Method and device for enhanced composition delivery

Abstract

To provide methods and devices that provide enhanced delivery of a composition to a body region of a patient utilizing radiofrequency energy.SOLUTION: Methods and devices that provide enhanced delivery of a composition to a body region of a patient utilizing radiofrequency energy include directing a first electrode and a second electrode coupled to a radiofrequency energy source to a location proximate to the body region. Radiofrequency energy is provided in modulated pulses from the radiofrequency energy source to the body region from at least one of the first electrode and the second electrode to provide a delivery condition configured to enhance delivery of the composition. The composition is delivered proximate to the body region using a composition delivery element. Devices for enhanced composition delivery are also disclosed.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 410,685, filed October 20, 2016, the entirety of which is incorporated herein by reference.

[0002] Field The present invention relates to methods and devices for improved composition delivery. [Background technology]

[0003] background Current methods and devices for treating blockages in the body (in blood vessels or grafts) employ the use of balloon catheters or stents to deliver drugs inside the blood vessel. Drug-eluting stents offer the advantage that the device can be designed to extend the delivery of drugs for weeks or months by altering the drug elution profile, but most often leave behind a metal scaffold. Drug-coated balloons offer the advantage of leaving nothing behind, but the period during which the drug is delivered is shorter due to the fact that the blood vessel is occluded by the balloon while the drug is being delivered.

[0004] In both devices, the primary mechanism of delivery is simple diffusion of the drug into the vessel wall, subject to efflux of the drug during flow conditions. Furthermore, since simple diffusion is the primary mechanism of delivery, in both devices the drug is delivered to the surface of the vessel wall. Summary of the Invention

[0005] overview A method for enhanced delivery of a composition to a body region of a patient utilizing radio frequency energy includes directing a first electrode and a second electrode coupled to a radio frequency energy source to a location proximate to the body region. Radio frequency energy is delivered to the body region from at least one of the first electrode and the second electrode in modulated pulses from the radio frequency energy source to provide delivery conditions configured to enhance delivery of the composition. The composition is delivered proximate to the body region using a composition delivery element.

[0006] The device for enhanced delivery of a composition to a body region of a patient utilizing radio frequency energy includes a first longitudinal member having a proximal end and a distal end with at least one lumen extending between the proximal end and the distal end. A composition delivery element is disposed at the distal end of the longitudinal member. The composition delivery element has a composition coated on its outer surface. At least two electrodes are coupled to a radio frequency source and disposed within the composition delivery element. The electrodes are insulated such that the at least two electrodes can generate an electric field to enhance delivery of the composition to the body region.

