BALLOON CATHETER

Abstract

The invention locally delivers a chemotherapeutic or a radiographic contrast agent to an upper tract urothelial carcinoma (UTUC). The invention includes a balloon catheter with a working channel and a balloon placed into the ureter/renal pelvis via retrograde or antegrade ureteral access. The balloon is inflated to temporarily obstruct the ureter, and a formulation with a chemotherapeutic agent is infused into the working channel of the catheter and allowed to dwell in the ureter/renal pelvis for a time sufficient to allow the formulation to adhere to and penetrate the urothelial wall. The formulations can be liposomal or non-liposomal formulations. At least portion of the infused chemotherapeutic-agent formulation adheres to the urothelial wall while it is instilled and dwells in the ureter/renal pelvis. The methods of the invention can be performed as an adjuvant therapy to other methods of treating UTUC, including ureteroscopic ablation or resection of the tumor.

Claims

1. A catheter 101 having a proximal end 111 and a distal end 112, the catheter 101 comprising: a balloon inflation lumen 130 in fluid communication with a balloon infusion port 161 in the proximal end 111 of the catheter 101 and also in fluid communication with an expandable occlusion balloon 140 in the distal end 112 of the catheter 101; a guidewire/drainage/instillation lumen 170 in fluid communication with a guidewire/drainage/instillation port 171 in the proximal end 111 of the catheter 101 and also in fluid communication with at least one hole in the distal end 112 of the catheter 101, the guidewire/drainage/instillation lumen 170 for passing urine from the at least one hole to the guidewire/drainage/instillation port 171; and a guidewire entrance hole 355 in fluid communication with the guidewire/drainage/instillation lumen 170 and located in the distal end 112 of the catheter 101, the guidewire entrance hole 355 to load and advance the catheter 101 over a guidewire with the guidewire passing through the guidewire entrance hole 355, the guidewire/drainage/instillation lumen 170, and the guidewire/drainage/instillation port 171; a pressure relief valve 175 disposed along the guidewire/drainage/instillation lumen 170 between the guidewire/drainage/instillation port 171 and the expandable occlusion balloon 140 and configured to release luminal fluid into the guidewire/drainage/instillation lumen 170 when a predetermined ureteral pressure is exceeded; and the expandable occlusion balloon 140 in fluid communication with the balloon inflation lumen 160 and disposed at the distal end 112 of the catheter 101, wherein the expandable occlusion balloon 140 is configured to withstand a force greater than the predetermined ureteral release pressure of the valve 175.

2. The catheter 101 of claim 1, wherein the expandable occlusion balloon 140 is configured to be expanded within a ureter of a patient.

3. The catheter 101 of claim 1, wherein the expandable occlusion balloon 140 is configured to be expanded within a ureteral lumen of a patient.

4. The catheter 101 of claim 1, wherein the expandable occlusion balloon 140 is an occlusion balloon.

5. The catheter 101 of claim 1, wherein the expandable occlusion balloon 140 is a dilation balloon.

6. The catheter 101 of claim 1, wherein at least one of the balloon infusion port 161 and the guidewire/drainage/instillation port 171 is detachable from the catheter 101.

7. A method for treating upper tract urothelial carcinoma (UTUC) in a subject in need thereof, comprising delivering a chemotherapeutic agent to the ureter or renal pelvis of the subject, the method comprising: A. placing a catheter according to claim 1 into the ureter; B. expanding the occlusion balloon 140 balloon of the catheter such that the ureter or renal pelvis is temporarily obstructed; C. loading a formulation comprising a therapeutic dose of a chemotherapeutic drug into the guidewire/drainage/instillation lumen 170 of the catheter; D. instilling the formulation into the ureter or renal pelvis; and E. allowing the instilled formulation to dwell in the ureter or renal pelvis for a time sufficient to allow at least a portion of the formulation to adhere to and partially penetrate the urothelial wall.

8. The method according to claim 7, wherein the chemotherapeutic agent is at least one of a taxane class drug, a platinum-based drug, 5-fluorouracil, mitomycin C, gemcitabine, epirubacin, thiotepa, or a combination thereof.

9. The method of claim 8, wherein the formulation is a liposomal formulation.

10. The method of claim 9, wherein the liposomal formulation comprises: (A) a taxane class drug or a platinum-based drug; (B) dimyristoyl phosphatidylcholine (DMPC), and (C) dimyristoyl phosphatidyl glycerol sodium (DMPG) wherein the weight/weight ratios of A:B:C are 1:(1.3-4.5):(0.4-2.5)

11. The method of claim 10, wherein the taxane class drug is paclitaxel, and the weight/weight ratios of A:B:C are (1):(1.43):(0.47).

