Apparatus and methods for delivering a bolus of therapeutic material

Apparatus and method utilizing fluid to deliver a bolus of therapeutic material through a lumen to a delivery or discharge control portion of the apparatus, where the bolus may be discharged or delivered to a desired location.

BACKGROUND OF THE INVENTION

This invention relates generally to catheters, and more particularly, to a catheter for delivering a bolus of therapeutic materials to tissue to be treated.

There are many instances in which it is desirable to deliver a therapeutic material to a target location, such as directly to tissue to be treated by the therapeutic material. It is often desirable, or unavoidable, that the therapeutic material be in the form of a bolus, rather than liquid form. Known techniques for delivering liquid therapeutic materials are often not useful for delivering boluses of therapeutic materials. Moreover, many known techniques for delivering boluses of therapeutic material require complicated delivery devices or have disadvantages and limitations that render then unsuitable for some applications.

SUMMARY OF EMBODIMENTS OF THE INVENTION

The disclosed embodiments of methods and apparatuses strive to address some of the disadvantages and limitations of known techniques for delivering boluses of therapeutic materials. The described embodiments employ fluid to transport a bolus of therapeutic material through a lumen to a delivery or discharge control portion of the apparatus and optionally to discharge or deliver the bolus. In some embodiments the apparatus has a second lumen into which fluid from the first lumen is discharged in connection with transporting the bolus. In some embodiments the delivery or discharge control portion of the apparatus includes a valve or other obstruction by which the bolus is selectively retained until it is to be delivered or discharged.

DETAILED DESCRIPTION OF THE INVENTION

The various embodiments of apparatuses and methods disclosed below are for the delivery of one or more therapeutic materials. The therapeutic material can be delivered to any desired location, typically internal to a human or other body. In one embodiment, the therapeutic material is delivered into a body cavity or deposited or inserted into an organ or other tissue. Exemplary applications are delivery or implantation of therapeutic material into the myocardium or prostate.

As used herein, the terms “therapeutic agent,” “therapeutic material,” “active material,” and similar terms includes, but is not limited to, any therapeutic agent or active material, such as drugs, genetic materials, and biological materials. Suitable genetic materials include, but are not limited to, DNA or RNA, such as, without limitation, DNA/RNA encoding a useful protein, DNA/RNA intended to be inserted into a human body including viral vectors and non-viral vectors, and RNAi (RNA interfering sequences). Suitable viral vectors include, for example, adenoviruses, gutted adenoviruses, adeno-associated viruses, retroviruses, alpha viruses (Semliki Forest, Sindbis, etc.), lentiviruses, herpes simplex viruses, ex vivo modified and unmodified cells (e.g., stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytes, macrophage), replication competent viruses (e.g., ONYX-015), and hybrid vectors. Suitable non-viral vectors include, for example, artificial chromosomes and mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)) graft copolymers (e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP, SP1017 (SUPRATEK), lipids or lipoplexes, nanoparticles and microparticles with and without targeting sequences such as the protein transduction domain (PTD).

Suitable biological materials include, but are not limited to, cells, yeasts, bacteria, proteins, peptides, cytokines, and hormones. Examples of suitable peptides and proteins include growth factors (e.g., FGF, FGF-1, FGF-2, VEGF, Endothelial Mitogenic Growth Factors, and epidermal growth factors, 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), transcription factors, proteinkinases, CDK inhibitors, thymidine kinase, and bone morphogenic proteins (BMP's), such as 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 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. Cells can be of human origin (autologous or allogeneic) or from an animal source (xenogeneic), genetically engineered, if desired, to deliver proteins of interest at a desired site. The delivery media can be formulated as needed to maintain cell function and viability. Cells include, for example, whole bone marrow, bone marrow derived mono-nuclear cells, progenitor cells (e.g., endothelial progentitor cells), stem cells (e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem cells, fibroblasts, macrophage, and satellite cells.

