Title:  High efficiency local drug delivery

United States Patent:  6,369,039

Assignee:  Scimed Life Sytems, Inc. (Maple Grove, MN)

Filed:  December 3, 1998

A method of site-specifically delivering a therapeutic agent to a target location within a body cavity, vasculature or tissue. The method comprises the steps of providing a medical device having a substantially saturated solution of therapeutic agent associated therewith; introducing the medical device into the body cavity, vasculature or tissue; releasing a volume of the solution of therapeutic agent from the medical device at the target location at a pressure of from about 0 to about 5 atmospheres for a time of up to about 5 minutes; and withdrawing the medical device from the body cavity, vasculature or tissue. In another aspect, the present invention includes a system for delivering a therapeutic agent to a body cavity, vasculature or tissue, comprising a medical device having a substantially saturated solution of the therapeutic agent associated therewith.

DETAILED DESCRIPTION OF THE INVENTION

The present invention overcomes the deficiencies of conventional localized drug delivery techniques by providing a site-specific, minimally-invasive method of delivering therapeutic agents to tissue. The method of the present invention advantageously makes use of low delivery pressures and short delivery durations to provide for the quick and safe localized delivery of therapeutic agents to any suitable lumen, cavity, or tissue in the body such as, for example, blood vessels, heart tissue, and locations within the gastrointestinal tract and urological and gynecological systems. The terms "drug" and "therapeutic agent" are used interchangeably herein and include pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus, polymers, proteins, and the like, with or without targeting sequences.

In the localized delivery of therapeutic agents, pressure-driven convection and concentration-driven diffusion are the two predominant transport mechanisms in the target tissue. The relative importance of these mechanisms, however, has previously not been well-understood. Convective flow is defined as fluid flow through a solvent space due to a pressure difference acting across a region of tissue. Convective solute transport occurs when dissolved solutes are carried along with the fluid flow. Although small molecules are generally easily convected with the fluid flow, a sieving effect by the tissue tends to retard large molecules. In contrast to convective transport, molecular diffusion is defined as solute transport from regions of high concentration to regions of low concentration due to random molecular motions. Transport due to molecular diffusion is directly proportional to an applied concentration gradient.

The inventors have surprisingly discovered that under appropriate conditions, therapeutic agents are transported into tissue in a manner consistent with molecular diffusion. Correspondingly, the inventors have surprisingly found that variations in applied pressure during localized drug administration has no significant effect on the transport of drug agents or other therapeutic agents into target tissue. The present invention makes use of this finding by providing for drug delivery based on the principles of concentration-driven diffusion. Delivery of therapeutic agents is thus achieved by controlling the concentration of therapeutic agent at a target location, rather than relying on pressure-driven processes.

In one aspect, the present invention includes a method of site-specifically delivering a therapeutic agent to a target location within a body cavity, vasculature or tissue of a mammal. The method comprises the steps of providing a medical device having a substantially saturated solution of therapeutic agent associated therewith; introducing the medical device into the body cavity, vasculature, or tissue sought to be treated; releasing the solution of therapeutic agent from the medical device at the target location at a pressure of from about 0 to about 5 atmospheres; and withdrawing the medical device from the target location within about 5 minutes from the time of releasing the solution from the medical device.

To achieve high efficiency drug delivery by concentration-driven molecular diffusion, the therapeutic agent is incorporated into the medical device as a substantially saturated solution. As used herein, "substantially saturated solution" means that the concentration of dissolved therapeutic agent in a solvent, such as water or another physiologically acceptable carrier, is at least about 75%, preferably at least about 80%, 85%, 90%, 95% or 100% of the limit of solubility of the therapeutic agent in the solvent. Alternatively, the concentration of the therapeutic agent is limited by the concentration that results in an undesirable toxic response from a patient. The substantially saturated solution is "associated with" the medical device in that the therapeutic agent is held in a cavity(ies) of the device, such as in an infusion style catheter such as a channel balloon catheter; or the therapeutic agent is coated onto the surface of the device as a coating per se or as part of a coating; or the substantially saturated solution is held within or passes through the medical device, such as in a needle injection catheter.

The present invention is described herein with specific reference to an expandable catheter as the medical device. Other medical devices within the scope of the present invention include implantable devices such as needle injection catheters, hypodermic needles, stents, blood clot filters, vascular grafts, stent grafts, aneurysm filling coils, trans myocardial revascularization ("TMR") devices, percutaneous myocardial revascularization ("PMR") devices etc., as are known in the art.