12. A method according to claim 7, wherein the instilled formulation is allowed to dwell in the at least one of the ureter and renal pelvis for at least about 1 minute, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about one hour, or about 2 hours.

13. A method for visualizing a ureter or renal pelvis of a subject, the method comprising: A. placing a catheter according to claim 1 into the ureter; B. expanding the occlusion balloon 140 balloon of the catheter such that the ureter or renal pelvis is temporarily obstructed; C. loading a composition comprising a radiographic contrast agent into the guidewire/drainage/instillation lumen 170 of the catheter; D. instilling the composition comprising the radiographic contrast agent into the ureter or renal pelvis; and E. allowing the instilled composition to dwell in the ureter or renal pelvis for a time sufficient to allow to allow visualization of the ureter or renal pelvis with fluoroscopy or radiography, while minimizing pyelo-venous backflow exposure to the patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIGS. 1A and 1B illustrate an exemplary catheter in accordance with the invention.

[0023] FIG. 2 depicts delivery of a liposomal formulation of a chemotherapeutic formulation into the ureter and renal pelvis via retrograde access. Line 1 depicts a ureteroscope.

[0024] FIG. 3 shows a perspective view of an exemplary catheter of the invention.

[0025] FIGS. 4A and 4B show a top view and a side view, respectively, of an exemplary catheter of the invention.

[0026] FIG. 5 shows exemplary valves used in a catheter of the invention.

DETAILED DESCRIPTION

[0027] The invention relates to systems and methods for administering a drug to a target site in a body lumen. One example of the invention relates to systems and methods for locally delivering a chemotherapeutic agent to an upper tract urothelial carcinoma (UTUC). FIG. 1A shows an example catheter 101 of the invention, which has a tube-like body with lumens passing through the body. The catheter 101 includes a hollow balloon inflation lumen 160 and a hollow guidewire/drainage/instillation lumen 170 extending from proximal end 111 of catheter 101, including proximal end of balloon inflation lumen 161 and proximal end of guidewire/drainage/instillation lumen 171, respectively. The proximal end of the balloon inflation lumen 161 can function as a balloon infusion port in fluid communication with the balloon inflation lumen 160.

[0028] The balloon inflation lumen 160 and the guidewire/drainage/instillation (GDI) lumen 170 interface in Y-body Luer hub 165 to form two separate channels (lumens) in lumen shaft 105. The lumen shaft 105 is elastic and generally cylindrical and can be inserted into a luminal organ, including a ureter, a renal pelvis, an infundibulum, a renal calyx, and a kidney. As shown further in FIG. 1B, the lumen shaft 105 has a generally circular cross section and includes at least two lumens, balloon inflation lumen 160, and guidewire/drainage/instillation lumen 170. Balloon inflation lumen 160 and guidewire/drainage/instillation lumen 170 are formed longitudinally parallel through the length of lumen shaft 105. Lumen shaft 105 extends lengthwise from proximal ends of balloon inflation lumen and guidewire/drainage/instillation lumen 161, 171, along a working length WL to distal tip 150.

[0029] Catheter 101 includes an inflatable balloon 140 with an exposed outer surface 142 positioned near distal tip 150. The balloon 140 is in fluid communication with and receives a solution via balloon inflation lumen 160. In one example of the invention, balloon 140 is approximately 10-20 mm in length and is positioned 15 mm (from 10 mm to 20 mm, for example) from the end of distal tip 150. In its uninflated state (at rest), balloon 140 is approximately 8 mm in diameter and is coaxial with the center of lumen shaft 105. In its inflated state, balloon 140 remains 20 mm in length secured by RO marker bands 144 but can inflate to different diameters (up to approximately 20 mm) to occlude the different luminal organ of interest, including ureter, renal pelvis, and kidney. Example balloon volumes in their inflated state include balloon volumes of 2 cc to 12 cc. In one example of the invention, the balloon volume is 3 cc, and with 3 cc of fluid (e.g., water), the diameter of the balloon is approximately 1.6 cm. With 4 cc of fluid, the diameter of the balloon is approximately 1.8 cm (8 French and 24 French, respectively).

[0030] One example balloon catheter of the invention is made of silicone or PVC, for example, and has a diameter of about 3.2 French, an internal diameter of 0.38, and has a 1-cm elongated oval balloon. The balloon pressure can be adjusted as needed, and can, for instance, reach a maximum of 10 mm Hg. The catheter device can be inserted and positioned with assistance of an imaging technique, such as fluoroscopy, enhanced with a radiological contrast. In one example method of the invention, after positioning, the balloon is inflated to a volume sufficient to occlude the ureter and a liposomal formulation is instilled directly into the proximal ureter as described further below.

