DRUG DELIVERY BALLOON APPARATUS

TMs application is a non-provisional of and claims priority to U.S, Provisional Application No. 61/809,176 entitled “Drag Delivery Balloon Apparatus& Methods for Use," filed on April 5, 2013, which is hereby incorporated by reference in its entir ety.

Local drag delivery Is the process by which therapeutic agents are delivered to specific areas within the vasculature of a human or animal patient. This localized treatment permits an increased concentration of the drag or therapeutic agent at the intended target area but avoids toxicity that may result through general systemic delivery within the circulatory system. Known localized chug delivery methods include drug-eluting stents or balloons, porous drug infusion balloons and direct catheter delivery.

The present invention is directed to methods and apparatus for the delivery of a drug solution or a therapeutic agent to a selected site within the vascular system using a drug delivery balloon apparatus. The drug delivery- balloon apparatus of the present invention may beneficially- permit an increased balloon length that may be up to four tiroes longer than that of other known balloons providing the advantage of treating larger injury sites in a single procedure. The drag delivery balloon apparatus of the present invention may also provide a plurality of grooves for receiving the drag solution during delivery- to the target passage. These grooves may beneficially guide the flow of the drag solution through the target passage, while at the same time slowing the drug flow to increase the amount of time that the drag is in contact with tire wall of the target passage. Tire drag delivery balloon apparatus Mid Its associated channels also can help to minimize the volume of drag solution required by occupying a portion of the luminal volume. In addition, the drug deliver}- balloon apparatus may further include an occlusion balloon that may inflate upstream from the drug delivery balloon to permit adequate pressure to be maintained in the system during infusion to effectively advance the drug or therapeutic agent into and along the plurality' of grooves on the outer surface of the drug delivery balloon. The occlusion balloon also helps to prevent peripheral washout by blocking Mood flow from die treatment area.

Thus, in a first aspect, the present invention provides a drug delivery balloon apparatus comprising: (a) at least two lumens, comprising a first lumen Mid a second lumen,

(b) a balloon inflation port in communication with the first lumen, (c) a drag delivery port in communication with the second lumen, (d) a guidewire port in communication with either the second lumen or a third lumen, (℮) an occlusion balloon, (I) a drag delivery balloon, wherein an outer' surface of the drug delivery balloon defines a plurality of grooves extending from a first end of the drug delivery balloon to a second end of the dr ug delivery balloon, wherein the occlusion balloon is disposed between the drag delivery balloon and the balloon inflation port, wherein the occlusion balloon and the drag delivery balloon are in communication with the first lumen, (g) one or more drug delivery channels extending The length of die second lumen, (h) one or more drag delivery ducts extending from the one or more drag delivery' channels to an exterior surface of the second lumen, and wherein the one or more drag delivery ducts are defined only in a portion of the second lumen that is disposed between the occlusion balloon and die drag delivery balloon.

In one embodiment, the invention provides that the plurality of grooves may be axially aligned with a central axis of the drag delivery balloon. In varions other embodiments, the plurality of grooves may be spiraled, helical, substantially straight, sinusoidal, or cross-hatched, for example. Further, in one example the drag delivery port may be branched such that two, three, four or more different drug solutions or other solutions may he introduced into the drug delivery port.

In another embodiment, the invention may provide that the one or more drag delivery channels comprises four channels and each drug delivery channel may be in communication with three drug delivery ducts such that ther e are a total of twelve drug delivery ducts.

In a second aspect, the present invention also provides a method for administering at least one drag to a subject in need thereof using a drag delivery balloon apparatus, the method comprising: (a) introducing the drag delivery balloon apparatus according to the first aspect of the invention to a target passage, (b) inflating the occlusion balloon and the drug delivery balloon, (c) injecting a drug solution into the drag delivery port, and (d) advancing the drag solution through the second lumen to the one or more drag delivery ducts into the target passage hr the subject aud then into and along a plurality of grooves defined in an outer surface of the drag delivery balloon.

Figure 1Α is a side view of drug delivery balloon apparatus, in accordance with one embodiment of the invention.

