Drug delivery device and system for local drug delivery to the upper urinary tract

Abstract

The present invention provides a drug delivery device and system for delivering drugs to the upper urinary tract of patients who require them. [Solution] The drug delivery device is deployed directly into the renal pelvis 1902 via the patient's ureter 1940, bladder 1930, and urethra, and the drug delivery device can be held therein for localized, continuous, controlled release of the drug over a long period of time.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 757,798, filed Nov. 9, 2018, which is incorporated herein by reference in its entirety.

[0002] (Field of the Invention) The present disclosure generally relates to an in vivo deployable drug delivery device for the controlled local delivery of therapeutic and prophylactic agents to the upper urinary tract of a patient who needs it, and more specifically, to a drug delivery device and method for the local administration of drugs to a patient's renal pelvis over a long period of time.

Background Art

[0003] Implantable drug delivery devices are known to be targeted, for example, for local or topical drug delivery, to avoid one or more problems associated with systemic drug delivery. However, there is room for significant improvement in the targeted drug delivery to some tissue sites. Such sites include the kidneys and ureters.

[0004] Currently available drug delivery device - based therapies are invasive and / or can deliver drugs only while the delivery catheter extends from outside the patient's body into the body. Some such systems, such as the BENEPHIT (trademark) renal infusion system, deliver therapeutic agents directly to the kidneys via the renal artery through a catheter system, but require an arterial puncture that is undesirable in an interventional or surgical procedure.

Summary of the Invention

Problems to be Solved by the Invention

[0005] There is still a need for minimally invasive drug delivery devices and methods for providing drug delivery to the upper urinary tract, e.g., into the renal pelvis, particularly over a long period of time, preferably continuously, and while the patient is walking.

Means for Solving the Problems

[0006] Improved drug delivery devices and systems, as well as methods for drug delivery, are provided herein. The drug delivery device may be deployed directly into the renal pelvis via the natural lumen of the patient's body, i.e., via the ureters, bladder, and urethra, and the drug delivery device may be permanently retained therein for drug delivery over a long period, for example, several days or several weeks, without relying on external supply of the drug and catheters that remain in the body during the administration period. In some embodiments, the drug delivery device is inserted into the renal pelvis and configured to deliver the drug continuously therein, preferably providing a primary release rate of a therapeutically effective amount of the drug.

[0007] In one embodiment, a drug delivery device is provided that is configured to be deployed in the renal pelvis of a patient. In this embodiment, the device comprises (i) an elongated elastic body having a guidewire lumen and a separate drug reservoir lumen, and (ii) a drug payload disposed within the drug reservoir lumen, the drug payload containing a drug, wherein the drug delivery device is elastically deformable between (a) a deployment shape configured to pass the drug delivery device through the ureter into the renal pelvis of a patient, and (b) a retaining shape configured to reduce movement of the device from the renal pelvis. In some preferred embodiments, the retaining shape is helical. In some embodiments, the elastic body includes (i) an outer tube with an elongated outer wall, and (ii) an elongated arc-shaped inner wall located within the outer tube, integrally connected to the inner surface of the outer wall along two opposing edges of the arc-shaped inner wall, wherein the outer and inner walls together define (a) a guide wire lumen on the concave side of the inner wall and (b) a drug reservoir lumen on the opposing convex side of the inner wall, the drug reservoir lumen being closed at its opposite end.

[0008] In another embodiment, a system is provided for the local administration of a drug to the renal pelvis of a patient. In some embodiments, the system includes a drug delivery device as described herein and a guidewire deployment system for deploying the drug delivery device in the renal pelvis, the guidewire deployment system including (i) a guidewire and (ii) a plunger device for pushing the drug delivery device on the guidewire.

[0009] In yet another embodiment, a method is provided for administering a drug to a patient in need of the drug. In some embodiments, the method comprises deploying a drug delivery device in the patient's renal pelvis and continuously releasing the drug from the deployed drug delivery device into the urine in the renal pelvis for a long-term treatment period of at least 24 hours, wherein the drug delivery device is entirely housed in the renal pelvis, with the optional exception of a retrieval string extending at least into the patient's ureter. [Brief explanation of the drawing]

[0010] Detailed descriptions are provided with reference to the accompanying drawings. The use of the same reference numeral may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components shown in the drawings are not necessarily drawn to scale. Throughout this disclosure, singular and plural terms may be used interchangeably depending on the context. [Figure 1A] This is a perspective view of one embodiment of a drug delivery device having a helical retaining shape disclosed herein. [Figure 1B] Figure 1A is a perspective view of the drug delivery device in a linearized configuration. [Figure 1C] This is a cross-sectional view of the drug delivery device shown in Figure 1B, along the cutting line CC in Figure 1B. [Figure 2] This is a perspective view of one embodiment of a drug delivery device having a single coil holding configuration as disclosed herein. [Figure 3]This is a cross-sectional view of one embodiment of a drug delivery device having a triple lumen design as disclosed herein. [Figure 4A] This is a linearized plan section view of one embodiment of a drug delivery device as disclosed herein, the cross-sectional plane extending longitudinally through the ends of the device and the lumen of the drug reservoir. [Figure 4B] Figure 4A is a plan view of the drug delivery device shown. [Figure 4C] Figure 4A is a side cross-sectional view of the drug delivery device, where the cross-sectional plane extends longitudinally through the end of the device and through the lumen of the drug reservoir and the lumen of the guidewire. [Figure 5A] This is a plan section view of a linearized configuration of another embodiment of a drug delivery device disclosed herein, the cross-sectional plane extending longitudinally through the ends of the device and the lumen of the drug reservoir. [Figure 5B] Figure 5A is a plan view of the drug delivery device shown. [Figure 5C] Figure 5A is a side cross-sectional view of the drug delivery device, where the cross-sectional plane extends longitudinally through the end of the device and through the lumen of the drug reservoir and the lumen of the guidewire. [Figure 6] This is a perspective view of one embodiment of a drug delivery device having a spiral holding shape and straight ends. [Figure 7] This is a perspective view of another embodiment of a drug delivery device having a spiral retaining shape and straight ends. [Figure 8] This is a perspective view of one embodiment of a drug delivery device having a spiral holding shape with two relatively linear intermediate portions. [Figure 9] This is a perspective view of one embodiment of a drug delivery device having a spiral holding shape with a single, relatively linear intermediate portion. [Figure 10A] This is a perspective view showing a part of one embodiment of a drug delivery device having tapered ends. [Figure 10B]A side cross-sectional view in a straightened configuration of another embodiment of a drug delivery device having a tapered end, where the cross-sectional plane extends longitudinally through the end of the device and through the drug reservoir lumen and the guide wire lumen. [Figure 11] A graph of the in vitro drug release rate from a drug delivery device according to two different embodiments described herein. [Figure 12] A graph of the in vitro drug release rate from a drug delivery device according to two different embodiments described herein. [Figure 13] A perspective view and a front view of one embodiment of a crescent-shaped drug tablet as disclosed herein. [Figure 14A] A perspective view of one embodiment of a deployment system for deploying a drug delivery device as disclosed herein, for example, into the renal pelvis of a patient. [Figure 14B] A perspective view of the deployment system shown in FIG. 14A after advancement of the drug delivery device along the guide wire. [Figure 15] A side cross-sectional view in a straightened configuration of one embodiment of a drug delivery device, where the cross-sectional plane extends longitudinally through the end of the device and through the drug reservoir lumen and the guide wire lumen, showing one embodiment of an attached retrieval string. [Figure 16] A side cross-sectional view in a straightened configuration of one embodiment of a drug delivery device, where the cross-sectional plane extends longitudinally through the end of the device and through the drug reservoir lumen and the guide wire lumen, showing another embodiment of an attached retrieval string. [Figure 17] A plan cross-sectional view of a spacer for insertion into the end of the lumen of one embodiment of a drug delivery device as described herein, the spacer including a lateral through-hole through which a retrieval string is secured. [Figure 18] A block diagram of one embodiment of a method for deploying a drug delivery device as described herein into a patient's body, for example, into the renal pelvis of a patient. [Figure 19]An embodiment of a drug delivery device as described herein is shown, having a spiral retaining shape and positioned within the renal pelvis, with an attached retrieval string extending from the drug delivery device through the ureter into the bladder. [Modes for carrying out the invention]

[0011] Drug delivery devices, systems, and methods that may be used to treat one or more conditions of the upper urinary tract are provided herein. One or more conditions of the upper urinary tract may include renal cancer, ureteral cancer, or other diseases affecting the kidneys and / or ureters. The drug delivery devices described herein may be deployed in the upper urinary tract, for example, within the renal pelvis. The drug delivery devices are capable of releasing drugs into the upper urinary tract over a prolonged period.

[0012] After deployment, the device can advantageously deliver drugs locally into the renal pelvis for several days or weeks, without the use or need of an external pump, ureteral stent, or transurethral catheter. In other words, the entire drug payload and means for beneficially controlling drug release are integrated into the renal pelvis.

[0013] In some embodiments, a drug delivery device for deployment into a patient's renal pelvis comprises (i) an elongated elastic body having a guidewire lumen and a separate drug reservoir lumen, and (ii) a drug payload disposed within the drug reservoir lumen, the drug payload containing a drug, and the drug delivery device is elastically deformable between (a) a deployment shape configured to pass the drug delivery device through the ureter into the patient's renal pelvis and (b) a retaining shape configured to reduce movement of the device from the renal pelvis. In some preferred embodiments, the retaining shape is helical. In some embodiments, the helical retaining shape has 2 to 10 turns.

[0014] The device is an elastic wire configured to bias the guidewire into a retaining shape when the guidewire is not inserted into the guidewire lumen, by an elastic body further comprising (i) a retaining frame lumen and a retaining frame positioned within the retaining frame lumen. The retaining frame is an elastic wire configured to bias the drug delivery device into a retaining shape.