[0007] The present technology provides several advantages, including providing more efficient and effective devices and methods for delivering compositions to body regions. The devices and methods of the present technology allow the composition to remain in the body region site for an extended period of time, resulting in improved treatment. In particular, the use of cavitation, shock waves, electroporation, etc., generated by radio frequency energy or other energy sources, aids in the delivery of the composition. The present technology advantageously provides an improved method for delivering drugs into the vessel wall or occlusion, such that the drug remains in the target site for a longer period of time without leaving anything behind. The sustained action of the drug in the target site may result in improved outcomes (e.g., reduced reocclusion, restenosis, or revascularization rates). [The present invention 1001] 1. A method for enhanced delivery of a composition to a body region of a patient utilizing radio frequency energy, comprising: bringing a first electrode and a second electrode coupled to a radio frequency energy source into proximity with the body region; providing radio frequency energy in modulated pulses from the radio frequency energy source from at least one of the first electrode and the second electrode to the body region to provide delivery conditions configured to enhance delivery of the composition; and delivering said composition to said body area in proximity with a composition delivery element; The method comprising: [The present invention 1002] The method of claim 10, wherein said composition is a therapeutic agent or pharmaceutical compound. [The present invention 1003] 1003. The method of claim 1002, wherein said therapeutic agent or pharmaceutical compound is a thrombolytic agent, a fibrinolytic enzyme, a thrombin inhibitor, an antiplatelet agent, an anticoagulant agent, an antirestenosis agent, or an anticancer agent. [The present invention 1004] The method of claim 1001, wherein said body region is a vessel, a graft, or a duct. [The present invention 1005] The method of claim 1004, wherein the body region includes an occlusion located therein. [The present invention 1006] The method of claim 1001, wherein said body region is a gland, an organ, or a tumor located within said body region. [The present invention 1007] The method of claim 1001, wherein the composition delivery element is a balloon, a stent, a microbubble, a rib, or a catheter. [The present invention 1008] The method of claim 1007, wherein the balloon, rib, or catheter is expandable. [The present invention 1009] The method of claim 1007, wherein said composition delivery element has a surface coated with or embedded with said composition. [The present invention 1010] The method of claim 1007, wherein said composition delivery elements are microbubbles filled with said composition. [The present invention 1011] The method of claim 1001, wherein the delivery condition is one of cavitation, microjets, shock waves, electrical stimulation, or chemical reactions. [The present invention 1012] The method of claim 1011, wherein the delivery condition is a shock wave having an instantaneous magnitude of 0.1 MPa to 20 MPa. [The present invention 1013] The method of the present invention 1011, wherein the delivery condition is at least one region of cavitation bubbles having a diameter of 1 um to 10 mm. [The present invention 1014] The method of claim 1001, wherein delivering said radiofrequency energy provides long-term delivery and embedding of said composition within said body region. [The present invention 1015] determining one or more impedance measurements based on the delivery of said radio frequency energy; and optimizing the delivery of the radiofrequency waves based on the one or more impedance measurements. The method of the present invention 1001 further comprises: [The present invention 1016] 1001. The method of claim 1001, wherein the first electrode and the second electrode have a dielectric barrier for conducting a low intensity plasma discharge. [The present invention 1017] 1001. The method of claim 1001, wherein said modulated pulse has a pulse width of about 0.05 to about 500 microseconds. [The present invention 1018] 1001. The method of claim 1001, wherein the modulated pulse has a pulse width of about 500 microseconds to 1 second. [The present invention 1019] The method of claim 1001, wherein the modulated pulse has a pulse width of less than 0.05 microseconds. [The present invention 1020] The method of claim 1001, wherein said modulated pulses of radio frequency energy are gated using an ECG or other waveform signal obtained from the body. [The present invention 1021] The method of claim 1001, wherein said modulated pulses are grouped into bursts having a burst width of 100 ms to 1 s and an interval between each burst of 1 ms to 100 ms. [The present invention 1022] The method of the present invention 1001, wherein the voltage of the high-frequency energy is 400V to 4000V. [The present invention 1023] The method of the present invention 1001, wherein the voltage of the high frequency energy is less than 400V. [The present invention 1024] The method of claim 1001, wherein the incident intensity of said high frequency energy is about 0.1 to 5 joules per square millimeter. [The present invention 1025] The method of claim 1001, further comprising delivering said radiofrequency energy until an electrical limit is reached. [The present invention 1026] The method of claim 1025, wherein said electrical limit is less than 100 ohms. [The present invention 1027] The method of claim 1001, wherein the delivery of said radiofrequency energy provides a mechanical force to enhance diffusion of said composition into said body region to enhance delivery of said composition. [The present invention 1028] The method of claim 1001, wherein the delivery of said radiofrequency energy results in vasodilation, increased cell permeability, or reversible electroporation to enhance said delivery of said composition. [The present invention 1029] The method of claim 1001, wherein said composition is delivered to said body area prior to the delivery of said radiofrequency energy. [The present invention 1030] The method of claim 1001, wherein the first electrode and the second electrode are delivered on a single longitudinal member. [The present invention 1031] The method of claim 1030, wherein the single longitudinal member is a catheter or a guidewire. [The present invention 1032] The method of claim 1001, wherein the first electrode is delivered on a first longitudinal member and the second electrode is delivered on a second longitudinal member. [The present invention 1033] The method of claim 1032, wherein said first longitudinal member and said second longitudinal member are separate, non-overlapping guidewires or catheters. [The present invention 1034] The method of claim 1032, wherein said delivering comprises delivering