Figure IB is a front cross-sectional view of a two lumen configuration of the drag delivery balloon apparatus, in accordance with one embodiment of the invention.

Figure 1C is a front cross-sectional view of a three lumen configuration of the drag delivery balloon apparatus, in accordance with one embodiment of the invention.

Figure ID is a side view of the occlusion balloon and the drug delivery balloon of the drug delivery balloon apparatus, in accordance with one embodiment of the invention.

Figure IE is a detail cross-sectional side view of the drug delivery balloon, in accordance with one embodiment of the invention.

Figure 2 Is a flow chart depicting functions that can be carried out in accordance with example embodiments of the disclosed methods.

Exemplary methods and systems are described herein. It should be understood that the word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” .Any embodiment or feature described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments or features. The exemplary embodiments described herein are not meant to be limiting. It will be readily understood that certain aspects of the disclosed systems and methods can be arranged and combined in a wide variety' of different configurations, all of winch are contemplated herein.

Furthermore, the particular arrangements shown in the Figures should not be viewed as limiting. It should be understood that other embodiments may include more or less of each element shown in a given Figure. Further, some of the illustrated elements may be combined or omitted. Yet further, an exemplary embodiment may include elements that are not illustrated in the Figures.

As used herein, with respect to measurements, ‘'about" means +/- 5 %. Further, as used herein, “target passage" refers to the blood vessel or artery in winch the drug delivery balloon is deployed to effectively administer a drug solution. The target passage may further include artificial lumens used, for example, as teaching aids.

In addition, as used herein, “drug solution" refers to any flowable material that may be administered into a target passage. When the thug solution comprises a therapeutic to be administered to a subject, any suitable drug that can be administered in solution can he used, hi various non-limiting embodiments, the therapeutic may comprise sirolimus, heparin, and cell-based therapies; and antineoplaslic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel, (e.g., TAXOL.RTM. by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxotere.RTM., from A vernis S.A., Frankfurt,. Germany), methotrexate, azathioprine, vincristine, vinblastine, iluorouracii, doxorubicin hydrocMoride (e.g., Adriamycin.RTM. from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.. Mutamycin.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antipJatelets, anticoagulants, antifibrin, and antithrombins include aspirin, sodium heparin, low molecular weight heparins, heparinoids, iiintdin, argatroban, forskoiin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein nb/IQa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomas a (Biogen, Inc., Cambridge. Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g., Capoten.RTM, and Capozide.RTM. from Bristol-Myers Squibb Co.. Stamford, Conn.), cilazapril or lisinopril (e.g., Pnmvil.RTM. and Prinzide.RTM. from Merck & Co., Inc., Whitehouse Station, N.J.), calcium channel Mockers (such as nifedipine), colchicine, proteins, peptides, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor.RTM. from Merck & Co.. Inc., Whitehouse Station, N.J.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), mtroprusside, phosprhodiestera.se inhibitors, prostaglandin inhibitor's, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazoiopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate agents include cisplatin, insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin, alpha-interferon, genetically engineered epithelial cells, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antivirals, anticancer drugs, anticoagulant agents, free radical scavengers, estradiol, antibiotics, nitric oxide donors, super oxide dismutases, super oxide dismutases mimics, 4-ammo-2,2,6,6-tetramethylpiperidine-l -oxyl (4-amino-TEMPO), tacrolimus, dexamerhasone, ABT-578, clobetasol, cytostatic agents, prodrugs thereof, codrugs thereof, and a combination thereof. Other therapeutic substances or agents may include rapamycm and structural derivatives or functional analogs thereof, such as 40-Ο-(2-hydroxy)ethyi-rapamycin (known by the trade name of EVEROLIMUS), 40-Ο-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycm, and 40-O-tetrazole-rapamycin. In addition, non-therapeutic fluids, such as water, may be used, if the drag delivery balloon apparatus is being used in a teaching model or training demonstration, for example.