[0015] In some embodiments, the drug delivery device typically includes a retrieval string attached at one end to an elongated elastic body, the retrieval string being long enough so that its end is in the patient's bladder when the drug delivery device is deployed in the renal pelvis.

[0016] The drug payload may be in any preferred form, but in some preferred embodiments, the drug payload is in the form of a powder or a plurality of tablets. In some embodiments, the elongated elastic body includes a water-permeable wall configured to allow urine to diffuse into the lumen of the drug reservoir and come into contact with the drug payload. In some embodiments, the elongated elastic body includes a drug-permeable wall adjacent to the lumen of the drug reservoir, which is configured to allow the drug to diffuse from the device in solution. The elongated elastic body may further include a drug-impermeable wall adjacent to the lumen of the drug reservoir, for example, to limit the area available for transwall diffusion of the drug, thereby slowing / extending the release of the drug. In some embodiments, the elastic body is formed from one or more thermoplastic polyurethanes, such as aliphatic polyethers. For example, in some embodiments, the drug-permeable wall includes Tecophilic® polyurethane and the drug-impermeable wall includes Tecoflex® polyurethane. The drug-permeable wall may be in the form of a drug-permeable stripe extending along the length of the elastic body.

[0017] The opposing ends of the drug reservoir lumen are typically sealed by end spacers, while the guidewire lumen is left open at both ends to allow the guidewire to pass through.

[0018] The drug delivery device may further include one or more intermediate spacers positioned approximately midway between the opposing ends of an elongated elastic body within the lumen of the drug reservoir. The elastic body, end spacers, and / or intermediate spacers may include, for example, a radiopaque filling material to facilitate placement within the renal pelvis and to allow visualization of the device in vivo.

[0019] In some embodiments, the drug reservoir lumen has a crescent-shaped cross-section, and the drug payload comprises a powder or a plurality of crescent-shaped tablets.

[0020] In some embodiments, the elastic body of the drug delivery device includes (i) an outer tube with an elongated outer wall, and (ii) an arc-shaped elongated inner wall located within the outer tube, integrally connected to the inner surface of the outer wall along two opposing edges of the arc-shaped inner wall, wherein the outer and inner walls together define (a) a guide wire lumen on the concave side of the inner wall and (b) a drug reservoir lumen on the opposing convex side of the inner wall, the drug reservoir lumen being closed at its opposite end.

[0021] In some embodiments, the elastic body of the drug delivery device has at least one straight end portion. In some embodiments, each of the two opposing end portions is a straight end portion. In some embodiments, the elastic body includes one or more intermediate straight portions and / or one or more helical portions, the straight portions or helical portions being located between the opposing end portions of the elastic body.

[0022] In some embodiments, the outer tube of the drug delivery device comprises two different constituent materials, the first of which is permeable to water but impermeable to the drug when the drug is in solution, and the second of which is permeable to water and permeable to the drug when the drug is in solution. The second material may be adjacent to the drug payload. As used herein, the phrase “impermeable to drug” means a material that is substantially impermeable to the drug so that the drug is not released through the material over the therapeutic release period. In some embodiments, the drug delivery device is operable in vivo to allow water to diffuse into the lumen of the drug reservoir through the first and second materials to solubilize the drug payload, and to controllably release the solubilized drug from the drug delivery device through the second material. In one embodiment, the second material is a drug-permeable wall formed of Tecophilic® polyurethane, and the first material is a drug-impermeable wall formed of Tecoflex® polyurethane. In some embodiments, these walls are connected laterally to one another, resulting in each directly forming a boundary and together defining a drug reservoir within the device. In some cases, this means that the walls together define an annular structure.

[0023] In some alternative embodiments, the first material is both water-impermeable and drug-impermeable, while the second material is both water-permeable and drug-permeable.

[0024] One embodiment of a drug delivery device described herein is shown in Figures 1A to 1C. Figure 1A shows a drug delivery device 100 comprising an elongated elastic body 102 and a retrieval string 180 attached to one end of the elongated elastic body 102. In Figure 1A, the device 100 is shown in a helical retaining configuration. Figure 1B shows the device 100 in a linearized deployment configuration. As shown in Figures 1B to 1C, the elastic body 102 includes a guidewire lumen 112 extending through its interior and a separate drug reservoir lumen 114 extending within the elastic body 102. The drug payload 116 is placed within the crescent-shaped drug reservoir lumen 114. In this embodiment, the drug payload 116 is in the form of a plurality of crescent-shaped tablets. The elastic body 102 includes an outer tube 104 with an elongated outer wall 106, and an elongated arc-shaped inner wall 108 located inside the outer tube, which is integrally connected to the surface of the outer wall along the opposing edges of the arc-shaped inner wall 108. The drug reservoir lumen 114 is defined longitudinally on the convex side of the inner wall 108, and the guidewire lumen 112 is defined longitudinally on the opposing concave side of the inner wall 108. The opposing ends of the drug reservoir lumen 114 are each sealed with end spacers 120.

[0025] In the embodiments shown in Figures 1A to 1C, the elastic body is formed of two constituent materials: one material forming a drug-impermeable wall 122 and the other material forming a drug-permeable wall 124. The drug-permeable wall 124 defines at least a portion of the drug reservoir lumen 114 and is therefore adjacent to the drug payload 116 located within the drug reservoir lumen 114. The material forming the drug-impermeable wall 122 may also form the arcuate inner wall 108 and the remainder of the outer tube 104, i.e., the portion of the drug-permeable material excluding the stripe that functions as the drug-permeable wall 124 as shown. In this embodiment, as shown in Figure 1A, the end 190 of the elastic body is obtuse, i.e., not tapered, and the terminal portion of the elastic body is helical when in a helical retaining shape.

[0026] The drug-permeable wall (stripe) 124 traverses the entire length of the drug delivery device 100, providing a pathway for drug release. The width of the drug-permeable stripe may be selected to adjust the effective rate of transwall diffusion of the drug through it. Since the outer tube 104 has a circular cross-section, the width of the drug-permeable stripe can be characterized by the arc angle of the stripe. In the embodiment shown in Figure 1C, the arc angle α is approximately 60°. However, the angle and / or length and / or shape of the drug-permeable stripe can be varied to change the drug release rate.

[0027] Figure 2 shows another embodiment of the drug delivery device. Here, the drug delivery device 200 includes an elastic body 202 and a retrieval string 280. This has a similar configuration to that of the drug delivery device 100, but the retaining shape is a single coil with overlapping end portions.

[0028] Figure 3 shows another embodiment of the drug delivery device. Here, the drug delivery device 300 includes an elastic body 302. Similar to the configuration of the drug delivery device 100, it includes a guidewire lumen 312 extending through the interior and a separate crescent-shaped drug reservoir lumen 314 that extends the length of the elastic body 302 and houses a drug payload 316 located within the drug reservoir lumen 314. The elastic body 302 further includes a third lumen, which is a retaining frame lumen 330 in which a retaining frame 332 is located. In this illustrated embodiment, the retaining frame lumen 330 is defined near the intersection of the edges of the arc-shaped inner wall 308 and outer wall 306. Similar to the configuration of the drug delivery device 100, the outer wall 306 may be formed by double-material polyurethane extrusion, and the drug reservoir lumen is at least partially defined by stripes of a secondary polyurethane material that is permeable to water and drugs. In some cases, the majority of the tube is made from water-permeable polyurethane. The drug delivery device 300 may have a spiral holding shape as shown in Figure 1A.

[0029] Figure 6 shows an embodiment of a drug delivery device 600 having an elastic body with an intermediate helical portion 674 and opposing straight end portions 672. The straight end portions 672 include a tapered end 676. The straight end portions 672 extend in a direction substantially perpendicular to the winding plane of the central helical portion 674, i.e., they extend in the longitudinal direction of the device. The straight end portions 672 may be thermally shaped. Although these end portions are referred to as “straight,” it is understood that they do not need to literally coincide with a single straight line. As is evident in Figure 6, the straight end portions 672 have a slight curvature but are relatively straight compared to the helical portion 674, and differ from the helical end portions of device 100 in Figure 1A. The straight end portions 672 extend from both sides of the helical portion 674 such that when the device is in a holding shape, one straight end portion 672 (e.g., the tip) is substantially aligned (diagonally with respect to the device) with the other straight end portion 672 (e.g., the rear end). This configuration has advantages in that (i) it facilitates loading and deploying the drug delivery device on the guidewire, (ii) it can improve retention within the renal pelvis, and (iii) it assists in the precise placement of the device within the renal pelvis because the leading straight end portion substantially maintains its position (because it is not coiled) when it is pushed out from the guidewire.

[0030] Another modification of this embodiment is shown in Figure 7. The drug delivery device 700 similarly includes a central helical portion 774 and a straight end portion 772. However, the straight end portion is not aligned obliquely to the drug delivery device, but instead is generally located on the same side as the helical portion 774 and aligned along a line substantially parallel to the longitudinal axis of the drug delivery device 700. The straight end portion 772 includes a tapered end 776.

[0031] In some other embodiments, the elongated body of the drug delivery device has one or more intermediate straight sections positioned between coils or helices. Non-limiting examples of these embodiments are shown in Figures 8-9. These configurations may be particularly suitable for use in patients with specific renal pelvis anatomical structures and / or sizes. For example, intermediate straight sections may be suitably positioned within the pinching point area of ​​the renal pelvis of smaller kidneys, providing retention without applying excessive pressure to the pinching point tissue. Similar to the linear terminal sections, the intermediate straight sections may have slight curvature, but are clearly more linear than the windings or coils in the helical sections described above.

[0032] Figure 8 shows an embodiment of a drug delivery device 800, which includes an elongated body comprising three loops 874 separated by two intermediate straight sections 878. This device includes a tapered end 876. Figure 9 shows an embodiment of a drug delivery device 900, which includes an elongated body comprising two loops 974 separated by a single intermediate straight section 978. This device includes a tapered end 976.