[0031] The balloon 140 is formed into a membrane form, from a heat-resistant resin or polymer such as polyurethane, PET (polyethylene terephthalate), elastomer, rubber, silicone, plastic, and other resins or polymers. In use, the balloon 140 is inflated to take the form of a rotating body, such as a substantially spherical form by filling a solution in the balloon 140. In one example of the invention, the solution is a mixture of physiological saline and a contrast agent, but the solution can be either a liquid or a gas, such as saline, sterile water, air, carbon dioxide, and other fluids. The shape of the balloon 140 can be other various shapes (other than the spherical shape) based upon the shape of an intraluminal wall, for example. For example, the balloon 140 can be a spherical shape with minor and major axes equal to each other, an oblate spheroid shape with a minor axis defined as a rotation axis, a prolate spheroid shape with a major axis defined as a rotation axis, a sand bag shape, and other shapes. Regardless of the specific shape of the balloon 140, the balloon 140 should be formed from an elastic member which is deformable when coming in close contact with an intraluminal wall.

[0032] Within the lumen shaft 105 of the catheter 101, balloon inflation lumen 160 provides a solution transport path communicating from a solution source (not shown separately) through Y-body Luer hub 165 to a filling portion formed inside the balloon 140 to deliver or convey the solution to the balloon 140 to inflate (and deflate) balloon 140. The solution source can include a chamber that communicates with the solution transport path (balloon inflation lumen 160) that holds a certain amount of the solution. A stopcock, syringe, valve, or other flow control device can be used to precisely regulate the amount of solution delivered from the solution source through the balloon inflation lumen 160 to balloon 140. As solution is delivered to the balloon 140, the balloon inflates. A piston, or other pressure regulating device, can be placed in line with the balloon inflation lumen 160 to keep balloon 140 inflated to a predetermined pressure or to a determined diameter to occlude the ureteral luminal organ of interest. To deflate the balloon 140, the pressure can be removed from the piston or other pressure regulating device, and the elasticity of the balloon 140 provides compression deformation to deflate the balloon 140 by forcing the solution back through the balloon inflation lumen 160 (from the distal end 112 of the catheter to the proximal end of the balloon inflation lumen 161) to the solution source.

[0033] In use, the inflation fluid remains in a closed system. When inflated, the inflation fluid only enters the balloon inflation lumen 160 and the interior of the balloon 140. When so inflated, the inflation fluid never exits the balloon inflation lumen 160 or the balloon 140 until a health care professional or other user specifically deflates the balloon 140, typically with a syringe or other flow control device similar to the one that was used to the inflate the balloon 140.

[0034] Guidewire/drainage/instillation lumen 170 receives a guidewire via guidewire entrance hole 355 (shown in FIG. 3), which guides distal tip 150 to a target site in a luminal organ target site. The guidewire/drainage/instillation lumen 170 is in fluid communication with the body cavity (e.g., the bladder, the ureter, the renal pelvis, or the kidney) for draining fluid from the body cavity. While this guidewire/drainage/instillation lumen 170 can be used for many purposes (e.g., carrying and delivering radiation therapy devices, instilling pharmaceutical products, placing a camera or other visualization device, removing an obstruction, and other uses), in the invention, the guidewire/drainage/instillation lumen 170 is used to infuse/instill a chemotherapeutic agent in the luminal organ, as described further below. The guidewire/drainage/instillation lumen 170 can also be used to instill radiographic contrast to define the anatomy of the upper ureteral collection system with fluoroscopy or radiography. The guidewire/drainage/instillation lumen 170 can also be used to collect a sample of urine for histological, cytological, or molecular assessment of urothelial cells.

[0035] Valve 175 is placed in-line with guidewire/drainage/instillation lumen 170 after the catheter 101 is placed in a treatment location. In one example of the invention, valve 175 is a modular attachment that mates to the catheter 110 and forms the proximal end of the guidewire/drainage/instillation lumen (GDI port) 171. With a modular construction, the valve 175 can be removed and/or replaced, such as through a conventional Luer or a screw-threaded connection.

[0036] Pyelorenal backflow is essentially a traumatic pressure phenomenon, for example, where leakage of the contrast medium injected up the ureter occurs at the calyceal fornix angle into the renal sinus fat and into the tributaries of the renal veins. To guard against this, some urologists, when injecting contrast media up the ureters, use a funnel and rubber tube and run it in by gravity. The pressure used in injecting with the hand syringe is surprisingly high, even up to 200 mm Hg. Pain is not a reliable guide to the state of filling of the renal pelvis during retrograde pyelography. Some patients tolerate pressures of over 100 mm Hg without discomfort, while some have severe discomfort at 20 mm. The appearance of backflow is a variable phenomenon, occurring at a pressure as low as 25 mm Hg, and pain may or may not accompany it.