said first longitudinal member and said second longitudinal member to said body region in the same direction. [The present invention 1035] The method of claim 1032, wherein said delivering comprises delivering said first longitudinal member and said second longitudinal member to said body region from opposite directions. [The present invention 1036] The method of claim 1001, wherein one of the first electrode or the second electrode is disposed on a patch placed on the outside of the body region. [The present invention 1037] providing a third electrode disposed on a patch placed on the exterior of the body region, the third electrode being electrically coupled to the first electrode and the second electrode; The method of the present invention 1001 further comprises: [The present invention 1038] 1. An apparatus for enhanced delivery of a composition to a body region of a patient utilizing radio frequency energy, comprising: a first longitudinal member having a proximal end and a distal end with at least one lumen extending between the proximal end and the distal end; a composition delivery element disposed at the distal end of the longitudinal member, the composition delivery element having the composition disposed on an outer surface thereof; and at least two electrodes coupled to a radio frequency source and disposed within the composition delivery element, the at least two electrodes capable of generating an electric field to enhance delivery of the composition to the body region; The apparatus comprising: [The present invention 1039] The device of claim 1038, wherein the composition delivery element comprises a balloon. [The present invention 1040] The device of claim 1039, wherein the balloon has a porous surface. [The present invention 1041] The device of claim 1038, wherein said composition delivery element further comprises one or more raised elements configured to scratch said body area. [The present invention 1042] The device of claim 1041, wherein the raised elements are longitudinal or circumferential elements. [The present invention 1043] The device of claim 1041, wherein the raised element has a circular cross-section. [The present invention 1044] The device of claim 1041, wherein the raised element has a triangular cross-section. [The present invention 1045] The device of claim 1041, wherein said raised elements are constructed of metal or polymer. [The present invention 1046] The device of claim 1041, wherein the composition is disposed on the raised elements. [The present invention 1047] The device of claim 1038, wherein the composition delivery element comprises an expandable rib. [The present invention 1048] The device of the present invention 1038, wherein the at least two electrodes are disposed on a second longitudinal member and a third longitudinal member, respectively, and the second longitudinal member and the third longitudinal member are configured to be inserted into the lumen of the first longitudinal member. [The present invention 1049] The device of claim 1048, wherein said second longitudinal member and said third longitudinal member are guidewires. [The present invention 1050] The apparatus of claim 1049, wherein the second longitudinal member is configured to be disposed within the third longitudinal member. [The present invention 1051] The apparatus of claim 1038, wherein the at least two electrodes are disposed on a second longitudinal member configured to be inserted into the lumen of the first longitudinal member. [The present invention 1052] The device of claim 1038, wherein the at least two electrodes are balloon markers. [The present invention 1053] The apparatus of claim 1038, wherein said at least two electrodes are insulated in a manner capable of withstanding the occurrence of a plasma discharge around said at least two electrodes. [The present invention 1054] The apparatus of claim 1038, wherein said at least two electrodes are at least partially wrapped around said first longitudinal member. [The present invention 1055] The device of claim 1038, wherein the composition is a therapeutic agent or pharmaceutical compound. [The present invention 1056] The device of claim 1053, wherein said therapeutic agent or pharmaceutical compound is a thrombolytic agent, a fibrinolytic enzyme, a thrombin inhibitor, an antiplatelet agent, an anticoagulant, an antirestenotic agent, or an anticancer agent. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a schematic diagram of an exemplary device for composition delivery using radio frequency energy of the present technology. [Diagram 2] FIG. 1 is a schematic diagram of another exemplary device for composition delivery using radio frequency energy of the present technology positioned in a body area having an obstruction. [Diagram 3] FIG. 13 is a schematic diagram of a further exemplary device for composition delivery using radio frequency energy of the present technology positioned in a body area having an obstruction. [Figure 4] FIG. 4 is a schematic diagram of an alternative embodiment of an apparatus for delivering a composition shown in FIG. 3. [Diagram 5] 2 is a schematic diagram of an exemplary device for composition delivery using radiofrequency energy shown in FIG. 1, showing an exemplary connection between the electrodes and a radiofrequency energy source. [Figure 6]6 is a schematic end view of the longitudinal member of FIG. 5 with two coupled insulated electrodes. FIG. [Figure 7] FIG. 2 is a schematic diagram of an exemplary apparatus for composition delivery using another exemplary composition delivery element. [Figure 8] 13 is a schematic diagram of a configuration for securing an exemplary raised element to an exemplary composition delivery element that can be used in a composition delivery device of the present technology. [Figure 9] 9A-9C illustrate an exemplary method for enhanced composition delivery using radiofrequency energy. [Figure 10] 1 illustrates a schematic diagram of another exemplary composition delivery device comprising a composition delivery element having a porous surface. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description An exemplary composition delivery device 10 for enhanced delivery of a composition to a patient's body region utilizing radio frequency energy is shown in Figures 1 and 5. Although radio frequency energy is described, other energy modalities may be utilized, such as, for example, ultrasound or laser energy. The composition delivery device 10 includes a first longitudinal member 12 including electrodes 14(1) and 14(2), a radio frequency energy source 16, and a composition delivery element 18, although the composition delivery device 10 may include other types and / or numbers of elements, components, and / or devices in other configurations, such as additional electrodes and / or longitudinal members. This exemplary technique provides several advantages, including providing more efficient and effective composition delivery to a patient's body region.