[0033] The size, number, and arrangement of the intermediate straight and coiled sections can be selected to accommodate both the varying drug payload volumes required by different patients and the anatomical features of the renal pelvis. The overall size and deployability of the device can also influence the selected design of the drug delivery device. For example, a drug delivery device may have a shorter non-coiled length by using fewer turns in the helical section. Alternatively, a tighter coil can be achieved by reducing the outer diameter of the coil. A small drug delivery device with an outer coil diameter of approximately 8 mm, or even 7 mm, may be an effective retention size for smaller kidneys, while a drug delivery device with an outer coil diameter of approximately 12 mm or more may be an effective retention size for larger kidneys. While the outer coil diameter can be reduced to 7 mm or less, loading the device onto the guidewire and deploying it may become more difficult.

[0034] Elastic body The elastic body functions as a housing for the drug payload and controls the release of the drug by transwall diffusion and / or osmotic pressure. In some embodiments, the elastic body includes walls defining a drug reservoir lumen, a guidewire lumen, and optionally a retaining frame lumen. The walls forming the elastic body of the drug delivery device described herein may be formed by an extrusion (or co-extrusion) process such that the outer tube and inner wall are integrally connected. In some embodiments, the elastic body is thermally shaped to have a retaining shape.

[0035] In some embodiments, the elastic body generally has an external shape that is a long, thin tube, and in the retaining shape, it is wound around itself, for example, in a helical shape. The lumen extending along the length of the elastic body may have essentially arbitrary size or shape, allowing for the loading of a sufficient drug payload volume, and may accommodate a guidewire of sufficient diameter to bring the device into the renal lumen. The walls that boundary / define the lumen need to be thick enough to allow the device to be small enough to fit into the renal pelvis, and the wall thickness and area to be sized to achieve desired water permeability and drug release kinetics, while at the same time allowing the device to be flexible during deployment, use, and retrieval while maintaining adequate mechanical robustness.

[0036] The elastic body may be formed of one or more materials having sufficient flexibility so that the drug delivery device described herein is deformable and can therefore assume a deployment shape and a retaining shape. In particular, the material may be a biocompatible elastomer, such as a thermoplastic elastomer known in the art. The device is typically biased into a retaining shape and therefore has a retaining shape when there is no load (e.g., a load effective in elastically deforming toward / to a linearized shape or a deployment shape). The load may be applied by the presence of a guidewire extending through the lumen of the guidewire within the elastic body.

[0037] In some embodiments, the outer tube of the drug delivery device comprises two different constituent materials, the first of which is impermeable to the drug when the drug is in solution, and the second of which is permeable to the drug when the drug is in solution. The second material may be adjacent to the drug payload. In other words, the second material is positioned such that at least a portion of the drug placed in the drug delivery device can come into contact with at least a portion of the second material before, during, and / or after the drug is dissolved.

[0038] In some embodiments, the drug delivery device described herein includes a drug-permeable stripe of a second material. In some embodiments, the drug-permeable stripe crosses about 50% to 100%, about 80% to 100%, about 90% to 100%, or 100% of the longitudinal length of the outer tube. In some embodiments, the drug delivery device described herein includes an outer tube having two or more distinct parts formed from the second material. One or more distinct parts may have any preferred size or dimensions.

[0039] If the drug delivery device described herein includes a drug-permeable stripe of a second material, the drug-permeable stripe may have arc angles of approximately 30° to approximately 120°, approximately 40° to approximately 120°, approximately 45° to approximately 120°, approximately 55° to approximately 120°, approximately 60° to approximately 120°, approximately 60° to approximately 120°, approximately 60° to approximately 110°, approximately 60° to approximately 100°, approximately 60° to approximately 90°, or approximately 60° in cross-section. The “arc angle” of the drug-permeable stripe is, in other words, the angle formed between a first line and a second line extending from the center of the outer tube to the first and second sides of the drug-permeable stripe.

[0040] In some embodiments, the inner diameter of the outer tube is approximately 1.0 mm to approximately 2.3 mm. In some embodiments, the outer diameter of the outer tube is approximately 2.2 mm to approximately 2.4 mm. In some embodiments, the wall thickness (i.e., the difference between the outer and inner diameters) of the outer tube, the first inner tube, and / or the second inner tube is approximately 0.1 mm to approximately 1.4 mm, or approximately 0.15 mm to approximately 0.25 mm. In some embodiments, the thickness of the outer tube is different from the thickness of the first inner tube, the second inner tube, or a combination thereof.

[0041] Generally, the elastic body of a drug delivery device described herein may be made of one or more materials that impart sufficient flexibility to the drug delivery device to allow it to deform between a holding shape and a deployment shape. If the elastic body comprises a first material and a second material as described herein, the first material may generally include any flexible material, such as an elastomer, that is substantially impermeable to the drug contained in the drug delivery device. In some cases, this elastomer is water-permeable. The second material may generally include any flexible material, such as an elastomer, that is permeable to water and the drug contained in the drug delivery device.

[0042] The first and second materials may be selected from a variety of suitable materials, such as silicone, polyurethane, ethylene vinyl acetate (EVA), thermoplastic silicone polyether polyurethane, aliphatic thermoplastic silicone polyether polyurethane, segmented polyether polyurethane, thermoplastic polyether polyurethane, thermoplastic polycarbonate polyurethane, BIONATE® PCU, BIOSPAN® SPU, CARBOSIL® TSPCU, ELASTHANE® TPU, PURSIL® TPU (DSM), aliphatic and aromatic polycarbonate-based thermoplastic polyurethanes, other thermoplastic polyurethanes (TPU), such as CARBOTHANE® TPU, TECOFLEX® TPU, TECOTHANE® TPU, PELLETHANE® TPU, and TECOPHILIC® TPU, as well as combinations or blends thereof.

[0043] In some embodiments, the second material is selected from TECOPHILIC® thermoplastic polyurethane, HYDROTHANE® thermoplastic polyurethane (AdvanSource Biomaterials Corp.), QUADRAPHILIC® thermoplastic polyurethane (Biomerics, LLC) (ALC grade is aliphatic polycarbonate-based, and ALE grade is aliphatic polyether-based hydrophilic polyurethane), HYDROMED® (AdvanSource Biomaterials Corp.), or DRYFLEX® (HEXPOL TPE). Another hydrophilic polymer that may be selected for the second material is polyether block amide PEBAX® MV 1074 SA 01 MED (Arkema), which is a thermoplastic elastomer made from flexible and hydrophilic polyether and rigid polyamide.

[0044] In some embodiments, the elastic body comprises one, two, or more water-permeable thermoplastic polyurethanes. For example, the elastic body may be formed by an extrusion process that forms an elongated body comprising two parallel lumens and (i) more than 50% by weight of a first water-permeable thermoplastic polyurethane and (ii) less than 50% by weight of a second water-permeable thermoplastic polyurethane. In some of these cases, the first water-permeable thermoplastic polyurethane is drug-impermeable, and the second water-permeable thermoplastic polyurethane is drug-permeable.

[0045] In some embodiments, the elastic body comprises a first material and a second material, the first material comprising Tecoflex polyurethane and the second material comprising tecophilic polyurethane. In some embodiments, the Tecoflex polyurethane comprises TECOFLEX® EG-80A-B20, 20% barium sulfate-added Tecoflex polyurethane (Lubrizol Life Sciences, USA). In some embodiments, the Tecoflex polyurethane comprises TECOFLEX® EG-100A-B20, 20% barium sulfate-added Tecoflex polyurethane (Lubrizol Life Sciences, USA). In some embodiments, the tecophilic polyurethane comprises TECOPHILIC® HP-60D-35 TPU (thermoplastic polyurethane) (Lubrizol Life Sciences, USA). In some embodiments relating to specific drugs, the Tecoflex polyurethane is a drug-impermeable material with barium sulfate addition, which may allow visualization during insertion or retrieval of the device. In some embodiments relating to specific drugs, TECOPHILIC® TPU is a water-permeable and drug-permeable material that allows water to enter the drug delivery device and allows solubilization or liquid drugs to pass through the second material and enter the space surrounding the drug delivery device.

[0046] For use in the renal pelvis, the deployed device should be conformable to avoid or reduce discomfort and irritation to the patient (i.e., easily bendable and soft to the touch), but not so conformable that it easily and unintentionally moves from the renal pelvis into the renal calyces or ureter, for example, being carried into the ureter with the flow of urine. Therefore, the durometers of the first and second materials of the structure may be important, and the proportion of high-durometer material may be limited in constructing an elastic body of a given size while maintaining suitable conformity within the renal pelvis. For example, TECOPHILIC® thermoplastic polyurethane (Lubrizol Corp.) may have a Shore hardness higher than 70A, e.g., 80A to 65D, while other drug-impermeable thermoplastic polyurethanes may have a lower or higher Shore hardness than TECOPHILIC®, such as less than 90A. Therefore, it may be advantageous to utilize a combination of two different polymer materials to obtain the desired mechanical properties of the device, rather than fabricating the entire device from a second material that is water-swellable, hydrophilic, and drug-permeable.

[0047] In some embodiments, the drug delivery device may have a tapered end rather than a blunt end, such that the terminal portion of the elongated elastic body is narrower than the central portion of the elongated elastic body. Figure 10A shows one embodiment of a drug delivery device in which the elastic body 1002 includes a tapered terminal portion 1060. The tapered end can advantageously increase the ease with which the drug delivery device can be inserted into the patient's ureter and reach the renal pelvis, as the tapering reduces tissue capture at the end of the device. Similarly, the tapered end can also facilitate the withdrawal of the device from the renal pelvis during the removal process, facilitating entry into the ureter and possibly into the urethra. Therefore, either or both of the leading and trailing ends of the device may be tapered. The tapered end may be part of a straight or coiled terminal portion.