The term “therapeutic agent” and similar terms also includes non-genetic agents, such as: anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid, amlodipine and doxazosin; anti-inflammatory agents such as glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, adriamycin and mutamycin; endostatin, angiostatin and thymidine kinase inhibitors, taxol and its analogs or derivatives; 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 antibodies, anti-platelet receptor antibodies, aspirin (aspirin is also classified as an analgesic, antipyretic and anti-inflammatory drug), dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; vascular cell growth promotors such as growth factors, Vascular Endothelial Growth Factors (VEGF, all types including VEGF-2), growth factor receptors, transcriptional activators, Insulin Growth Factor (IGF), Hepatocyte Growth Factor (HGF), and translational promotors; vascular cell growth inhibitors such as antiproliferative agents, 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, and agents which interfere with endogenous vasoactive mechanisms; anti-oxidants, such as probucol; antibiotic agents, such as penicillin, cefoxitin, oxacillin, tobranycin; angiogenic substances, such as acidic and basic fibrobrast growth factors, estrogen including estradiol (E2), estriol (E3) and 17-Beta Estradiol; and drugs for heart failure, such as digoxin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors including captopril and enalopril.

Preferred therapeutic materials include anti-proliferative drugs such as steroids, vitamins, and restenosis-inhibiting agents such as cladribine. Preferred restenosis-inhibiting agents include microtubule stabilizing agents such as Taxol, paclitaxel, paclitaxel analogues, derivatives, and mixtures thereof. For example, derivatives suitable for use in the present invention include 2′-succinyl-taxol, 2′-succinyl-taxol triethanolamine, 2′-glutaryl-taxol, 2′-glutaryl-taxol triethanolamine salt, 2′-O-ester with N-(dimethylaminoethyl)glutamine, and 2′-O-ester with N-(dimethylaminoethyl) glutamide hydrochloride salt. Other preferred therapeutic materials include nitroglycerin, nitrous oxides, antibiotics, aspirins, digitalis, and glycosides.

As described above, the present invention relates to the delivery of boluses of therapeutic material. A bolus is a non-fluid mass of one or more therapeutic materials. For example, a solid or semi-solid mass of one or more therapeutic agents. The bolus may be formed entirely of one or more therapeutic agents or may be carried, combined, or mixed with other materials. In one embodiment, the bolus is in the form of a solid pellet or plug formed in a shape compatible with delivery via the disclosed catheter lumen. For example, in some embodiments, the bolus is cylindrical, ovular or cubic. In one embodiment, the bolus is sufficiently large that it sealingly, slidably, engages the interior wall of the lumen or can be smaller. In another embodiment, the bolus is small enough such that it does not sealingly, slidably engage the interior wall of the lumen. The bolus may also include a coating or encapsulating outer layer. Such a layer can help maintain the integrity of the bolus during transport through the delivery lumen and passage through the discharge control mechanism. The layer can also inhibit attachment of the bolus to the lumen wall and subsequent distortion or smearing of the bolus along the lumen wall. An encapsulating layer could be formed of a biocompatible/biodegradable polymer material.

A generic representation of a catheter100incorporating the principles of the invention is illustrated schematically inFIG. 1. Catheter100includes a transport portion110, and can optionally include a delivery or discharge control portion160. Transport portion110uses fluid to transport one or more boluses of therapeutic material to a distal end of the catheter. Delivery or discharge control portion160controls the delivery or discharge of one or more boluses from transport portion110. Control apparatus170may be coupled to catheter100to supply fluid to and/or remove fluid from transport portion110, to monitor fluid pressure in transport portion110, and to provide any other desired catheter control functions.

A first embodiment of catheter200is illustrated schematically inFIG. 2. Transport portion210includes a catheter body220, which may be of any conventional catheter construction. Catheter body220has two internal lumens—a delivery lumen230and a fluid return lumen240. Delivery lumen230is sized to accommodate a bolus B of therapeutic material having a desired circumference or cross-sectional area. In the illustrated embodiment, the bolus B and delivery lumen230are sized and have cross-sectional shapes such that the bolus B sealingly engages the internal surface of the lumen230. Lumens230,240are fluidically coupled near the distal end of catheter body220by a connecting channel250, which may be in the form of a conduit, port, or other passage for communicating fluid between lumens230,240.