[0010] 1 in more detail, the composition delivery device 10 includes a first longitudinal member 12 configured to be advanced into the patient's body and positioned near a body region of the patient. The body region may be various regions of the body, such as organs, body lumens or cavities, such as various ducts or ducts, blood vessels, grafts, glands, etc. In one example, the body region may be an area within the body that includes an obstruction or tumor requiring treatment. In that example, the first longitudinal member 12 includes a lumen 19 extending between a proximal end 20 and a distal end 22 of the first longitudinal member 12, although the longitudinal member 12 may include additional lumens. The lumen 19 is configured to receive additional longitudinal members, such as, by way of example only, a guidewire, a catheter, a microcatheter, or a probe.

[0011] In this example, longitudinal member 12 has electrodes 14(1) and 14(2) disposed thereon to provide a bipolar arrangement of electrodes 14(1) and 14(2), although electrodes 14(1) and 14(2) may be disposed on other elements in other configurations to provide a bipolar arrangement.

[0012] 2, composition delivery device 10 further includes a second longitudinal member 13 configured to be inserted into lumen 19 of first longitudinal member 12 and delivered adjacent to a region of a patient's body. In this example, second longitudinal member 13 is a guidewire or catheter having electrodes 14(1) and 14(2) disposed thereon to provide a bipolar configuration.

[0013] In yet another example, as shown in Figure 3, the composition delivery device 10 further includes a third longitudinal member 23 configured to be inserted into the lumen 19 of the first longitudinal member. By way of example only, the third longitudinal member 23 can be a guidewire or a catheter. The second longitudinal member 13 and the third longitudinal member 23, being separate, non-overlapping guidewires or catheters, can be delivered to a body region in the same or opposite directions as described below.

[0014] In a further example, one of electrodes 14(1) or 14(2) is disposed on a patch that can be placed on the patient's skin in close proximity to the patient's body area to be treated. The patch is placed in close proximity to the body area to allow for a bipolar arrangement between electrodes 14(1) and 14(2).

[0015] 4, in one example, the lumen 19 of the first longitudinal member 12 includes multiple lumen portions for separately delivering the second longitudinal member 13 and the third longitudinal member 23 to a body region. In yet another example, the second longitudinal member 13 can be configured to receive the third longitudinal member 23 such that the third longitudinal member 23 is disposed within the second longitudinal member 13. Referring again to FIG. 3, in this example, electrodes 14(1) and 14(2) are disposed on the second longitudinal member 13 and the third longitudinal member 23, respectively, to provide a bipolar arrangement.

[0016] In one example, electrodes 14(1) and 14(2) can be balloon markers, although other types of electrodes can be utilized. With reference to FIG. 5, electrodes 14(1) and 14(2) are coupled to radio frequency energy source 16 via wires 17(1) and 17(2). Wires 17(1) and 17(2) are wound in a helical configuration around first longitudinal member 12. Wires 17(1) and 17(2) deliver radio frequency energy from radio frequency energy source 16 to provide radio frequency energy to a body region, although other energy sources configured to provide other energy modalities may be used.

[0017] 6, electrodes 14(1) and 14(2) are insulated, such as with a dielectric barrier, to allow the two electrodes 14(1) and 14(2) to generate an electric field in the body region. Additionally, the insulation is selected to allow the electrodes 14(1) and 14(2) to withstand the generation of a plasma discharge around the electrodes 14(1) and 14(2). The electrodes 14(1) and 14(2) may further have a dielectric barrier disposed over the exposed portions of the electrodes 14(1) and 14(2) to further aid in withstanding the generation of a plasma.

[0018] Referring again to FIGS. 1 and 5 in more detail, radio frequency energy source 16 provides a source of radio frequency energy that is delivered to the body region via electrodes 14(1) and 14(2), although other energy modalities may be employed. In one example, radio frequency energy source 16 provides modulated pulses of radio frequency energy to electrodes 14(1) and 14(2). In one example, radio frequency energy source 16 is configured to provide modulated pulses having a pulse width of about 0.05 to about 500 microseconds, although modulated pulses having pulse widths of less than 0.05 microseconds or between 500 microseconds and 1 second may also be employed. Radio frequency energy source 16 may further be configured to provide modulated pulses in packets. By way of example only, each packet of modulated pulses may have between 2 and 10 pulses. In another example, the modulated pulses are grouped into bursts having, by way of example only, a burst width of 100 ms to 1 s and an interval between each burst of 1 ms to 100 ms.