[0048] Figure 10B shows a cross-sectional view of one embodiment of a drug delivery device 1000 having a tapered end 1060. The elongated elastic body includes an outer wall 1006 having a drug permeable stripe 1024. The drug reservoir lumen is closed by a spacer 1020 which may be placed therein before the end is formed into a tapered end. As shown, the outer wall 1006, the drug permeable stripe 1024, the inner wall 1008, and the spacer 1020 may be plastically deformed (e.g., thin and rounded) in the process of forming a taper toward the end of the drug delivery device, but the process of forming the tapered end should not narrow or crush the guidewire lumen 1012 to any extent that it completely or at least prevents the passage of the guidewire. This may result in the tapered end portion being asymmetrical about the longitudinal central axis of the device, as shown in Figure 10B.

[0049] The length of the elastic body of the drug delivery device described herein may be selected depending on a variety of factors, including the amount of drug payload that needs to be managed over the course of treatment in which the device is deployed, the release kinetics of a particular drug, and the overall shape and size required to keep the device within the renal pelvis.

[0050] In some embodiments, the elastic body has lengths of approximately 5 cm to 15 cm, 5 cm to 12 cm, 6 cm to 12 cm, 7 cm to 12 cm, 8 cm to 12 cm, 10 cm to 12 cm, 10 cm, or 12 cm when in a relatively linearized deployment shape.

[0051] In some embodiments, the elastic body of the drug delivery device described herein may be manufactured to be fully or partially biodegradable so that recovery of the drug delivery device is not required after drug release. In some embodiments, the drug delivery device is partially biodegradable so that, upon partial erosion, it breaks down into non-erosive pieces small enough to be excreted through the upper urinary tract. As used herein, the term “biodegradable” means that the drug delivery device or a part thereof is degraded in vivo by dissolution, enzymatic hydrolysis, erosion, absorption, or a combination thereof. In some embodiments, this degradation occurs within a timeframe that does not interfere with the intended kinetics of drug release from the drug delivery device. For example, substantial erosion of the drug delivery device may not occur until after the drug has been substantially or completely released. In some embodiments, the drug delivery device is erosive, and drug release is controlled, at least partially, by the degradation or erosive properties of the erosive drug delivery device body.

[0052] Drug reservoir lumen The drug delivery devices described herein include a drug reservoir lumen. In some embodiments, the drug reservoir lumen is defined between (i) an elongated outer wall of an elastic material and (ii) an arc-shaped elongated inner wall of an elastic material. The outer and inner walls may be a single monolithic structure, such as an elastomer structure, formed, for example, by an extrusion process. In some embodiments, the elongated drug reservoir lumen is closed at its opposite ends.

[0053] The drug reservoir lumen of the drug delivery device described herein may generally have any cross-sectional shape. In some embodiments, the drug reservoir lumen has a crescent cross-sectional shape. Examples of drug reservoir lumen having a crescent cross-sectional shape are shown in Figures 1B and 1C. Other cross-sectional shapes are conceivable, for example, depending on the overall shape of the outer tube wall, the shape of the inner wall, and the presence, shape, and location of the guidewire lumen and retaining frame lumen, if present.

[0054] Each end of the drug reservoir lumen of a drug delivery device described herein is typically sealed to accommodate a drug payload within the drug reservoir lumen. The drug reservoir lumen may be sealed thermally and / or with an adhesive (e.g., TECOFLEX® 1-MP TPU adhesive, Lubrizol, USA). The drug reservoir lumen may have a first end and a second end, and in some embodiments, a first spacer and a second spacer are positioned at the first and second ends of the drug reservoir lumen. The spacers may be formed from any biocompatible material. In some preferred embodiments, the spacers are heat-set (melted / reformed) to a fixed sealed position within the drug reservoir lumen. In some other embodiments, the spacers may be held within the drug reservoir lumen by friction, adhesive, mechanical features (e.g., tabs or other locking mechanisms), or a combination thereof. For example, the spacers may have dimensions exceeding the cross-sectional dimensions of the drug reservoir lumen so that the spacers are held by friction.

[0055] In some embodiments, the spacer comprises a radiopaque filler material. In some embodiments, the material used to form the spacer is a barium-doped material, which may allow the spacer to function as a visibility point within the drug delivery device during and / or after deployment, removal, or a combination thereof.

[0056] Guidewire lumen The drug delivery devices described herein may include a guidewire lumen. In some embodiments, the guidewire lumen is defined between (i) at least a portion of an elongated outer wall of an elastic material and (ii) at least a portion of an arc-shaped elongated inner wall of an elastic material. The guidewire lumen and the drug reservoir lumen are located on either side of the inner wall. The outer and inner walls may be a single monolithic structure, such as an elastomer structure, formed, for example, by an extrusion process. The elongated guidewire lumen has an open end to accommodate a guidewire extending through the guidewire lumen.

[0057] The guidewire lumen may generally have any cross-sectional size and shape that allows the drug delivery device to move along the guidewire suitable for renal pelvis placement. In some embodiments, the guidewire lumen has a substantially circular cross-sectional shape. However, other cross-sectional shapes are conceivable, including, but not limited to, polygonal, e.g., hexagonal, octagonal, or non-polygonal, e.g., oval, elliptical cross-sectional shapes.

[0058] Retaining and deployment shape The drug delivery devices described herein are elastically deformable between a relatively straightened shape suitable for insertion through the lumen into the patient's renal pelvis and a retaining shape suitable for holding the device within the renal pelvis. In some embodiments, the drug delivery device may have a naturally assumed retaining shape and may be deformed into a relatively straightened shape manually or with the help of an external device for insertion into the body. After deployment, the device may spontaneously or naturally return to its initial retaining shape for holding within the body by removing the corrective force imparted by the presence of a guidewire extending through the lumen of the device body, for example.

[0059] As used herein, the term “retaining shape” generally refers to any shape suitable for retaining the drug delivery device described herein within the renal pelvis.

[0060] Similarly, the term “deployment configuration” generally refers to any configuration suitable for deploying the drug delivery device described herein into the renal pelvis through the patient’s urethra, bladder, and ureters.

[0061] In some embodiments, the elastic body itself is configured to provide a retaining shape function for the drug delivery device. That is, the elastic body may be formed from a suitable material (e.g., high durometer silicone) and dimensioned to impart the essential elastic and spring constants required by the drug delivery device. In some embodiments, the drug delivery device includes a retaining frame to provide a retaining shape function for the drug delivery device.

[0062] The retaining elastic body may have essentially arbitrary shapes and sizes, which conform to the renal pelvis and make multifaceted or lateral contact with the wall of the renal pelvis, i.e., in multiple directions, thereby resisting movement and facilitating the retention of the device. In addition, this shape can facilitate the delivery of drugs to numerous different tissue surfaces within the kidney, and, when treating tumors, can advantageously obscure drug delivery relative to the tumor's location. Examples of such shapes include coils, helices, and other configurations in which elongated, narrow tubes are wound back and forth or around themselves to form an overall 3D shape having substantially circular features, e.g., spherical, cylindrical. In these embodiments, the device may be elastically essentially linear in shape for deployment on / through a guidewire or other deployment instrument.

[0063] The outer tube dimensions should be selected to prevent twisting when the tube is thermally formed. The critical bending radius (R) of an elastic tube under pure bending conditions. * ) can be approximated using the following formula.

[0064]

number

[0065] In some embodiments, the retaining shape includes a coil. As used herein, the term “coil” generally refers to a single loop formed of elastic material in a drug delivery device. An embodiment of a drug delivery device having a coil retaining shape is shown in Figure 2.

[0066] In some embodiments, the retaining shape includes a spiral. As used herein, the term “spiral” generally refers to an elastic body forming two or more coils having the same or different coil diameters, where at least a portion of the elastic body resembles a corkscrew or a helical spring. In some embodiments, a drug delivery device having a spiral retaining shape includes two, three, four, five, six, seven, eight, nine, or ten turns. Each turn (coil) of the drug delivery device may or may not be in contact with an adjacent coil. Each coil of the drug delivery device may define the same or different shapes.

[0067] When the drug delivery device described herein is in a retaining configuration, the drug delivery device for adult patients may have dimensions selected to retain the drug delivery device within the renal pelvis. For example, when the drug delivery device has a helical retaining configuration, the drug delivery device may have a length of about 8 cm to about 15 cm, about 8 cm to about 12 cm, or about 10 cm to about 12 cm when in a relatively linearized deployment configuration. In the case of a helical retaining configuration, the drug delivery device described herein may have a length of about 0.8 cm to about 2 cm, about 0.8 cm to about 1.8 cm, about 0.8 cm to about 1.5 cm, about 0.8 cm to about 1.4 cm, about 0.8 cm to about 1.2 cm, or about 1 cm. When in a helical retaining configuration, the "length" of the drug delivery device is measured along an axis enclosed by two or more coils. When in a helical retaining configuration, the drug delivery device described herein may have a maximum width of about 0.5 cm to about 1.4 cm, or about 0.5 cm to about 1 cm. If two or more coils are substantially circular and have substantially the same coil diameter, the width of the drug delivery device may be substantially the same regardless of the axis along which the width is measured (the axis corresponding to the width, which is perpendicular to the axis along which the length is measured). If two or more coils are non-circular and / or have different coil diameters, the width may vary depending on the axis along which the width is measured. Thus, the aforementioned range defines the “maximum width” of some embodiments of drug delivery devices described herein.

[0068] As a further example, if the drug delivery device has a coil-holding shape, the length of the drug delivery device may be about 4 cm to about 8 cm, or about 4 cm to about 6 cm, when in a relatively linearized deployment shape. A drug delivery device with a coil-holding shape may have a maximum width of about 1 cm to about 3 cm, or about 1.5 cm to about 3 cm, when in the holding shape. Again, the elastic body may form a substantially non-circular loop when the drug delivery device has a coil-holding shape, and thus the "maximum width" is provided by the aforementioned range.

[0069] In pediatric patients, the dimensions of the drug delivery device may be smaller, for example, proportional, based on anatomical size differences and / or differences in drug dosage between adult and pediatric patients. In addition to enabling insertion, relatively smaller drug delivery devices can reduce patient discomfort and trauma to the upper urinary tract, including the renal pelvis. The drug delivery device may also be small enough to allow slight mobility within the renal pelvis in its retaining shape, although mobility, if present, is preferably minimized to prevent the ends of the device from being taken into the urine and flowing into the urine. Movement of the drug delivery device can facilitate uniform drug delivery throughout the renal pelvis.