Discharge control portion260is disposed at the distal end of catheter body220, and includes a valve262disposed at the distal end of delivery lumen230. Valve262may be any suitable one-way, pressure-responsive, or other similar valve. Valve262is normally closed, and thus obstructs or closes the distal end of delivery lumen230. Valve262is also configured to open (and permit bolus B to be discharged from delivery lumen230and pass through the valve). Hence, valve262is sized to permit bolus B to pass through the valve when it is open. In this embodiment, valve262is configured to open in response to a predetermined differential between the pressure of fluid in delivery lumen230(on the lumen side of the valve) and the ambient pressure (on the opposite side of the valve).

Control apparatus270includes a first fluid source272and a second fluid source274, as well as a fluid supply line271coupling first fluid source272to the proximal end of delivery lumen230and a fluid return line273coupling second fluid source274to the proximal end of fluid return lumen240. In the illustrated embodiment, fluid sources272,274are instrumented with pressure sensors275,276to detect the pressure of fluid provided by the sources, and are automatically regulated by a control system277(which may be a programmable pressure control system) such that each source is capable of establishing and maintaining selected fluid pressures. In an alternative embodiment, the pressure is manually regulated by an operator of catheter200. The fluid sources, fluid supply lines, and control system function to circulate the fluid through the lumens and channel, which together form a fluid passage.

The operation of catheter200and control apparatus270to deliver or discharge bolus B is described below with reference to FIGS.2and3A-3C. Transport portion210is filled with fluid, so that delivery lumen230, fluid return lumen240, and connecting channel250contain fluid. In one embodiment, transport portion210is filled with fluid and one or more boluses prior to use. The fluid is preferably a liquid, such as water or saline and blood. Other bio-compatible fluids could be selected based on their density, viscosity and other properties depending on the properties of the bolus, e.g., a low-density fluid for a high-viscosity bolus, a high-density fluid for a low-viscosity bolus, etc. Blood (whole blood or plasma) may also be used as the fluid, such as in instances where the bolus is composed of a material that needs to be kept in blood or a blood-like fluid. The fluid could also be a gas, such as CO2or air, or a combination of liquids and gases. Bolus B is disposed in delivery lumen230near the proximal end of catheter200. Valve230is closed. Catheter200is introduced into the body of a subject to be treated, and the distal end is inserted into tissue to be treated with the therapeutic agent contained in bolus B (such as myocardial tissue).

First fluid source272and/or second fluid source274increases the pressure (P1) in fluid supply line271with respect to a pressure (P2) in fluid return line273. The difference between pressure P1and P2produces a pressure differential across bolus B, because fluid in delivery lumen230on the proximal side of bolus B is at pressure P1, while fluid in fluid return lumen240, connecting channel250, and delivery lumen230on the distal side of bolus B is at pressure P2. When the force produced on bolus B by the fluid pressure differential exceeds the frictional forces between the outer surface of bolus B and the inner surface of delivery lumen230, bolus B begins to move distally along delivery lumen230.

As bolus B moves along delivery lumen230, fluid on the distal side of bolus B is displaced through channel250into return lumen240and toward second fluid source273, as shown by the arrow inFIG. 3A.

As bolus B reaches the distal end of delivery lumen230, it blocks channel250(as shown inFIG. 3B), preventing or decreasing volumetric discharge of fluid from portion of delivery lumen230distal to bolus B. This will produce a detectable change in pressure P1and/or P2, and/or the rate of fluid flow into delivery lumen230and/or out of return lumen240. Control apparatus270can thus determine that bolus B is at the distal end of delivery lumen230and therefore positioned adjacent valve262.