In a first aspect. Figure 1Α illustrates an example drag delivery balloon apparatus 100 in accordance with one embodiment of the invention. The drag delivery balloon apparatus 100 may include three ports: (!) a balloon inflation port 102 that inflates both an occlusion balloon 104 and a drag delivery balloon 106, (2) a drag delivery port 108 through which a drag solution is administered, and (3) a guidewire port 110 for receiving a guidewire and the inflated occlusion balloon 104 and drag delivery balloon 106. In one example embodiment as shown in Figure 1Α, the chug delivery port 108 may be bifurcated, such that two, three, torn' or more different drag solutions or other solutions may be introduced into the drag delivery port 108 as deemed appropriate for treatment.

In one example, the three ports lead to two parallel lumens 112. Figure IB illustrates a front cross-sectional view of the two lumens. The balloon apparatus 100 may include a first lumen 114 in communication with the balloon inflation port 102 and may be configured to receive a saline contrast mixture, or any other suitable fluid medium, to inflate the occlusion balloon 104 and the drug delivery balloon 106, Further, the balloon apparatus 100 may include a second lumen 116 in communication with the drug delivery port 108 and the guidewire port 110. In one embodiment, the second lumen 116 may be sized and shaped to receive a drug solution. In one embodiment, the second lumen 116 may also be sized and shaped to receive a guidewire having a diameter in the range from about 0.25 turn to about 1 aim, and preferably in a range from about 0.254 mm to about 0.9652 mm. In one embodiment, the first lumen 114 and the second lumen 116 may be enclosed in a sheath 118. The second lumen 116 may include one or more drug delivery channels 120 extending the length of die second lumen 116. These drag delivery channels 120 may be used to transport the drag solution from the drag delivery port 108 to a target passage. The second lumen 116 may also include a guidewire channel 122 extending the length of the second lumen 116. In another example, the second lumen 116 may include a single channel for both the guidewir e Mid drag solution.

In such a configuration, the guidewire may be removed alter use so that the drag solution can pass through the second lumen 116. In operation, the balloon apparatus 100 may be configured to infuse the drug solution while the guidewire is iu the second lumen 116. In such a configuration, the second lumen 116 would have a larger diameter than the guidewire from a location between the guidewire port 110 and the drag delivery port 108 until just distal to the drug delivery ducts 146. The second lumen 116 would shrink down to about the diameter of the guidewire just distal to die drag delivery ducts 146 to the distal end of the balloon. Further, the second lumen 116 would shrink down to about the diameter of the guidewire proximal to the thug delivery port 108, so as to prevent the drag solution from exiting the guidewire port 110. In another example, a flange or one-way valve may be used to prevent the drag solution from exiting the guidewire port 110. Other configurations are possible as well.

In another embodiment, the three ports may be coupled to three concentrically aligned lumens 124. For example. Figure 1C illustrates a front cross-sectional view of the three lumens 124. As shown in Figure 1C, the three concentrically aligned lumens 124 comprise an inner lumen 126, a middle lumen 128, and an outer lumen 130, where the first lumen is arranged as the inner lumen, the second lumen is arranged as the middle lumen and the third lumen is arranged as the outer lumen. The inner lumen 126 may be in communication with the guidewire port 110 and may be sized and shaped to receive a guidewire having a diameter in the range from about 0.25 mm to about 1 nun, and preferably in a range from about 0.254 mm to about 0.9652 mm. The middle lumen 128 may be in communication with the drug delivery port 108. The middle lumen 128 may include a plurality of flexible spacers 132 that extend between the inner lumen 126 and the outer lumen 130 to maintain the structural integrity of the middle lumen 128. These spacers 132, in combination with the middle lumen 128 and tire inner lumen 126, may further define a one or more drug delivery channels 134 extending the length of tire middle lumen 128, As discussed above, these drug delivery channels 134 may be used to transport the drag solution from the drug delivery port 108 to a target passage. The outer lumen 130 may be in communication with the balloon inflation port 102. The outer lumen 130 may also include a plurality" of flexible spacers 136 to help maintain the structural integrity of the outer lumen 130. These spacers 136, in combination with the outer lumen 130 and middle lumen 128. may also define a plurality of fluid delivery" channels 138 extending the length of the outer lumen 130. These fluid delivery channels 138 may be in fluid communication with the occlusion balloon 104 mid the drag delivery balloon 106.