[0070] Retaining frame In some embodiments, the drug delivery device may include a further elongated lumen separate from the guidewire lumen and the drug reservoir lumen. This further lumen may be a retaining frame lumen in which a retaining frame is positioned. The retaining frame lumen may be closed at its ends.

[0071] The retaining frame lumen includes an elastically deformable retaining frame positioned within it. The retaining frame functions to bias the elastic body of the drug delivery device into a retaining shape. The retaining frame may be an elastic wire. It may be formed of any elastic material effective in imparting to the elastic body, and consequently to a suitable modulus of elasticity or spring constant for the drug delivery device. In some embodiments, the retaining frame is a wire formed from a superelastic alloy, such as nitinol or another superelastic alloy. For example, the elastic wire may be thermally shaped to have a coiled or helical retaining shape.

[0072] Drug delivery device and deployment system In one embodiment, a drug delivery system or kit is provided. In some embodiments, the drug delivery system includes a drug delivery device as described herein and a deployment system for deploying the drug delivery device in the renal pelvis of a patient.

[0073] In some embodiments, the deployment system is a guidewire deployment system comprising (i) a guidewire and (ii) a plunger device for pushing a drug delivery device on the guidewire. The guidewire may be sized and have a shaped cross-sectional area to pass through the guidewire lumen of the drug delivery device.

[0074] In some embodiments, the plunger device includes a plunger, a handle, a sheath extending between the plunger and the handle, a sheath that transmits the driving force applied to the handle to the plunger, and an internal bore for receiving a guidewire, thereby enabling the plunger device to move along the guidewire.

[0075] In some embodiments, the drug delivery device 100 shown in Figures 1A-1C may be deployed in the renal pelvis using a special guidewire deployment system. Figures 14A-14B show embodiments of such a guidewire deployment system 1400 for deploying the drug delivery device in the renal pelvis. The guidewire deployment system 1400 generally includes a guidewire 1402 and a plunger device 1404. The guidewire 1402 is longer than the distance from the renal pelvis to the end of the urethra, so that when the guidewire 1402 is positioned in the urethra, its proximal end extends out of the urethra when its distal end is in the renal pelvis. The guidewire 1402 is sized and shaped to pass through the guidewire lumen of the drug delivery device 100. For example, the guidewire 1402 may have a cross-sectional area or diameter smaller than the cross-sectional area or diameter of the guidewire lumen.

[0076] The plunger device 1404 includes a plunger 1406 operably connected to the handle 1408 via a sheath 1410. The sheath 1410 is rigid enough to transmit driving force from the handle 1408 to the plunger 1406. The plunger 1406 and the sheath 1410 have an internal bore suitable for passing the plunger device 1404 over the guide wire 1402. When the plunger device 1404 is passed over in this manner, the handle 1408 is positioned at the proximal end of the guide wire 1402, and the plunger 1406 is positioned behind its distal end on the guide wire 1402, with the rigid sheath 1410 extending from the handle 1408 to the plunger 1406, thereby allowing the driving force applied to the handle 1408 to be transmitted to the plunger 1406.

[0077] During use, the guidewire 1402 may be positioned in the ureter such that its distal end is located in the renal pelvis and its proximal end is exposed outside the patient's body. The drug delivery device 100 may be passed over the guidewire 1402 with the guidewire 1402 passing through the guidewire lumen 112 as shown in Figures 1A and 1B. The plunger device 1404 may be passed over the guidewire 1402, and the handle 1408 may be advanced so that the rigid sheath 1410 moves along the guidewire 1402, advancing the plunger 1406 until the drug delivery device 100 is pushed out from the guidewire 1402. The guidewire 1402 may then be removed from the ureter, bladder, and urethra, leaving the drug delivery device in the renal pelvis, as shown in Figure 19.

[0078] In some embodiments, the plunger device 1404 further includes a stopper 1412. The stopper 1412 is positioned appropriately on the plunger device 1404 so that it contacts the patient's body when the drug delivery device 100 is separated from the guidewire 1402. In this way, the user is informed that the drug delivery device 100 has been deployed in vivo, and as a result, the user can stop advancing the handle 1408. In some embodiments, the stopper 1412 may be adjustable to accommodate differences in anatomical size. The user can adjust the stopper 1412 before advancing the plunger device 1404 as needed.

[0079] The guidewire 1402 can facilitate the straightening of the drug delivery device 100 from a holding shape suitable for holding the drug delivery device 100 in the renal pelvis to a deployment shape suitable for passing the drug delivery device 100 through the urethra and ureter. In some embodiments, the guidewire 1402 may be used in conjunction with a separate deployment catheter. In such embodiments, the guidewire 1402 may be passed through the deployment catheter, but other configurations are also possible. The guidewire 1402 may also have a J-shape or curved shape suitable for deploying the drug delivery device through the male urethra. The guidewire deployment system 1400 and the drug delivery device 100 may also be supplied together in a package.

[0080] In some embodiments, any of the deployment instruments described herein with reference to Figures 14A–14B may be provided as part of a kit. The kit may include a package containing one of the instruments and one of the drug delivery devices described herein. For example, the kit may include a guidewire, a deployment catheter, a plunger device, and a drug delivery device configured for renal pelvis deployment and retention. The package may protect the packaged components before the deployment procedure. For example, the components may be sterilized together and transported and stored together in the package until required for use. In such embodiments, the drug delivery device described herein may be pre-loaded in or on the deployment instrument before the deployment instrument is placed in the package, eliminating the need to load the drug delivery device during the deployment procedure, reducing the number of steps in the procedure, and reducing the risk of accidentally dropping or damaging the drug delivery device during loading. However, the drug delivery device does not need to be pre-loaded. Instead, the drug delivery device may be provided together with the deployment instrument or packaged separately. Also, the stylet may be packaged together with the deployment instrument, packaged separately, or omitted entirely. Regardless of which components are packaged together, the package may be sterilized using methods such as gamma irradiation or ethylene oxide sterilization.

[0081] Figure 19 shows an embodiment of a drug delivery device 1900 as described herein, having a spiral retaining shape and positioned in a deployment location within the renal pelvis 1920 of the kidney 1910, with an attached retrieval string 1902 extending from the drug delivery device through the ureter 1940 into the bladder 1930. In this embodiment, the drug delivery device 1900 provides local drug delivery to a tumor 1950, for example, renal cell carcinoma. However, in other cases, the drug delivery device can be used to treat other diseases and disorders other than cancers affecting the kidney.

[0082] Drug payload and drug Generally, the drug delivery devices provided herein include a drug payload placed within a drug reservoir lumen. The drug payload contains at least one drug. In some embodiments, the drug payload is in solid or semi-solid form. For example, the drug payload may be in particulate form (e.g., powder, granules), in the form of one or more solid drug units (e.g., beads, tablets, capsules), or a combination thereof. The solid units are typically formed on the outside of an elastic body to have selectively assigned uniform size and shape, and the solid units are then filled into the drug reservoir lumen. In certain embodiments, the units should have a longest dimension configured to maintain the orientation of the solid units (to be loaded) within the drug reservoir lumen, while at the same time keeping their dimensions short enough to have sufficient gaps (between adjacent units) so that the loaded device can elastically deform along its length. In some embodiments, the drug payload includes a plurality of solid tablets aligned end-to-end within the drug reservoir lumen.

[0083] Solid units may be produced by direct powder compression or tableting processes, molding processes, or other processes known in the pharmaceutical field. In some embodiments, crescent-shaped tablets may be produced by an improved tableting process in which a powder mixture is loaded into a specially shaped mold and then compressed to bind the powder into a tablet. In some other embodiments, the drug payload may be loaded into a drug delivery device in a working form and then cured / solidified within it.

[0084] A drug payload may comprise a formulation comprising at least one drug and at least one excipient. In some embodiments, the drug comprises one or more active ingredients (APIs), and the excipient comprises one or more pharmaceutically acceptable excipients. The formulation may comprise essentially any therapeutic, prophylactic, or diagnostic agent, such as one useful for topical delivery to the renal pelvis. The drug payload may consist solely of APIs or may comprise one or more excipients. As used herein, the term “drug” referring to any particular drug described herein includes its alternative forms, such as salt forms, free acid forms, free base forms, and hydrates. The term “excipient” is known in the art, and typical examples of excipients useful in this formulation include components such as binders, lubricants, disintegrants, colorants, fillers, diluents, coatings, or preservatives, as well as other non-active components for facilitating the manufacture, stability, dispersibility, wetting, and / or release kinetics of the drug, or administration of the formulation. The drug may be a small molecule, a macromolecule, a biological, antimetabolite, or a metabolite, among other forms / types of active ingredients. In some embodiments, the drug is a nucleoside analog.

[0085] To maximize the amount of drug that can be stored in and released from a given drug delivery device of a selected (small) size, the drug payload preferably comprises a high weight fraction of the drug or API and a reduced or low weight fraction of excipients as required by considerations for the manufacture of the solid drug unit and the manufacture of the drug delivery device assembly and for use. For the purposes of this disclosure, terms such as “weight fraction,” “weight percentage,” and “percentage by weight” with respect to the drug or API refer to the drug or API in the form used, such as salt form, free acid form, free base form, or hydrate form. For example, a solid drug unit having 90% by weight of a drug in salt form may contain less than 90% by weight of that drug in free base form.

[0086] In some embodiments, the drug payload is more than 50% by weight of drug. In some embodiments, 75% or more by weight of the drug payload is drug, and the remaining weight includes excipients such as lubricants and binders to facilitate the preparation of solid drug units. For the purposes of this disclosure, the term “high weight fraction” with respect to drug or API means that the excipients constitute less than 25% by weight, preferably less than 20% by weight, more preferably less than 15% by weight, and even more preferably less than 10% by weight of the drug payload. In some cases, the contents constitute about 75% or more of the weight of the drug payload. More specifically, the drug may constitute about 80% or more of the weight of the drug payload. For example, the drug may constitute about 85% to about 99.9% of the weight of the solid drug unit. In some embodiments, the excipient content can be omitted entirely.