[0019] The radio frequency energy source 16 provides radio frequency energy at a voltage between 400V and 4000V, although in some examples voltages less than 400V may be utilized. The radio frequency energy source 16 may provide radio frequency energy at a level that provides delivery conditions in the body region that enhance delivery of the composition, such as cavitation, microjets, shock waves, electrical stimulation, or chemical reactions. In one example, the radio frequency energy source 16 provides energy to generate shock waves having an instantaneous magnitude between 0.1 MPa and 20 MPa. In another example, the radio frequency energy source 16 provides energy to generate one or more regions of cavitation bubbles in the body region having diameters between 1 μm and 10 mm. The cavitation bubbles may be formed from a composition delivered to the body region using the composition delivery device 10.

[0020] 1 and 5 in more detail, composition delivery device 10 further includes a composition delivery element 18 disposed at a distal end 22 of first longitudinal member 12. Composition delivery element 18 includes a composition layer 24 of the composition to be delivered to the body area disposed on a surface 25 of composition delivery element 18. Composition layer 24 is coated on and / or embedded within surface 25 of composition delivery element 18. By way of example only, methods of applying composition layer 24 can include spraying, dip coating, vapor deposition, plasma deposition, using chemical bonding, or using electrical bonding.

[0021] In another example, the composition is injected inside the composition delivery element 18, rather than being placed on the outside of the composition delivery element. The composition delivery element 18 includes holes 50 that allow the composition to exit through the holes 50 and be delivered into a body area, such as an occlusion or a blood vessel wall, as shown in FIG. 10. This delivery of the composition is enhanced by radio frequency energy activation, as described further below. In another example, the composition is placed on the composition delivery element as a charged compound. Radio frequency energy is then delivered with a similar charge, causing the composition to be repelled from the composition delivery element 18 into the tissue. Additionally or alternatively, an electrically neutral therapeutic agent can be modified by adding a charged moiety, such that the modified therapeutic agent containing the charged moiety is more susceptible to the influence of an energy field. Additionally, the therapeutic agent can be immersed or dissolved in a conductive fluid, whereby the conductive fluid pathway under the influence of an energy field, as described above, acts as a medium to facilitate delivery of the therapeutic agent to the treatment area. As an example, a drug for treating anemia can be used.

[0022] The composition is a therapeutic agent or pharmaceutical compound. Non-limiting examples of compositions that may be utilized in the composition delivery device include thrombolytic agents, fibrinolytic enzymes, thrombin inhibitors, antiplatelet agents, anticoagulants, antirestenosis agents, or anticancer agents, although other therapeutic agents or pharmaceutical compounds may be delivered using the composition delivery device 10. The composition may be a drug, gas, or liquid that may affect a target body region. By way of example, the composition may be paclitaxel, or a drug taken from the limus family of drugs, and may be used to deliver to an occluded vascular body to reduce the likelihood of such vessels reoccluding or restenotic.

[0023] The present embodiments may be used in combination with other therapeutic agents or other bioactive substances, such as, but not limited to, amino acids, anabolic agents, analgesics and antagonists, anesthetics, anthelmintics, anti-adrenergics, anti-asthmatics, anti-atherosclerotic agents, antibacterials, anticholesterol agents, anticoagulants, antidepressants, detoxifying agents, antiemetics, antiepileptics, antifibrinolytics, anti-inflammatory agents, antihypertensives, antimetabolites, antimigraine agents, antifungal agents, antiemetics, antineoplastic agents, antiobesity agents, antiparkinsonian agents, antiprotozoal agents, antipsychotics, antirheumatic agents, antiseptics, antivertigo agents, antivirals, bacterial vaccines, bioflavonoids, calcium channel blockers, capillary strengthening agents, coagulants, corticosteroids, cytostatic treatments. It is contemplated that the compositions may be used to deliver antidotes for, contrast agents (such as contrast agents, radioisotopes, and other diagnostic agents), electrolytes, enzymes, enzyme inhibitors, gangliosides and ganglioside derivatives, hemostatic agents, hormones, hormone antagonists, hypnotics, immunomodulators, immunostimulants, immunosuppressants, minerals, muscle relaxants, neuromodulators, neurotransmitters and nootropics, osmotic diuretics, parasympatholytics, parasympathomimetics, peptides, proteins, respiratory stimulants, smooth muscle relaxants, sympatholytics, sympathomimetics, vasodilators, vasoprotectants, gene therapy vectors, viral vaccines, viruses, vitamins, and the like.

[0024] In this example, composition delivery element 18 is an expandable balloon having a porous surface 25 to which composition layer 24 is applied, although other composition delivery elements, such as an expandable catheter, or stent, may be utilized. In another example, composition delivery element 18 may be, by way of example, microbubbles filled with the composition that are delivered to the body region through lumen 19 of first longitudinal member 12. In another example, as shown in FIG. 7, composition delivery element 18 includes a plurality of expandable ribs having composition disposed thereon.