[0037] The valve 175 is normally closed and can be set to provide pressure relieve to the guidewire/drainage/instillation lumen 170 when pressure in the luminal organ meets or exceeds a predetermined pressure, such as 15 mm Hg, for example. The pressure relief setting of the valve 175 will be lower than the maximum ureteral pressure, which can be measured or estimated prior to using the catheter 101. The valve 175 of the invention can be set to permit release of luminal fluid/contents into the guidewire/drainage/instillation lumen 170 when the predetermined pressure is exceeded in the luminal organ or in the guidewire/drainage/instillation lumen 170. As shown in FIGS. 1A and 3, the valve 175 can be located near the proximal end of guidewire/drainage lumen 171, for example. As pressure builds up in the luminal organ from urine production and collection while balloon 140 occludes the luminal organ, the pre-determined pressure is exceeded and valve 175 opens to allow urine to drain from the distal tip 150 of the catheter 101 toward the proximal end of the guidewire/drainage/instillation lumen 171. Removing a volume of urine from the luminal organ relieves pressure (i.e., pressure decreases as intraluminal volume decreases) in that organ and prevents injury and pyelovenous exposure to the patient. When the pressure in the luminal organ drops to below the predetermined pressure, the valve 175 closes again and remains closed unless the pressure again builds to meet or exceed the predetermined pressure, when the valve 175 opens again. The normally-closed one-way check valve provides for intermittent injection of fluids while preventing back flow. The valve opens automatically when pressure is applied.

[0038] The valve 175 includes construction components that do not permit fluid from exiting the lumen 170 until a given pressure is overcome. For example, the valve 175 can include a housing with a lumen, a ball, and a spring within the lumen where the spring presses the ball against a defined opening. When pressure on the ball exceeds the force of the spring, the ball moves away from the defined opening and fluid moves around the ball and vents to the proximal end 171. By controlling tension on the spring, the pressure at which the valve releases pressure can be controlled. It can also be appreciated that the pressure release valve can be coupled to a Luer connector, which can be further coupled to additional valves, collection sources, and other drainage apparatus. The valve 175 can be selected based on pressure control characteristics. For example, pyelovenous feedback occurs around 15-20 cm of water pressure (or about 0.27 psi.), so our crack pressure (that is, the pressure at which the valve releases the fluid) should be around 0.27 PSI. FIG. 5 shows a number of example valves and their performance characteristics.

[0039] This given pressure can be selectable by the physician depending upon the one-way valve that is chosen for use, where the invention includes a set of one-way valves having different predetermined pressures that are available for use by the physician. As outlined above, the pressure can be set to correspond to desired maximum ureteral pressure values. Therefore, when used, the fluid exits the valve 175 at the proximal end of the guidewire/drainage/instillation lumen 171 well before the patient's maximum ureteral pressure is exceeded.

[0040] The methods involve placing a balloon catheter 101 that has a working channel (guidewire/drainage/instillation lumen 170) and a balloon 140 into the ureter/renal pelvis via retrograde (or antegrade) upper urothelial tract access. The catheter balloon 140 is inflated to temporarily obstruct the ureter, and a liquid liposomal formulation with a chemotherapeutic agent (or a non-liposomal chemotherapeutic formulation) is infused/instilled into the working channel (guidewire/drainage/instillation lumen 170) of the catheter 101. The infused liposomal formulation is allowed to dwell in the ureter and/or renal pelvis for a period of time sufficient to allow at least a portion of the formulation to adhere to (and partially penetrate) the urothelial wall. In methods of the invention, the dwell time is from about 1 to about 120 minutes. For example, the liposomal formulation can be allowed to dwell for at least 1 minute, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 105 minutes, or at least 120 minutes. In the methods of the invention, the infused chemotherapeutic-agent contacts and adheres, to the urothelial wall while it is instilled and dwells in the ureter and/or renal pelvis.