[0087] In some embodiments, the drug and excipients are selected such that the solid drug form is water-soluble so that the solid drug form is solubilized and the solubilized drug can be released when the drug delivery device is located in the renal pelvis.

[0088] Individual solid drug units may have essentially any selected shape and dimensions to fit into the drug reservoir lumen of the drug delivery device described herein. In some embodiments, the solid drug units are sized and molded so that the drug reservoir lumen is substantially filled by a selected number of solid drug units. Each solid drug unit may have a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, a drug unit may have an extruded crescent shape for positioning within a drug reservoir lumen having a crescent cross-sectional shape. Once loaded, the solid drug units can substantially fill the drug reservoir lumen in some embodiments.

[0089] In some embodiments, solid drug units are molded to align in a row within the lumen of the drug reservoir of the device. For example, each solid drug unit may have a cross-sectional shape corresponding to the cross-sectional shape of the lumen of the drug reservoir, and each solid drug unit may have an end-face shape corresponding to the end face of an adjacent solid drug unit. Gaps or breaks between solid drug units may allow individual drug units to maintain their solid form while adapting to deformation or movement of the drug delivery device, such as during deployment. Thus, since each drug unit may be able to move in relation to adjacent drug units, the drug delivery device may be relatively flexible or deformable despite being loaded with solid drugs.

[0090] In some other embodiments, the drug payload includes a formulation in a semi-solid form, such as an emulsion or suspension, gel, or paste. For example, the formulation may be a highly viscous emulsion or suspension. In some other embodiments, the formulation is in liquid form.

[0091] The lumen of the drug reservoir may hold a number of drug tablets or other solid drug units. In some embodiments, the device holds 4 to 400 drug tablets, for example, 10 to 100 drug tablets, 5 to 50 tablets, or 10 to 40 tablets.

[0092] In some embodiments, the drug tablet has a crescent-shaped cross-section. That is, the cross-section of the tablet may have a convex side and an opposing concave side connected at their ends / edges by a shorter, rounded side. In other embodiments, not shown, the convex and concave sides may intersect at a point, resulting in a crescent-shaped cross-section. For convenience, these kidney-shaped and crescent-shaped tablet cross-sections are referred to herein as “crescent” shapes. In the crescent shape, the drug tablet approximates the shape of the lumen of a crescent-shaped drug reservoir, fits into it, and can fill a substantial portion, e.g., 80% to 99%, of the cross-sectional area of ​​the drug reservoir lumen. The crescent-shaped tablet may have flat ends.

[0093] An example of a crescent-shaped tablet is shown in Figure 13. The tablet 1300 has a crescent-shaped cross-section including a principal surface 1342 and a secondary surface 1340. The principal surface 1342 and the secondary surface 1340 are rounded curves, but it is conceivable that these surfaces may be flat surfaces or may include flat surfaces (for example, the principal or secondary curves of the cross section may be analogous to three sides of a pentagon, three sides of a hexagon, etc.). The principal and secondary curves may intersect at a point at one or both ends of the tablet when viewed in cross-section, as when two overlapping circles form a crescent shape, or the principal and secondary curves may be connected at one or both ends of a table by a rounded portion of a table, as characterized in the embodiment shown in Figure 13. The crescent-shaped tablet may have a structure in which the distance between the principal and secondary curves tapers, is substantially constant, or a combination thereof. A tablet is considered to have a crescent-shaped cross-section if the maximum distance between its main and secondary curves is 95% or less of its height.

[0094] The drug may be a low-solubility drug. As used herein, the term “low-solubility” refers to a drug having a solubility of about 0.01 mg / mL to about 10 mg / mL in water at 37°C. In some other embodiments, the drug is a high-solubility drug. As used herein, the term “high-solubility” refers to a drug having a solubility greater than about 10 mg / mL in water at 37°C. For example, the approximate solubility of certain formulations is as follows: trospium chloride: 500 mg / mL; lidocaine HCl: 680 mg / mL; lidocaine base: 8 mg / mL; gemcitabine HCl: 80 mg / mL; gemcitabine base: 15 mg / mL; oxybutynin HCl: 50 mg / mL; oxybutynin base: 0.012 mg / mL; and triterodine tartrate: 12 mg / mL.

[0095] In some embodiments, drug delivery devices are used to treat diseases of the upper urinary tract, including upper urinary tract cancers such as upper urothelial carcinoma. Possible drugs include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or combinations thereof. Representative examples of drugs that may be suitable for the treatment of upper urinary tract cancer include Calmette-Guérin vaccine (BCG), docetaxel, cisplatin, doxorubicin, barurubicin, gemcitabine, mycobacterial cell wall-DNA complexes (MCCs), methotrexate, vinblastine, thiotepa, mitomycin (e.g., mitomycin C, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide), selective estrogen receptor modifiers (i.e., SERMs such as tamoxifen), botulinum toxin, and cyclophosphamide. Drugs may also include monoclonal antibodies, TNF inhibitors, anti-leukins, etc. The substance may also be an immunomodulator, such as a TLR agonist containing imiquimod or another TLR7 agonist. The drug may also be a kinase inhibitor, such as a fibroblast growth factor receptor-3 (FGFR3) inhibitor, a selective tyrosine kinase inhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or a mitogen-activated protein kinase (MAPK) inhibitor, or a combination thereof. Other examples include celecoxib, erolotinib, gefitinib, paclitaxel, polyphenon E, barrubicin, neocarutinostatin, apadicon, bellinostat, ingenol mebutate, urocidine (MCC), proxinium (VB4845), and BC819 (BioCancell). Examples include keyhole limpet hemocyanin (Lorus Therapeutics), LOR2040 (Lorus Therapeutics), urocanic acid, OGX427 (OncoGenex), and SCH721015 (Schering-Plough). Drug therapy may be used in combination with conventional radiotherapy or surgery targeting cancerous tissue.

[0096] In some other embodiments, the drug delivery device may be used to treat pain, and the drug payload may include anesthetics, analgesics, and combinations thereof. For example, the anesthetic may be an aminoamide (e.g., lidocaine), an aminoester (e.g., benzocaine), or a combination thereof. In some embodiments, the analgesic may include an opioid agonist.

[0097] In some other embodiments, the drug delivery device may be used to treat inflammatory conditions such as interstitial cystitis, radiation cystitis, bladder pain syndrome, prostatitis, urethritis, postoperative pain, and kidney stones. Non-limiting examples of specific drugs for these conditions include lidocaine, glycosaminoglycans (e.g., chondroitin sulfate, throdextrine), pentosan polysulfate sodium (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, cyclosporine, or combinations thereof. For kidney stones, the drug(s) may be selected to treat pain and / or to promote the dissolution of the kidney stones.

[0098] In some embodiments, the drug delivery device may be used to treat urinary incontinence, including urge urinary incontinence and neurogenic incontinence, frequent urination, or urinary urgency, as well as cystic trigonitis. Possible drugs include anticholinergics, antispasmodics, antimuscarinic agents, β-2 agonists, alpha-adrenergic agonists, anticonvulsants, norepinephrine reuptake inhibitors, serotonin reuptake inhibitors, calcium channel blockers, potassium channel openers, and muscle relaxants.

[0099] In some embodiments, drug delivery devices may be used to treat infections related to the kidneys, ureters, bladder, and urethra. Antibiotics, antibacterial agents, antifungal agents, antiparasitic agents, disinfectants, antiviral agents, and other anti-infective agents may be administered to treat such infections.

[0100] In some embodiments, the drug is selected from lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, trospium, tolterodine, oxybutynin, and mitomycin C.

[0101] Other drug delivery device features Imaging features section The drug delivery devices described herein may include radiopaque portions or structures to facilitate detection or viewing (e.g., by X-ray imaging or fluoroscopy) of the drug delivery device by a medical practitioner as part of the deployment and / or retrieval procedures.

[0102] In some embodiments, the elastic body is composed of a material including an image sensor. The image sensor may include a radiopaque filler material, such as barium sulfate or another radiopaque material known in the art. The image sensor may include one or more radiopaque marker bands fixed to the elastic body. Some elastic bodies may be made radiopaque by blending a radiopaque filler, such as barium sulfate or another suitable material, during the processing of the material on which the elastic body is formed. In some embodiments, the first material on which the elastic body is formed is a barium sulfate-added material, i.e., a material containing barium sulfate. In some embodiments, at least one spacer of the drug delivery device includes an imaging material, but is not limited to, a radiopaque filler material such as barium sulfate. In a preferred embodiment, the drug delivery device includes two end spacers and at least one intermediate spacer, all of which are located within the lumen of the drug reservoir. The drug delivery device can be imaged in vivo using ultrasound imaging or fluoroscopy. To improve the visual sensitivity of the drug delivery device during insertion or by other means, the barium sulfate concentration can be increased in an elastic material (e.g., a first material, a second material, or a combination thereof), one or more spacers, or a combination thereof.

[0103] Retrieval string The drug delivery devices described herein may further include recovery features such as recovery strings, loops, tabs, or other structures that facilitate the removal of the drug delivery device from the renal pelvis. In some embodiments, the recovery feature is a recovery string having a distal end fixed to the end of the drug delivery device and a proximal end configured to extend through the ureter into the bladder after the device has been deployed. The device can then be removed from the renal pelvis by grasping and pulling the proximal end of the recovery string, for example, after the completion of the treatment period (e.g., after releasing some or all of the drug payload into the renal pelvis).