[0025] Referring again now to FIG. 1 and FIG. 5 in more detail, a composition delivery element 18, such as a balloon, includes one or more raised elements 28 disposed on its surface 25. The raised elements 28 are configured to scratch or cut a body area, such as an occlusion, in parallel such that the composition can more easily spread into the area into which the composition delivery element 18 is inserted. The raised elements 28 may include longitudinal or circumferential elements disposed on the composition delivery element 18. In one example, the raised elements 28 have a triangular cross-section, although other configurations may also be utilized. The raised elements 28 are constructed of metal or polymer, by way of example, although other materials may also be utilized. The composition layer 24 may be applied directly to the raised elements 28 of the composition delivery element 18. In this example, the raised elements 28 are directly connected to the composition delivery element 12. Alternatively, referring now to FIG. 8, the raised elements 28 may be directly connected to the first longitudinal member 12, although other configurations may also be utilized.

[0026] An example of a method for enhanced delivery of a composition to a patient's body region utilizing radio frequency energy will now be described with reference to Figures 1-8. First, a longitudinal member 12 including a composition delivery element 18 having a composition layer 24 disposed on a surface 25 is delivered to a patient's body region to be treated. The body region can be various regions within the body, such as organs, body lumens or cavities, such as various ducts or ducts, blood vessels, grafts, glands, etc. In one example, the body region can be an area within the body that includes an occlusion or tumor in need of treatment. The composition layer 24 can be coated or embedded on the surface 25 of the composition delivery element 18, while in other examples, the composition layer 24 can be disposed on a raised element that protrudes from the surface 25 of the composition delivery element 18, such as an expandable balloon.

[0027] Once positioned in the body region, the composition delivery element 18 can be expanded to apply the composition layer 24 to the body region. The composition is a therapeutic agent or pharmaceutical compound. Non-limiting examples of compositions that may be utilized with the composition delivery device include thrombolytic agents, fibrinolytic enzymes, thrombin inhibitors, antiplatelet agents, anticoagulants, antirestenosis agents, or anticancer agents, although other therapeutic agents or pharmaceutical compounds may be delivered using the composition delivery device 10.

[0028] A first electrode 14(1) and a second electrode 14(2), which are coupled to a radio frequency energy source 16, are then brought into position adjacent to the body region. In one example, longitudinal member 12 has electrodes 14(1) and 14(2) disposed thereon such that electrodes 14(1) and 14(2) are delivered simultaneously with longitudinal member 12, as shown in Figures 1 and 5.

[0029] 2, electrodes 14(1) and 14(2) are delivered on a second longitudinal member 13 that is configured to be inserted into lumen 19 of first longitudinal member 12 and delivered adjacent to a body region of a patient. In this example, electrodes 14(1) and 14(2) are directed to the body region after delivery of composition delivery element 18.

[0030] 3, electrodes 14(1) and 14(2) are separately directed through the lumen 19 of the first longitudinal member 12 to a body region on second and third longitudinal members 13 and 23, which are each independent, non-overlapping guidewires or catheters. In this example, the second and third longitudinal members 13 and 23 can be delivered to the body in the same or opposite directions using an antegrade / retrograde approach, as described in U.S. Pat. No. 9,561,073, the disclosure of which is incorporated herein by reference in its entirety.

[0031] As disclosed in U.S. Patent No. 7,918,859 by the same inventor, which is incorporated herein in its entirety, in the controlled antegrade and retrograde tracking (CART) technique, the retrograde approach utilizes an intercoronary artery passageway. Such a passageway may be an epicardial passageway, an interatrial passageway, an interseptal passageway (also called a septal side branch), or a bypass graft. The basic concept of the CART technique is to create a passageway through the obstruction, preferably with limited incisions, by approaching the obstruction both antegradely and retrogradely.

[0032] In a further example, a patch including one of electrodes 14(1) or 14(2) is placed on the patient's skin adjacent to the patient's body area to be treated. The patch is placed in close proximity to the body area to allow for a bipolar arrangement between electrodes 14(1) and 14(2).

[0033] Radio frequency energy is then delivered from radio frequency energy source 16 to electrodes 14(1) and 14(2) in modulated pulses. In one example, radio frequency energy source 16 provides modulated pulses having a pulse width of about 0.05 to about 500 microseconds, although modulated pulses having pulse widths of less than 0.05 microseconds, or between 500 microseconds and 1 second may also be used. Radio frequency energy source 16 may further provide modulated pulses in packets having, by way of example only, 2 to 10 pulses. In another example, the modulated pulses are grouped into bursts having, by way of example only, burst widths of 100 ms to 1 s and intervals between each burst of 1 ms to 100 ms.