The catheter used with the present invention is any suitable catheter such as, for example, an infusion catheter (such as a channeled balloon catheter as described in U.S. Pat. No. 5,254,089, incorporated herein by reference, transport catheter, or microporous balloon catheter), an angioplasty balloon catheter, a double balloon catheter, or an infusing sleeve catheter, as are known in the art. The therapeutic agent is applied to, or is incorporated into, the expandable portion of such catheters. For example, the therapeutic agent is included as part of a polymer coating that is applied to said expandable portions. Alternatively, the therapeutic agent is incorporated directly into the expandable portion. Alternatively, the therapeutic agent is introduced into the catheter after the catheter is positioned to the target tissue by infusing the therapeutic agent through the infusion port of an-infusion catheter.

In accordance with the present invention, once the catheter is positioned at the target location, the therapeutic agent is released at a pressure of not more than about 5 atmospheres, preferably not more than about 1 atmosphere, and more preferably, not more than about 0.1 atmosphere. The catheter is held at the target site for therapeutic agent delivery for a duration of not more than about 5 minutes, preferably not more than about 2 minutes, and more preferably not more than about 1 minute. Because the present invention makes use of concentration-driven molecular diffusion rather than pressure-driven convention for the delivery of therapeutic agents, it allows for low delivery pressures and durations not heretofore known in the art. The delivery techniques of the present invention thus minimize the risk of tissue damage, ischemia, etc., commonly associated with conventional localized delivery techniques.

With specific reference to FIG. 1, the delivery of a therapeutic agent to a target location is accomplished with the use of a medical device 100 comprising a catheter 110 having an expandable portion 120. The expandable portion 120 of the catheter 110 is optionally coated with a polymer for holding the therapeutic agent during delivery into the body. The polymer coating 130 is preferably capable of absorbing a substantial amount of drug solution. The polymer coating 130 is placed onto the expandable portion 120 by any suitable mean such as, for example, by immersion, spraying, or deposition by plasma or vapor deposition. The polymer is typically applied to a thickness of about 1 to 30 microns, 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 30 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coating onto the expandable portion 120 of catheter 110. Such multiple layers can be of the same or different polymer materials, and may perform different functions (e.g., for biocompatibility, to control drug release, etc.).

The polymer coating 130 comprises any polymeric material capable of absorbing or otherwise holding the therapeutic agent to be delivered. The polymeric material is, for example, hydrophilic, hydrophobic, and/or biodegradable, and is preferably selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyurethanes, silicones, polyorthoesters, polyanhydrides, polycarbonates, polypropylenes, polylatic acids, polyglycolic acids, polycaprolactones, polyhydroxybutyrate valerates, polyacrylamides, polyethers, and mixtures and copolymers thereof. Coatings from polymer dispersions such as polyurethane dispersions (BAYHDROL, etc.) and acrylic latex dispersions are also within the scope of the present invention. Preferred polymers include polyacrylic acid as described in U.S. Pat. No. 5,091,205, the disclosure of which is incorporated herein by reference; and aqueous coating compositions comprising an aqueous dispersion or emulsion of a polymer having organic acid functional groups and a polyfunctional crosslinking agent having functional groups capable of reacting with organic acid groups, as described in U.S. Pat. No. 5,702,754, the disclosure of which is incorporated herein by reference.

The therapeutic agent is introduced onto the expandable portion 120, or alternatively, into the polymer coating 130, by any suitable method. For example, the therapeutic agent is placed in solution, which is thereafter applied to the expandable portion 120 or polymer coating 130 by any suitable means, including dipping into the drug solution or applying the solution by pipet or spraying. In the former method, the amount of drug loading is controlled by regulating the time the polymer coating 130 is immersed in the drug solution, the extent of polymer coating cross-linking, the interactions between the polymer and drug (i.e., bonding, Van der Waals forces, charge interactions, etc.), the concentration of the drug in the solution and/or the amount of polymer coating 130. In another embodiment of the invention, the drug is incorporated directly into the polymer used in the polymer coating 130 prior to the application of the polymer as a coating onto a medical device. When the medical device used in the present invention is an infusion catheter 400, such as that shown in cross-section in FIG. 2, the substantially saturated solution of therapeutic agent (shown in FIG. 2 as 405) is not coated onto the catheter, but rather is delivered to the target tissue by infusing through the channels 410 of the infusion catheter 400.

The therapeutic agents used in the present invention include, for example, pharmaceutically active compounds, proteins, oligonucleotides, ribozymes, anti-sense genes, DNA compacting agents, gene/vector systems (i.e., anything 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 which 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 polymers that are selected from a number of types depending on the desired application. For example, biologically active solutes include anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, PPACK (dextrophenylalanine proline arginine chloromethylketone), rapamycin, probucol, and verapimil; angiogenic and anti-angiogenic agents; anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin and thymidine kinase inhibitors; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin anticodies, anti-platelet receptor antibodies, 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 endogeneus vascoactive mechanisms; survival genes which protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; and combinations thereof. These and other compounds are added to the polymer coating using similar methods and routinely tested as set forth in the specification. Any modifications are routinely made by one skilled in the art.