[0104] In some embodiments, the deployed drug delivery device may be removed from the renal pelvis by engaging a retrieval string to pull the drug delivery device through the ureter, bladder, and urethra. The drug delivery device may be configured to take a relatively narrow or linear shape when pulled into the ureter and then into the urethra by the retrieval mechanism. The retrieval string has a first end portion attached to the drug delivery device and an opposing second end portion that engages to pull the drug delivery device through the ureter, bladder, and urethra. The retrieval string may be long enough so that the second end of the retrieval string is in the bladder when the drug delivery device is deployed in the renal pelvis, as shown in Figure 19. The retrieval string is generally formed from a biocompatible woven or nonwoven material. In some embodiments, the retrieval string is made of suture materials known in the art, such as silk, nylon, polyester, PVDF, and polypropylene. The retrieval string may be attached to any part of the drug delivery device, including the terminal or intermediate portion of the elongated body of the drug delivery device. In some embodiments, the drug delivery device includes two or more retrieval strings.

[0105] The retrieval string may be attached to the device body in a number of different ways, including different means and locations for connecting these components. For example, Figures 15-16 show two different embodiments in which the retrieval string is fixed to the end of a drug delivery device, and Figure 17 shows another embodiment of the retrieval string fixed to an end spacer before the assembly is placed inside the lumen of a drug delivery device (not shown).

[0106] One embodiment is shown in Figure 15, which shows a drug delivery device 1500 having an elongated tubular body having an outer wall 1506 and an inner wall 1508 that form the boundary between (i) a drug reservoir lumen 1507 containing a drug payload 1590 and (ii) a guidewire lumen 1512. A spacer 1520 is fixed within the drug reservoir lumen and closed at its end. The outer wall 1506 includes a hole 1586 through which a retrieval string 1580 passes. The retrieval string 1580 forms a loop by itself, with a first portion of the retrieval string fixed between the spacer 1520 and the outer wall 1506, a second portion of the retrieval string passing along the outer surface of the outer wall, and the second portion of the retrieval string being tied to the first portion of the retrieval string at a knot 1582. Alternatively, in addition to a knot, the retrieval string 1580 may be held in place by friction between the spacer 1520 and the inner portion of the outer wall 1506, and / or with the aid of adhesive. In a variation of this embodiment (not shown), the hole extends into the spacer, and the retrieval string passes through both the hole in the outer wall and the hole in the spacer, such that the first portion of the retrieval string is fixed between the spacer and the inner wall instead of the outer wall.

[0107] Another embodiment is shown in Figure 16, which shows a drug delivery device 1600 having an elongated tubular body having an outer wall 1606 and an inner wall 1608 that form the boundary between (i) a drug reservoir lumen 1607 containing a drug payload 1690 and (ii) a guidewire lumen 1612. A spacer 1620 is fixed within the drug reservoir lumen and closed at its end. The outer wall 1606, the inner wall 1608, and one of the spacer 1620 all have a hole 1686 through which they extend. A retrieval string 1580 passes through the hole 1686 and forms a loop by itself, with a first portion of the retrieval string passing along the outer surface of the outer wall and a second portion passing along the inner wall within the guidewire lumen, and the first portion of the retrieval string being tied to the second portion of the retrieval string at a knot 1682. Alternatively, in addition to a knot, the retrieval string 1680 may be held in place by the aid of an adhesive. In one modification (not shown), the holes in the spacer are offset from the holes in the outer and inner walls (instead of being aligned with each other as in the illustrated embodiment), and as a result, a portion of the retrieval string is captured by frictional engagement between the spacer and the inner and / or outer walls. In another modification (not shown), the holes may extend laterally through the outer wall of the apparatus body at two points without penetrating the inner wall.

[0108] Figure 17 shows one embodiment of a spacer having a retrieval string. The spacer 1720 is an elongated cylindrical body having a hole 1784 extending perpendicular to the longitudinal axis of the body. The retrieval string 1780 extends through the hole 1784, forms a loop, and is tied to itself at a knot 1782. This assembly of spacer and retrieval string may then be fixed within the end of the lumen of a drug reservoir in a drug delivery device described herein.

[0109] In yet another embodiment, the recovery string is embedded directly into the spacer. For example, the recovery string may be attached during the formation of the spacer, for example, incorporated together with the thermoplastic material during the molding process for producing the spacer. In yet another embodiment, the recovery string is attached directly to the apparatus body in parts and / or locations that do not contain spacers. For example, the recovery string may be glued to and / or fixed to the side wall of the apparatus body.

[0110] In some embodiments, the drug delivery device may include a retrieval tab. The retrieval tab may be part of the device body, for example, formed integrally with it. The device may be removed from the renal pelvis by grasping the retrieval tab with forceps or another instrument, or by engaging it in another way, in order to pull the drug delivery device through the ureter, bladder, and urethra. For example, a ureteroscope may be used to guide the distal end of the instrument through the urethra, bladder, and ureter into the renal pelvis and reach the device. The drug delivery device may be configured to take on a relatively narrow or linear shape when the drug delivery device is pulled into the urethra or ureter by the tab.

[0111] Methods of drug delivery The drug delivery devices, systems, and methods disclosed herein are particularly adapted for use in humans. They may also be adapted for use in other mammals, such as in veterinary or livestock applications. Accordingly, the term “patient” may refer to a human or another mammalian subject.

[0112] In some embodiments, a method for providing controlled release of a drug to a patient includes (i) deploying a drug delivery device described herein within the patient, for example, in the renal pelvis, and (ii) continuously releasing the drug from the lumen of a drug reservoir within the device into the local environment of the renal pelvis for a duration, i.e., more than 24 hours. For example, the drug may spread through the renal pelvis into the urine and then diffuse into adjacent tissues. In some embodiments, the drug is released locally to the tissue at the deployment site in the renal pelvis. In some embodiments, the released drug may be distributed to adjacent tissues. In some embodiments, the released drug may be carried from the renal pelvis into the urine to treat the ureters, bladder, and urethra. Having the drug delivery device entirely within the renal pelvis without a ureteral stent may be particularly advantageous for continuously treating tissues of the upper tract (e.g., kidneys and ureters) with a therapeutic agent over a long period of time.

[0113] Release may occur, for example, via transwall diffusion through the elastic body of the device, or by osmotically driving the drug through one or more openings in the body of the device. In some embodiments, the device has an elastic body including an outer tube through which the drug diffuses (by transwall diffusion) only through the second material, comprising (i) a first material that is impermeable to the drug and (ii) a second material that is permeable to the drug. The drug delivery device may include any feature or combination of feature described herein.

[0114] In some embodiments, urine diffuses into the lumen of a drug reservoir by transwall diffusion through a first material, a second material, or a combination thereof, comes into contact with the drug contained in the lumen of the drug reservoir, and forms a drug solution, which then diffuses into the renal pelvis through the second material by transwall diffusion.

[0115] In some embodiments, the deployed drug delivery device remains in the renal pelvis for a predetermined treatment period and releases the drug in a controllable manner over that period. After deployment, the drug delivery device may deliver the drug for several days, several weeks, several months, or longer treatment periods.

[0116] Once deployed, the drug delivery device releases a desired amount of drug over a desired predetermined period. In preferred embodiments, the drug delivery device can continuously deliver a desired dose of drug over 24 hours or more, for example, 1–90 days, 2–60 days, 3–45 days, 3–30 days, 3–21 days, 3–14 days, 7–45 days, 7–30 days, 7–14 days, 7–10 days, 3–10 days, 24–72 hours, 36–60 hours, or 48–90 hours. The drug delivery rate and dose can be selected depending on the drug being delivered and the disease or condition being treated. In some embodiments, the drug release rate from the drug delivery device is substantially zero-order for at least 36 hours. In some embodiments, the drug release rate from the drug delivery device is substantially zero-order for at least 7 days.

[0117] In some embodiments, the drug is gemcitabine, for example, gemcitabine hydrochloride. In some of these embodiments, at least 25 mg / day of gemcitabine is released over 7 days. In other embodiments, at least 1 mg / day of gemcitabine hydrochloride is released over 7 days to 3 months.

[0118] In some embodiments, drug elution from a drug delivery device occurs after the drug has been dissolved within the device. For example, urine enters the drug delivery device, comes into contact with the drug, solubilizes it, and the dissolved drug is then released from the drug delivery device, for example, by diffusion and / or osmotic pumping. In some embodiments, releasing a drug from a drug delivery device involves solubilizing the drug with water absorbed through a second material of the outer tube, or through both the first and second materials of the outer tube.

[0119] In some embodiments, the drug delivery device may have two drug payloads to be released at different times. The first payload may be adapted for relatively rapid release, and the second payload may be adapted for longer-term release. The drugs in the two payloads may be the same drug or two different drugs.

[0120] Methods for deploying and retrieving equipment Generally, this method involves deploying a drug delivery device as described herein into the patient's renal pelvis, the drug delivery device being entirely contained within the patient's renal pelvis, with the optional exception of a retrieval string configured to extend into the patient's bladder or through the bladder and urethra. The drug delivery device may be retrieved from the body, for example, if the drug delivery device is not reabsorbable or needs to be removed by another means. In alternative embodiments, the drug delivery device is entirely or partially bioerosive, reabsorbable, or biodegradable, and either the entire drug delivery device is reabsorbed or it breaks down sufficiently into pieces small enough to be excreted with the urine flowing from the renal pelvis, thus eliminating the need for retrieval. In embodiments, the drug delivery device may not be retrieved or reabsorbed until some, or preferably most or all, of the drug has been released. If necessary, a newly loaded drug delivery device may be subsequently deployed during the same procedure as retrieval or at some time later.