[0034] The delivery of the modulated pulses may be gated using an electrocardiogram (ECG) or other waveform signal obtained from the patient's body. In one example, a third patch including an electrode may be placed outside the body region and electrically coupled to electrodes 14(1) and 14(2). In yet another example, a third electrode may be placed near the body region to measure impedance based on the delivery of radiofrequency energy. The impedance measurements may then be utilized to optimize the delivery of radiofrequency energy.

[0035] The radio frequency energy source 16 provides radio frequency energy at a voltage between 400V and 4000V, although in some instances voltages less than 400V may be utilized. In one example, the incident intensity of the radio frequency energy at the body region is about 0.1 Joules to 5 Joules per square millimeter. In one example, the radio frequency energy is delivered until an electrical limit, such as 100 Ohms, is reached, although other electrical limits may be employed.

[0036] The radio frequency energy source 16 provides radio frequency energy at a level that provides delivery conditions in the body region that enhance delivery of the composition, such as cavitation, microjets, shock waves, electrical stimulation, or chemical reactions. In one example, the radio frequency energy source 16 provides energy to generate shock waves having an instantaneous magnitude of 0.1 MPa to 20 MPa. In another example, the radio frequency energy source 16 provides energy to generate one or more regions of cavitation bubbles in the body region having diameters of 1 μm to 10 mm. The cavitation bubbles can be formed from a composition delivered to the body region using the composition delivery device 10.

[0037] The delivery of radio frequency energy provides for long-term delivery and embedding of the composition in the body region, resulting in improved treatment. The radio frequency signal can be adjusted using several modifications to the pulse, such as by shortening or lengthening the duration of the pulse, or by adjusting the pulse period. As an example, shortening the duration of the pulse into the microsecond or nanosecond range can provide a stronger mechanical effect, inducing a stronger mechanical effect of the composition in the body region (i.e., a deeper injection or embedding). Embedding the composition deeper can provide a longer duration of the composition in the body region, potentially allowing for a more sustained effect from the composition.

[0038] By way of example, radiofrequency energy delivery can be used to provide a mechanical force that enhances the diffusion of the composition into the body region, or it can be used to produce effects on the body region itself, such as vasodilation, increased cell permeability, or reversible electroporation, that enhance the effectiveness of delivery of the composition to the body region.

[0039] As an example, the method can be utilized to treat an occlusion. Radiofrequency energy is applied between two electrodes 14(1) and 14(2) to generate plasma and utilize the effects of plasma generation, such as cavitation or shock waves, to modify the surrounding plaque or occlusion or vessel wall. The composition is delivered to the occlusion, which is now more susceptible to diffusion or delivery of the composition due to the effects of plasma generation, thus improving delivery of the composition to the vessel wall. Delivery of radiofrequency energy to the vessel wall or occlusion can improve delivery of the composition by inducing vasodilation, altering cell permeability, or by electroporation, etc. By adjusting the radiofrequency signal, the composition can be delivered deeper within the vessel wall, thereby allowing the composition to remain in the vessel wall for an extended period of time and improving the persistence of the composition within the vasculature.

[0040] In another example, electrodes 14(1) and 14(2) are placed on the same device as the composition, thereby allowing for simultaneous modification of the surrounding tissue and delivery of radiofrequency energy to enhance delivery of the composition. In this example, a composition delivery element 18, such as a balloon catheter, has a composition layer 24 placed on the balloon's outer surface 25. Electrodes 14(1) and 14(2) are placed inside the composition delivery element 18 as an attachment to the first longitudinal member 12, as shown in FIG. 1, or delivered through a lumen 19 of the first longitudinal member 12, as shown in FIGS. 2 and 3. Radiofrequency energy is then delivered, and the effects of the radiofrequency energy are transmitted through the composition delivery element 18, such as a balloon, to the composition layer 24 and the vessel wall, enhancing delivery of the composition to the vessel wall.

[0041] Another exemplary method for enhanced delivery of a composition to a patient's body region, such as an occlusion, utilizing radio frequency energy is described with reference to Figures 9A-9C. In this example, electrodes 14(1) and 14(2) are directed to the occlusion area within a blood vessel on second longitudinal member 13 and third longitudinal member 23 prior to delivery of the composition to the body region, as shown in Figure 9A.

[0042] Radio frequency energy is then applied as described above. As shown in Figure 9B, application of radio frequency energy generates plasma and uses the effects of plasma generation, such as cavitation or shock waves, to modify the surrounding plaque or occlusion or vessel wall. Electrodes 14(1) and 14(2) are then removed from the body region.