Figure ID illustrates the occlusion balloon 104 and the drug delivery balloon 106 of the drug delivery' balloon apparatus 100. The occlusion balloon 104 may he composed of atraumatic compliant materials such as polyurethane, latex, or silicone, among other possibilities, that, results in a low burst pressure of about 5 atm, for example. However, the occlusion balloon 104 may be configured to withstand greater pressures, lor example up to about 20 atm. The occlusion balloon 104 may be configured to conform to tire shape and size of fee target passage via low pressure inflation, about 1 to 2 atm. Once inflated, the occlusion balloon 104 may provide occlusion in the target passage to allow for drug delivery into die target passage downstream from fee occlusion balloon 104 to minimize dilution of the drug solution from blood flow. The inflated diameter of the occlusion balloon 104 may range from about 2.5 mm to about 12 mm and is preferably in a range from about 2.5 mm to about 6 mm. The length of fee occlusion balloon 104 may range from about 20 turn to about 40 mm. In one embodiment, the inflated diameter of the occlusion balloon 104 ranges from about fee same as fee inflated diameter of fee drug delivery balloon 106 to about 2 mm larger than fee inflated diameter of the drag delivery balloon 106. In operation, the occlusion balloon 104 may be inflated prior to the introduction of fee drug solution into fee drag delivery port 108,

The drag delivery balloon 106 may be made of compliant materials such as polyurethane, latex, or silicone that results in a low burst pressure of about 5 atm, for example . The length of fee drag delivery balloon 106 may range from about 20 mm to about 200 mm. In various embodiments, fee length of the drag delivery balloon 106 ranges from about 80 mm to about 200 mm, from about 100 mm to about 200mm, from about 120 turn to about 200 mm, from about 140 turn to about 200 mm, from about 160 mm to about 200 mm, from about 180 mm to about 200 mm, from about 60 unu to about 120 mm, from about 60 nmi to about 100 mm, and from about 10 rum to about 80 rum. In one embodiment, fee drag delivery balloon 106 may have an inflated diameter ranging from about 2.5 mm to about 12 nmi and is preferably in a range from about 2.5 mm to about 6 mm. In various embodiments, the inflated diameter of the drag delivery balloon 106 may range from about 2.5 mm to about 3 mm, from about 4 mm to about 5 mm, and from about 5 mm to about 6 mm.

The outer surface of the drag delivery- balloon 106 may define a plurality of gr ooves 140 for receiving the drug solution. These grooves 140 may- extend from the first end 142 to the second end 144 of the drag delivery balloon 106. The plurality of grooves 140 may serve to (1) guide the flow of the drag solution and (2) slow the flow of the drag solution to increase the time of contact of the drug with the wall of the target passage. The plurality of grooves 140 are preferably axially aligned with a central axis of the drug delivery balloon 106 and may be spiraled, helical, sinusoidal or substantially straight, among other possibilities, in various embodiments. Spiraled, helical or sinusoidal grooves are preferred over straight grooves, because the more tortuous grooves provide more surface area to contact the vessel wall and further extend the amount of time that the drug solution contacts the vessel wall Further, any pattern of .gr ooves is contemplated including a cross-hatched or waffle pattern, for example.

The occlusion balloon 104 may be disposed between the drag delivery balloon 106 and the balloon inflation port 102 such that both the occlusion balloon 104 and the drag delivery balloon 106 may be in communication with the second lumen 116 or the outer lumen 130 and receive fluid from the balloon inflation port 102. The occlusion balloon 104 and the drug delivery balloon 106 may be separ ated from each other by a distance ranging from about 1 mm to about 10 mm, and preferably from about 3 mm to about 5 mm. This distance allows adequate pressure to be maintained in the system such that the drag solution may be effectively advanced into and along the plur ality' of grooves 140 on the outer surface of the drug delivery balloon 106.