[0041] As indicated above, the invention can be used to deliver a therapeutic dose of a drug to the ureter and/or renal pelvis via instillation. More particularly, the invention is generally used to deliver a chemotherapeutic drug formulation, such as, but not limited to, a taxane class drug, a platinum-based drug, 5-fluorouracil, mitomycin C, gemcitabine, epirubacin, or thiotepa, for the purpose of treating UTUC. Preferred chemotherapeutic drug formulations are liposomal formulations of chemotherapeutic drugs. Liposomal formulations according to the invention, generally, contain at least one phospholipid component that is a pharmaceutically acceptable phospholipid or mixture of pharmaceutically acceptable phospholipids. Natural as well as synthetic phospholipids may be used. Examples of phospholipids in liposomal formulations used with the invention include, but are not limited to distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, egg phosphatidylcholine, soy phosphatidylcholine, dimyristyl phosphatidyl glycerol sodium, 1,2-dimyristoyl-phosphatidic acid, dipalmitoylphosphatidylglycerol, dipalmitoyl phosphate, 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol, 1,2-distearoyl-sn-glycero-3-phosphatidic acid, phosphatidylserine and sphingomyelin. For example a liposomal formulation used with the invention may contain dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidyl glycerol sodium (DMPG). Therefore, a liposomal formulation delivered by a catheter described herein may contain paclitaxel, DMPC and DMPG. For example, the respective weight/weight ratios of paclitaxel, DMPC and DMPG in a liposome used with the invention may be 1:(1-10):(1-10), or any ratios therein.

[0042] A liposomal formulation according to the invention may also be composed of, or partially composed of lipids other than phospholipids, such as lipids containing no phosphoric acid, like a glycerolipid or a sphingolipid. Alternatively, liposomal formulations used with the invention, including liposomal formulations that contain one or more lipids other than phospholipids, may additionally contain a cholesterol, or cholesterol derivative component.

[0043] Liposomal formulations that can used with the invention also include formulations disclosed in: WO 2019/018619, which is directed to liposome formulations that include paclitaxel, lecithin, cholesterol, threonine, and glucose, including the paclitaxel formulation marketed under the trade name, Lipusu; and U.S. Patent Publication No. 2019/0015334 (“USPPN 2019/0015334”), which discloses liposomal formulations of paclitaxel, docetaxel, or cisplatin.

[0044] More preferred formulations for use with the invention are those described in USPPN 2019/0015334, which contain either paclitaxel, docetaxel, or cisplatin in combination with dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidyl glycerol sodium (DMPG). The most preferred formulations in USPPN 2019/0015334 contain (A) drug (paclitaxel, docetaxel, or cisplatin), (B) DMPC; and (C) DMPG in weight/weight ratios of (A):(B):(C) of (1):(1.3-4.5):(0.4-2.5), or any ratios therein, such as the combination of paclitaxel, DMPC and DMPG w/w ratios of (1):(1.43):(0.47).

[0045] A therapeutic dose of a chemotherapeutic drug is an amount of drug, that, when delivered to the ureter or renal pelvis of a subject with UTUC, ameliorates a sign or symptom of UTUC. For example, a therapeutic dose of a drug, when administered by the invention in either a single administration or multiple administrations, causes a reduction in tumor burden or a decrease in the number of size of metastases. The terms “ameliorating” or “treating” refer to the reduction in the number or severity of signs or symptoms of a disease, including the complete eradication of the disease. The amount of drug in a therapeutic dose, which may also be called an “effective dose”, depends on the stage, severity and course of the UTUC, previous therapy, the individual's health status, weight, response to the drugs, and/or the judgment of the treating physician. Exemplary therapeutic dose for a method of the invention include an amount of paclitaxel that ranges from is 1 to 1000 mg/m.sup.2. For example, the therapeutic dosage may be from: 1 to 100 mg/m.sup.2; 50 to 150 mg/m.sup.2; 100 to 200 mg/m.sup.2; 150 to 250 mg/m.sup.2; 200 to 300 mg/m.sup.2; 350 to 450 mg/m.sup.2; 400 to 500 mg/m.sup.2; 450 to 550 mg/m.sup.2; 500 to 600 mg/m.sup.2; 550 to 650 mg/m.sup.2; 600 to 700 mg/m.sup.2; 750 to 850 mg/m.sup.2; 800 to 900 mg/m.sup.2; 850 to 950 mg/m.sup.2; 900 to 1000 mg/m.sup.2; or 950-1000 mg/m.sup.2. The concentration of the administered therapeutic dose of paclitaxel in an exemplary use of the invention—the amount of paclitaxel instilled by a catheter according to the invention to the ureter or renal pelvis—may, for example, be at least 0.5 mg/ml, at least 1 mg/ml, at least 1.5 mg/ml, at least 2 mg/ml, at least 2.5 mg/ml, at least 3 mg/ml, at least 3.5 mg/ml, at least 4 mg/ml, at least 4.5 mg/ml, at least 5 mg/ml, or any concentration therein.