Polynucleotide sequences useful in practice of the invention include DNA or RNA sequences having a therapeutic effect after being taken up by a cell. Examples of therapeutic polynucleotides include anti-sense DNA and RNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA to replace defective or deficient endogenous molecules. The polynucleotides of the invention can also code for therapeutic polypeptides. A polypeptide is understood to be any translation product of a polynucleotide regardless of size, and whether glycosylated or not. Therapeutic polypeptides include as a primary example, those 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 incorporated into the polymer coating 130, or whose DNA can be incorporated, include without limitation, angiogenic factors including acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor .alpha. and .beta., platelet-derived enotheial growth factor, platelet-derived growth factor, tumor necrosis factor .alpha., hepatocyte growth factor and insulin like growth factor; growth factors; cell cycle inhibitors including CDK inhibitors; thymidine kinase ("TK") 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 monosite chemoattractant protein ("MCP-1"), and the family of bone morphogenic proteins ("BMP's"). 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 BMP's 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 DNA's encoding them.

In one exemplary embodiment of the present invention, the medical device has recombinant nucleic acid incorporated therein, wherein the recombinant nucleic acid comprises a viral vector having linked thereto an exogenous nucleic acid sequence. "Exogenous nucleic acid sequence" is used herein to mean a sequence of nucleic acids that is exogenous to the virus from which the vector is derived. The concentration of the viral vector, preferably an adenoviral vector, is at least about 10¹⁰ plaque forming units ("p.f.u.") per milliliter ("ml"), preferably at least about 10¹¹ p.f.u. per ml. Alternatively, the concentration of the viral vector is limited by the concentration that results in an undesirable immune response from a patient.

After the therapeutic agent is incorporated into the inflatable portion 120 or coating 130, the medical device 100 is introduced into the body and positioned to a target location through a body cavity or vasculature (e.g., coronary arteries, portal vein, ileofemoral vein, etc.) by torquing or other known techniques. Once the medical device 100 is positioned to a target location within the body, the expandable portion 120 is optionally expanded and the drug is released at a pressure of not more than about 5 atmospheres, preferably not more than about 1 atmosphere, and more preferably, not more than about 0.1 atmosphere. The medical device 100 is held at the target location for a duration of not more than about 5 minutes, preferably not more than about 2 minutes, and more preferably not more than about 1 minute. After delivery, the medical device 100 is removed from the body by known techniques.

In one embodiment, the medical device 100 of the present invention includes a stent 300 (FIG. 3) for placement in a body lumen. The present invention can thus be used for the dual purpose of localized drug delivery and stent placement. As known in the art, stents are tubular support structures that are implanted inside tubular organs, blood vessels or other tubular body lumens. The stent used with the present invention is of any suitable design, and is either self-expanding or balloon-expandable. The stent is made of any suitable metallic (e.g., stainless steel, nitinol, tantalum, etc.), polymeric (e.g., polyethylene terephthalate, polyacetal, polylactic acid, polyethylene oxide-polybutylene terephthalate copolymer, etc.) or biodegradable material. The stent 300 is preferably metallic and configured in a mesh design, as shown in FIG. 3. When used with the present invention, the stent 300 is placed over the expandable portion 120 of the catheter 110. The medical device 100 is thereafter delivered to a target location within the body. In this embodiment, the target location is situated within a body lumen. When the expandable portion 120 is expanded during the release of the drug agent from within the expandable portion 120 or the polymer coating 130, the stent 300 is likewise expanded. After the drug agent has been released from the expandable portion 120 or the polymer coating 130, the expandable portion 120 is compressed or deflated. The stent 300, however, remains in its expanded state within the body lumen.

Referring to the embodiment of the invention illustrated in FIG. 4, the expandable portion 120 of the catheter 110 is optionally covered by a protective sheath 210 while the medical device 100 is inserted into the body and positioned at a target location within a body lumen 200. Such a sheath is particularly advantageous in the case of long arterial transit times (i.e., to position the catheter to the target location) or when the therapeutic agent to be delivered is highly toxic. As the expandable portion 120 is positioned at a target occluded site 220, the protective sheath 210 is drawn back to expose the expandable portion 120 and thus to allow diffusion of the therapeutic agent into the target location 220. Alternatively, the sheath 210 remains stationary while the catheter 110 moves the expandable portion 120 forward into the occluded region. The sheath 210 protects the agent and coating 130, thus inhibiting premature release of the therapeutic agent.