[0043] The composition is then delivered to the occlusion using a composition delivery element 18, as shown in FIG. 9C. The occlusion is now more susceptible to diffusion or delivery of the composition due to the effects of plasma generation, thus improving delivery of the composition into the vessel wall. Delivery of radiofrequency energy to the vessel wall or occlusion can improve delivery of the composition by inducing vasodilation, altering cell permeability, or by electroporation, etc. By adjusting the radiofrequency signal, the composition can be delivered deeper into the vessel wall, thereby allowing the composition to remain in the vessel wall for an extended period of time, improving the persistence of the composition within the vasculature. EXAMPLES

[0044] Preclinical studies (Figure 11) have shown that at very high voltages, the effects of plasma-mediated ablation using radiofrequency energy in unoccluded vessels can result in a propagating effect in the vessel wall. In particular, medial dissection and / or perivascular bleeding can occur toward the outer vessel wall. However, by modifying the settings of the radiofrequency delivery, these effects can be controlled to improve delivery of the composition to the vessel wall or occlusion without producing adverse effects. Examples of modifications include lowering the voltage or current level, modifying the pulse period, modifying the duration of the pulse, or modifying the number of pulses delivered during radiofrequency delivery.

[0045] As an example, in the case of an occlusion in a vessel wall, it has been shown that a voltage in the range of 1200V to 2000V can be used to ablate tissue and form a passageway through the occlusion in a very short period of time. Because the goal is not to form a passageway but to improve delivery of the drug to the vessel wall, delivery of the drug or other composition is expected to require less energy or lower voltage. Similarly, very short pulses (on the order of nanoseconds) have been shown to generally produce greater mechanical forces (e.g., shock waves) than longer pulses. It is preferable to deliver sufficient mechanical force to improve delivery of the drug or composition into the vessel wall without causing damage to the wall itself.

[0046] Thus, as illustrated and explained by the examples herein, this technology provides more efficient and effective devices and methods for delivering compositions to body regions. The devices and methods of this technology allow the composition to remain in the body region site for an extended period of time, resulting in improved treatment. In particular, the use of cavitation, shock waves, electroporation, etc., generated by radio frequency energy or other energy sources, aids in the delivery of the composition. This technology also advantageously provides an improved method for delivering drugs into vessel walls or occlusions so that the drug remains in the target site for an extended period of time without leaving anything behind. The sustained action of the drug in the target site can result in improved outcomes (e.g., reduced reocclusion, restenosis, or revascularization rates).

[0047] Having thus described the basic concepts of the present invention, it will be readily apparent to those skilled in the art that the foregoing detailed disclosure is intended to be presented by way of example only, and not by way of limitation. Various changes, improvements, and modifications may be made that will occur to those skilled in the art, but that are not expressly described herein. These changes, improvements, and modifications are intended to be suggested by this specification and are within the spirit and scope of the present invention. Accordingly, the present invention is limited only by the appended claims and their equivalents.

Claims

1. 1. An apparatus (10) for enhanced delivery of a composition to a body region of a patient utilizing radio frequency energy, comprising: a first longitudinal member (12) having a proximal end (20) and a distal end (22), with at least one lumen (19) extending between the proximal end (20) and the distal end (22); a composition delivery element (18) disposed at the distal end of the longitudinal member, the composition delivery element having the composition (24) disposed on an outer surface (25) thereof; and at least two electrodes (14(1), 14(2)) disposed on a second longitudinal member (13) configured to be inserted into the lumen of the first longitudinal member to be disposed within the composition delivery element, the at least two electrodes coupled to a radio frequency source (16) to receive radio frequency energy from the radio frequency source and insulated to be capable of generating an electric field to enhance delivery of the composition to the body region, the radio frequency source providing packets of modulated pulses of radio frequency energy, each of the packets including at least two of the modulated pulses; The apparatus comprising:

2. The device of claim 1 , wherein the composition delivery element comprises a balloon.

3. The device of claim 2 , wherein the balloon has a porous surface.

4. The device of claim 1 , wherein the composition delivery element comprises an expandable rib.

5. The device of claim 1 , wherein the at least two electrodes are balloon markers.

6. The device of claim 1 , wherein the composition is a therapeutic agent or a pharmaceutical compound.

7. 7. The device of claim 6, wherein the therapeutic agent or pharmaceutical compound is a thrombolytic agent, a fibrinolytic enzyme, a thrombin inhibitor, an antiplatelet agent, an anticoagulant, an antirestenotic agent, or an anticancer agent.

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