One or more drug delivery ducts 146 may extend fr om the one or more drag delivery channels 120 defined in the second lumen Τ16 to an exterior surface of the second lumen 116. These drug delivery ducts 146 may be defined in a portion 148 of the second lumen 116 that is disposed between the occlusion balloon 104 and the drag delivery balloon 106. In other words, these drag delivery ducts 130 may be downstream from the occlusion balloon 104 in operation. In one embodiment, the one or more drag delivery channels 120 may comprise four to eight channels. In another embodiment, the one or more drug delivery channels 120 m each in fluid communication with one to six drug delivery ducts 146. hi a further embodiment, the one or more drag delivery channels 120 may comprise four channels and each drug delivery channel may be in fluid communication with three drug delivery duets such that there are a total of twelve drug delivery ducts. The number of drag delivery ducts may depend upon the length of portion 148 of the second lumen 116 extending between the occlusion balloon 104 and the drag delivery balloon 106 and/or the diameter of the drug delivery ducts 146, among other possibilities.

Figure IE illustrates a cross-sectional side view of the drug delivery balloon 106. As shown in Figure IE, the drag delivery balloon 106 includes a plurality of grooves 140. In operation, the drug solution advances downstream into and along the plurality of gr ooves 140 defined in the outer surface of the drag delivery balloon 106. Once the drag solution exits the plurality of grooves 140 at the second end 144 of the drag delivery balloon 106, the drag solution may be cleared via normal arterial blood flow and ultimate physiological function.

Figure 2 is a simplified flow chart illustrating a method according to an exemplary embodiment. Although the blocks are illustrated in a sequential order, these blocks may also be performed in parallel, and/or in a different order than those described herein. Also, the various blocks may be combined into fewer blocks, divided into additional blocks, and/or removed based upon the desired implementation.

At block 202, the method involves introducing the drug delivery balloon apparatus according to any of the foregoing embodiments to a target passage. The drug delivery balloon apparatus may be introduced and delivered in a standard coaxial manner, via overtire-wire or rapid exchange techniques, as examples.

At block 204, the method involves Inflating the occlusion balloon and the drag delivery balloon. In one embodiment, the occlusion balloon and the drag delivery balloon may be inflated by injecting a saline contrast mixture, for example, into the balloon inflation port. The saline contrast mixture may then be advanced through a first inmen to the occlusion balloon and the drug delivery balloon until both balloons are inflated. The occlusion balloon may inflate at a slightly faster rate, since the occlusion balloon and the drag delivery balloon are connected in series such that the occlusion balloon receives the saline contrast inflation mixture first In another embodiment, the occlusion balloon and drug delivery balloon may be inflated using any other suitable fluid medium.

After both the occlusion balloon and the drag delivery balloon have been inflated, the method continues at block 206 with injecting a drag solution into the thug delivery port. In one embodiment, the drag delivery port is bifurcated, such that two, three, four or more different drag solutions or other solutions may be introduced into the drag delivery- port as deemed appropriate.

At block 208, the method involves advancing the thug solution through a second lumen to the one or more drag delivery ducts into a target passage in the subject. At this stage, the space between the occlusion balloon and the drag deliver;/ balloon acts as a reservoir storing the drug solution as it is delivered via the drug delivery ducts. Due to the pressure at which the drag solution is being Introduced to the drag delivery port, the drag solution advances downstream into and along the plurality of grooves defined in the outer surface of the drag delivery balloon. The pressure at which the drag solution is administered should not exceed about 2 atm. Once the drag solution exits the plurality of grooves at the second end of the drag delivery balloon, the drag solution may be cleared via normal arterial blood flow and ultimate physiological function.

While varions aspects and embodiments have been disclosed herein, other' aspects and embodiments will be appar ent to those skilled in the art. All embodiments within and between different aspects of the invention can be combined unless tire context dearly dictates otherwise. The various aspects and embodiments disclosed herein are tor purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.