Pressures P1and P2are both increased so that the pressure exerted by bolus B (and/or by any fluid remaining in delivery lumen230between bolus B and valve262) on valve262exceeds the opening pressure threshold for valve262. Then, as shown inFIG. 3C, bolus B passes through valve262into the tissue or body lumen or cavity external to valve262. The discharge of bolus B will quickly reduce the fluid pressure in the delivery lumen adjacent valve262, which will then close, preventing discharge of excessive fluid. In addition to producing a detectable change in pressure P1and/or P2, the discharge of bolus B may also produce a detectable change in the rate of fluid flow into delivery lumen230and/or out of return lumen240. Control apparatus270can thus determine that bolus B has been discharged and accordingly reduce pressures P1and P2.

Pressures P1and P2can be of any appropriate desired values during the operation of the catheter, and each may be higher or lower than the ambient pressure external to the catheter (provided that they need to be higher than the pressure external to valve262when discharging bolus B). Suitable pressures may be between 100-400 psi, although pressures may vary beyond this range depending on the liquid used, the dimensions of the lumen, and the properties of the bolus.

There are many possible variations on the construction of the catheter, including the geometry and arrangement of the lumens. One example of an alternative catheter300is illustrated schematically inFIGS. 4A and 4B. Catheter body320is formed with a central delivery lumen330and an annular fluid return lumen340disposed concentrically about delivery lumen330. Channels350fluidically couple lumens330,340at their distal ends. Valve362is disposed at the distal end of delivery lumen330. Operation of the catheter of this embodiment is similar to that of catheter200above.

Another alternative catheter400is illustrated schematically inFIGS. 5A-5C. In this embodiment, catheter body420is formed with delivery lumen430and fluid return lumen440arranged in parallel, and terminating at their distal end in a chamber455. Valve462is disposed at the distal end of chamber455. Chamber455is sized to accommodate bolus B therein, adjacent to valve462(as shown inFIG. 5C), preparatory to discharging bolus B. Operation of the catheter of this embodiment is similar to that of catheter200above.

Another alternative catheter400, similar to the catheter400ofFIGS. 5A-5C, is illustrated schematically inFIG. 5D. In this embodiment electrostatic charges are use to inhibit passage of bolus B down fluid return lumen440. Bolus B includes a charged outer layer470. Layer470can be positively or negatively charged. Valve462or a portion464proximate to valve462is charged oppositely to charged layer470of bolus B to attract bolus B to valve462. Fluid return lumen440may also include portions444having the same charge as charged layer470to further inhibit bolus B from traveling down fluid return lumen440.

FIGS. 6A and 6Billustrate another alternative catheter500, which employs only one lumen530for fluid delivery of the bolus. Catheter body520has an outer canula522and an inner canula524that are moveable with respect to each other. Delivery lumen530is disposed within inner canula524. The distal end525of inner canula524is sharpened, so that it can pierce tissue. Inner canula525is thus essentially a needle.

An obstruction564is disposed at, and coupled to, outer canula522. Obstruction564extends into a position blocking the distal end of delivery lumen530. Obstruction564thus controls the discharge of bolus B from delivery lumen530when the canulas522,524are positioned as shown inFIG. 6A.

When the two canulas522,524are moved into a relative position illustrated inFIG. 6Bin which inner canula524extends outwardly from outer canula522, the obstruction564is displaced away from the distal end of delivery lumen530so that it no longer prevents the discharge of the bolus B from lumen530. Relative movement of the two canulas522,524can be achieved by any number of known manual or automatic devices, such as a linear displacement transducer.

Obstruction564can be formed of any suitable resilient material so that it can be deformed or deflected out of the blocking position. Alternatively, obstruction564can be constructed from rigid material in two relatively movable portions, so that the portion blocking delivery lumen130can be displaced by moving relative to the other portion.

The operation of the delivery catheter incorporating catheter body520is similar to that of the other embodiments above, except that there is not a fluid discharge lumen. Thus, bolus B is urged through and along delivery lumen530by pressurized fluid in delivery lumen530on the proximal side of bolus B. Any fluid in delivery lumen530on the distal side of bolus B would be expelled through the distal end of delivery lumen530.