In one embodiment, the medical device is a needle injection catheter rather than a balloon catheter. In this embodiment, the therapeutic agent is delivered to tissues atraumatically over a relatively short and clinically relevant time period, typically on the order of several seconds, by injecting a small volume (e.g., about 0.001 to about 1 ml) of a substantially saturated solution of therapeutic agent. Because the solution is substantially saturated, the concentration gradient of therapeutic agent resulting from injection drives the therapeutic agent deep into tissue by diffusion. Thus, in contrast to conventional local drug delivery techniques that make use of infusion pressure and volume to drive the drug deep into tissue, the method of the present invention achieves deep tissue penetration by a concentration driven mechanism. Consequently, the method of the present invention allows for the injection of therapeutic agent into tissues at low pressures, such as 1 atm or less, and with small volumes. One advantage of this embodiment over conventional techniques is that the low infusion pressure minimizes tissue damage, thus resulting in a potential increase in efficacy, transfection efficiency or the like.

Useful therapeutic applications to which the present invention can be applied include, without limitation, methods for treating, ameliorating, reducing and/or inhibiting any lumen or tissue injury, including those that result in denuding the interior wall of a lumen, namely its endothelial lining, including the lining of a blood vessel, urethra, lung, colon, urethra, biliary tree, esophagus, prostate, fallopian tubes, uterus, vascular graft, or the like. Such injuries result from disease, as in the case of atherosclerosis or urethal hyperplasia (strictures), and/or from mechanical injury from, for example, deployment of an endolumenal stent or a catheter-based device, including balloon angioplasty and related devices.

Vascular therapies that benefit using the methods disclosed herein include, without limitation, cardiomyopathies, cardiac and cerebral strokes, embolisms, aneurysms, atherosclerosis, and peripheral and cardiac ischemias. Delivery of genes encoding proteins competent to induce collateral blood vessel formation can be used to advantage in treating these disorders. Delivery of genes encoding proteins competent to interfere with neointimal (smooth muscle) cell proliferation also is particularly useful in treating restenosis.

Non-vascular therapies that benefit using the methods disclosed herein include urogential applications, including therapies for incontinence, kidney stones and the like. Here devices typically are implanted for a prescribed period of time and local delivery of genetic or chemical agents competent to induce an antibacterial, anti-inflammatory, or anti-encrustation effect are advantageous. In other applications, the delivery of anti-inflammatory agents, genetic or otherwise, is used to treat prostatitis, interstitial cystitis and other urogenital inflammatory disorders. Antiproliferative agents, genetic or otherwise, also can be used in endometriosis therapies. Still another application is in the delivery of anticancer agents, genetic or otherwise. The methods of the invention can be applied to therapies for bladder, prostate and uterine cancer. Similarly, delivery of agents to the interior of the lung to treat lung disorders, including cancers, cystic fibrosis and the like can be used to advantage.

The methods of the present invention can also be used to deliver diagnostic and/or imaging agents, including ultrasound contrasting agents such as perfluorocarbon. Other contrasting agents are well known to those skilled in the art. The contrasting agent is typically a microbubble encapsulated in a lipid, lipid-like or protein coat for catheter-based delivery. The microbubble further can have a tissue-targeting agent on its surface. Once delivered to the site of interest, the microbubble is burst or otherwise detected using ultrasound enhancement. The contrasting agent also can be combined with a therapeutic agent, genetic or otherwise, which then is delivered when the bubble is burst by ultrasound enhancement. Delivery to large surface areas such as lung and uterus interiors can benefit from this protocol.

Penetration enhancers are optionally used in any embodiment of the present invention. As is known in the art, penetration enhancers are substances or processes which facilitate the transport of solutes across biological membranes. When used in accordance with the present invention, penetration enhancers further increase the rate of penetration of therapeutic agents into tissues, thus allowing for more efficient drug transfer. Common classes of penetration enhancers include chelating agents such as EDTA, citric acid, salicylates, derivatives of collagen and diketones; surfactants such as SDS and polyoxyethylene-9-lauryl ether; non-surfactants such as cyclic ureas, 1-alkyl and 1-alkenylazacycloalkanone derivates; bile salts and derivates such as sodium deoxycholate, sodium, tauro-cholate, STDHF, and sodium glycodihydrofusidate; fatty acids and derivatives such as oleic acid, caprylic acid, capric acid, acylcarnitines, acylcholines, and mono and diglycerides; divalent and polyvalent cations; and enzymes such as elastase. Alternatively, a penetration enhancer used in conjunction with the present invention includes a process such as ultrasound, the application of an electric field, and/or other processes which increase the rate of penetration of therapeutic agents into tissues.

Claim 1 of 19 Claims

What is claimed is:

1. A method of site-specifically delivering a therapeutic agent to a target location within a body cavity, vasculature, or tissue of a mammal, comprising the steps of:

providing a catheter having a substantially saturated solution of therapeutic agent associated therewith, said therapeutic agent selected from the group consisting of pharmaceutically active molecules, proteins, and nucleic acids encoding an angiogenic factor,

introducing said catheter into the body cavity, vasculature, or tissue;

wherein a volume of said solution of therapeutic agent is released from said catheter at the target location at a pressure not more than about 0.1 atmospheres.

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