on the outer surface of sheet 150. Such devices are described in U.S. patent application Ser. No. 10/121,618, the disclosure of which is incorporated herein by reference.
In another embodiment, delivery mechanism 100 may comprise multiple layers. For example, it may comprise two layers of shape-memory material or other material with a third layer disposed between them. The third layer may comprise, for example, a polymer, therapeutic agent, patch, graft, or other substance or device. Multiple layers may be preferred in order to adjust the flexibility, thickness, or other properties of delivery mechanism 100. In some embodiments, the first and second layers may be separable at the distal end 101 (see
In another embodiment, the rolled delivery device may itself be a patch, graft, or other device to be adjoined to tissue. The integrated rolled delivery device/patch may be detached from the catheter once it has been unrolled and placed in the desired location. Thus, delivery mechanism 100 of
As shown in
When delivery mechanism 400 is unrolled, rolled portion 401 may rotate back to its original position so that the axis around which it is rolled is perpendicular to the longitudinal axis of catheter 430. Delivery mechanism 400 may then be unrolled as previously described. The rotation of rolled portion 401 may be accomplished using the same mechanism used to deploy delivery mechanism 400, such as fluid pressure, mechanical means, or other means (such as shape-memory material characteristics).
In the operation of the system, illustrated in
Referring to
Referring to
Referring to
As will be understood by one having skill in the art, the above-referenced drawings are for illustration purposes may not be to scale. For example, delivery mechanisms 100, 400, and 600 may be relatively thicker or thinner than shown. They may extend further from the end of the catheter than shown, or not as far as shown. Similarly, other dimensions may be modified from those shown without changing the nature or uses of the device relative to the present invention.
The term “therapeutic agent” as used throughout includes one or more “therapeutic drugs” or “genetic material.” The term “therapeutic agent” used herein includes pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus (such as adenovirus, adenoassociated virus, retrovirus, lentivirus and a-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences. The therapeutics administered in accordance with the invention includes the therapeutic agent(s) and solutions thereof.
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 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 ÿ and ÿ, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor ÿ, 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 can be applied to the medical device by any known method in the art including dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition, air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.
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.
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, implants and other devices used in connection with drug-loaded polymer coatings. 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.
One of skill in the art will realize that the examples described and illustrated herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the present invention.