The needle and obstruction structures of this embodiment could also be used as the discharge control mechanism for the catheter ofFIG. 2, i.e. in place of valve262. This combination is illustrated schematically inFIG. 7. The transport portion includes a catheter body620with a canula624protruding from the distal end. Canula624terminates in a sharpened end625. Delivery lumen630passes through catheter body620and canula624. Catheter body620also includes a fluid return lumen640. The lumens are fluidically coupled near the distal end of catheter body620by a connecting channel or port650.

Sharpened end625and obstruction664form the discharge control portion. Obstruction664is mounted to catheter body620for movement with respect to end625. In this embodiment, a portion of obstruction664may fluidically seal the distal end of delivery lumen630to prevent discharge of fluid contained in delivery lumen630as bolus B is displaced through the lumen. Until bolus B passes port650, fluid on the distal side of bolus B can be displaced into fluid return lumen640.

Control apparatus670includes first fluid source672and second fluid source674, as well as fluid supply line671coupling first fluid source672to the proximal end of delivery lumen630and fluid return line673coupling second fluid source672to the proximal end of fluid return lumen640. As with the embodiment ofFIG. 2, the fluid sources may be instrumented with pressure sensors to detect the pressure of fluid provided by the sources, and are preferably regulated such that each source is capable of establishing and maintaining selected fluid pressures.

In operation, sharpened end625may be inserted into tissue into which bolus B is to be delivered. Bolus B can be fluidically transported through delivery lumen630by differential fluid pressures in the two lumens until it reaches port650. Obstruction664may then be moved with respect to canula624so that it is not obstructing the distal end of delivery lumen630. The pressure in both lumens can then be increased to displace bolus B through the remainder of delivery lumen630and out of the distal end thereof into the tissue.

The embodiments are described with a single bolus B disposed in the delivery lumen. The artisan will recognize that the delivery lumen may be loaded with multiple boluses. All of the boluses would be transported along the delivery lumen until the most distal bolus reaches the discharge control mechanism. The most distal bolus would delivered as described above, and then the series of boluses would be further transported through the delivery lumen until the next bolus reaches the discharge control mechanism.

Alternatively, or in addition, a supply of boluses can be coupled to the proximal end of delivery lumen to selectively or automatically introduce additional boluses into the delivery lumen.

In the embodiments disclosed above, the bolus is described as sealingly engaging the inner wall of the delivery lumen. In such cases, fluid flows through the delivery lumen only in connection with movement of the bolus (at least unless or until the bolus passes to the distal side of any port or passage fluidically coupling the delivery lumen to the fluid return lumen). Further, a pressure differential can be established across the bolus (to provide a motive force to urge the bolus through the delivery lumen) hydrostatically, i.e. without fluid flow. However, it is not necessary for the bolus to sealingly engage the delivery lumen wall. If the bolus is smaller than the delivery lumen, such that fluid can flow around the bolus, the bolus can be entrained in the fluid flow, urged along the delivery lumen by dynamic fluid pressure forces. A smaller bolus can thus be transported through the delivery lumen at least to the location of the port of passage that fluidically couples the lumens (since the fluid flow that entrains the bolus will pass through the port). The passage or passages should be sized (this is just multiple passages) to prevent the bolus from entering the fluid return lumen. The fluid flow rates and/or pressures in one or both of the two lumens should change in a detectable way when the bolus reaches the port or passage so that the control system can then adjust the pressure in the two lumens to move the bolus to and through the discharge control mechanism, as described above.

In some embodiments above, the valve of the discharge control mechanism is disclosed as opening in response to pressure. Alternatively, the valve or other mechanism by which the bolus and/or fluid is prevented from being discharged from the delivery lumen can be opened by other means, such as mechanically, electronically, or magnetically, such as in response to a control signal supplied by the control system. As a further alternative, the discharge control mechanism could include a single-use mechanism rather than a multiple-use valve. For example, a frangible diaphragm could be used. The diaphragm would rupture upon application of a predetermined pressure differential between the pressure of fluid in the delivery lumen (on the lumen side of the diaphragm) and the ambient pressure (on the opposite side of the diaphragm).