[0121] In some embodiments, deploying a drug delivery device within a patient includes inserting the drug delivery device into the patient's renal pelvis via a deployment device. In some embodiments, deploying a drug delivery device within a patient's renal pelvis includes elastically deforming the drug delivery device into a deployment shape, inserting the drug delivery device through the patient's urethra, bladder, and ureters, and releasing the drug delivery device into the patient's renal pelvis such that it takes a retaining shape suitable for preventing or reducing the movement of the drug delivery device from the renal pelvis, for example, into the ureters or renal calyces. In some embodiments, deploying a drug delivery device within a patient includes inserting a guidewire into the patient's renal pelvis through the urethra, bladder, and ureters, advancing the drug delivery device along the guidewire, wherein the guidewire is positioned within the guidewire lumen until the drug delivery device is positioned within the renal pelvis, and then retracting the guidewire from the patient and from the guidewire lumen. In some embodiments, the drug delivery device is elastically deformable between a coiled or helical retaining shape and a relatively straightened insertion shape. During the step of advancing the drug delivery device along a guidewire, the guidewire, located within the guidewire lumen, applies load to the drug delivery device, biasing it into the relatively straightened insertion shape. After the step of retracting the guidewire from the guidewire lumen, the drug delivery device elastically returns to a coiled or helical retaining shape suitable for holding the drug delivery device within the patient's renal pelvis. In some embodiments, the drug delivery device contains a radiopaque marker or drug, and deployment includes determining the placement of the drug delivery device in the patient by radiography.

[0122] Figure 18 is a block diagram illustrating one embodiment of the method 1800 of use of the drug delivery device described herein in the body of a patient, for example, in the renal pelvis. In block 1802, the deployment device is inserted into the body and reaches the renal pelvis by providing a route through one of the patient's urethra, bladder, and ureters. Inserting the deployment device generally involves inserting the deployment device into the urethra, bladder, and ureters and driving the deployment device forward until the distal end is positioned in the renal pelvis, while the proximal end remains outside the body. In embodiments, the drug delivery device is deployed in the patient's renal pelvis either in a standalone procedure or in another urological procedure (e.g., lithotomy), either before, during, or after the other procedure.

[0123] In some embodiments, the deployment device is inserted into the body in block 1802 in conjunction with a cystoscope or urethoscope that allows visualization of the deployment procedure. In some embodiments, inserting the deployment device into the body in block 1802 also includes verifying that the distal end of the deployment device is positioned within the renal pelvis. The position of the distal end can be verified by visualizing the distal end of the deployment device with a cystoscope, ultrasound, or X-ray. In some embodiments, inserting the deployment device into the body in block 1802 also includes fixing the distal end of the deployment device within the renal pelvis, for example, by inflating a balloon positioned on the distal end.

[0124] In block 1804, the drug delivery device is operably associated with the deployment instrument. The type of association depends on the deployment instrument involved. If the instrument is a lumen instrument (e.g., cystoscope, urethroscope, catheter, etc.), the association step includes inserting the drug delivery device into the lumen of the instrument. If the instrument includes a guidewire, the association step includes inserting the guidewire into the guidewire lumen of the drug delivery device. Different combinations of deployment instruments and operable associations may be used. In a typical embodiment, the operable association includes elastically deforming the drug delivery device from its retaining shape to its deployment shape. When the deployment instrument and the drug delivery device are operably associated with each other, a lubricant may be used to facilitate sliding engagement between them. In some embodiments, the drug delivery device is pre-loaded on / inside the deployment instrument before the deployment instrument is inserted into the body. In such cases, the order of blocks 1802 and 1804 is reversed.

[0125] In block 1806, the drug delivery device is driven into the renal pelvis. In some embodiments, this step includes pushing the drug delivery device toward the distal end of the deployment device until the drug delivery device is separated from the deployment device (with the optional exception of a retrieval string whose distal end may remain with the deployment device), thereby releasing the drug delivery device into the renal pelvis. In the case of a lumen deployment device, the drug delivery device is pushed out from the opening in the distal end portion of the device, for example, using a stylet that moves through the lumen to the rear of the drug delivery device and / or an incompressible fluid (e.g., water, lubricant). In the case of a guidewire type deployment device, the drug delivery device is pushed out from the distal end of the guidewire, for example, using a plunger that rides up onto the guidewire. In some embodiments, following the separation of the drug delivery device from the deployment device, the drug delivery device typically spontaneously and elastically returns to its retaining shape once the device is no longer subjected to a load that induces straightening from the deployment device. In some embodiments, driving the drug delivery device into the renal pelvis in block 1806 includes observing the drug delivery device within the renal pelvis to ensure that the drug delivery device is properly positioned. For example, the drug delivery device may be observed using a urethroscope, ultrasound, or X-ray.

[0126] In block 1808, the deployment device is removed from the patient's body by withdrawing the device from the renal pelvis, ureter, bladder, and then urethra. If the deployment device includes multiple components, the components may be withdrawn simultaneously or in several steps, depending on the components and method desired to minimize patient discomfort and / or trauma to the luminal tissues through which the deployment device passes. If it includes a retrieval string to which a drug delivery device is attached, the free distal end of the retrieval string may be withdrawn together with the deployment device and released to a desired location within the patient (e.g., inside the bladder).

[0127] Subsequently, in block 1810, the drug delivery device remains deployed in the renal pelvis for a selected treatment period, releasing the drug from its drug payload at a selected rate / amount over the treatment period. That is, once deployed in vivo, the drug delivery device releases the drug from its drug payload for the treatment (or prevention) of one or more diseases or conditions.

[0128] In block 1812, the drug delivery device is removed from the patient's body, for example, at the completion of the treatment period or when all or most of the drug payload has been released. This step may include inserting a removal device into the body, positioning the drug delivery device or a part thereof, and withdrawing the drug delivery device from the body with the help of the removal device. The removal device may include a cystoscope, catheter, or ureteroscope, and may further include forceps, a lariat, or another grasping device. In embodiments in which the drug delivery device includes a retrieval string, the method of removing the device from the patient may include grasping the distal end portion of the retrieval string, which may be located in the patient's bladder, and then pulling the retrieval string to remove the drug delivery device from the patient through the ureters, bladder, and urethra. In some embodiments, the drug delivery device may be retracted into the distal end portion of a lumen removal device so that the device folds or assumes a deployed shape when entering the removal device. In some embodiments, the drug delivery device can be grasped using forceps that have passed through the removal device, and the drug delivery device can be partially or completely retracted into the removal device before the removal device is withdrawn. In some embodiments, the removal device may include a magnet for magnetic coupling to a portion of the drug delivery device configured for this purpose. Magnetic coupling can be advantageously performed in a blind procedure; that is, it is not necessary to visualize the device to secure it with the removal device. In some other embodiments, after any portion of the drug delivery device is firmly grasped (e.g., by a retrieval string), the removal device is withdrawn from the patient's body, and the drug delivery device follows behind rather than inside the removal device. In these embodiments, the drug delivery device may be retracted into its deployed shape as it enters the ureter and urethra, and these tissue structures allow the drug delivery device to pass through while maintaining its deployed shape. In various procedures, the drug delivery device may be withdrawn from the removal device, and then the removal device may be removed from the body, or the drug delivery device and removal device may be removed from the body simultaneously.

[0129] The drug delivery device in Method 1800 may be any suitable drug delivery device described herein, including embodiments of the drug delivery device 100 shown in Figures 1A to 1C, and the deployment device 1400 may be the device shown in Figures 14A to 14B. In one embodiment, the drug delivery device is deployed by guiding the drug delivery device using a deployment device, e.g., a ureteral catheter and / or a guidewire system, and releasing the drug delivery device from the deployment device into the renal pelvis. In these cases, the drug delivery device may take on a retaining shape (e.g., a coil or helical shape) once it emerges from the deployment device into the renal pelvis. The deployment device may include a guidewire deployment system as described herein. In some embodiments, deploying a drug delivery device into the patient's renal pelvis includes (i) elastically deforming the drug delivery device into a deployment shape, (ii) inserting the drug delivery device through the patient's urethra, bladder, and ureters, and (iii) releasing the drug delivery device into the patient's renal pelvis such that the drug delivery device assumes a retaining shape suitable for preventing unnecessary movement of the device.

[0130] Treatment method The deployed drug delivery device can deliver one or more drugs locally into the patient's renal pelvis for the local or local treatment or prevention of a wide variety of diseases or conditions. Non-limiting examples include urinary tract infections, kidney infections (pyelonephritis), renal cell carcinoma, hyperfibrinolysis, upper urothelial carcinoma, and urinary stones such as kidney stones, ureteral stones, and bladder stones. Treatment of other diseases and conditions is also envisioned.

[0131] In one embodiment, the patient requires treatment and / or prevention of kidney stones. Non-limiting examples of drugs delivered by the device include antibacterial agents, alkalizing agents, acidifying agents, urease inhibitors, anti-inflammatory agents, and anti-fibrotic agents. In some embodiments, the drug delivery device is inserted into the patient after treatment with extracorporeal shock wave lithotripsy (ESWL) for the treatment of kidney stones within the patient. Migration of smaller stone fragments to the lower part of the kidney or the inferior pole calyces has been observed to occur after ESWL treatment due to gravity and anatomical structure (Bourdoumis et al., "Lower Pole Stone Management," Med Surg Urol S1:002 (2012)). These stone fragments are repositioned within the lower calyces and act as nuclei for new stone formation, causing inferior pole calyx lithiasis. Therefore, in embodiments of this method, a drug that inhibits stone formation is released into the renal pelvis from the deployed device. The released drug may become concentrated and effective in these lower renal calyces due to gravity and anatomical structure.

[0132] In one embodiment, a patient requires treatment or prevention of a urinary tract infection (UTI) or pyelonephritis. In a particular embodiment, the treatment or prevention method includes delivering an antimicrobial agent via a drug delivery device. The antimicrobial agent may be an antibiotic, antibacterial agent, antifungal agent, antiviral agent, anthelmintic agent, disinfectant, or antiseptic agent known in the art. In a particular embodiment, the antimicrobial agent may be an aminoglycoside, a penetrating agent, or an iron mimetic. Non-limiting examples of specific antimicrobial agents that may be used in the treatment or prevention of UTIs or pyelonephritis include trimethoprim / sulfamethoxazole, trimethoprim, ciprofloxacin, levofloxacin, norfloxacin, gatifloxacin, ofloxacin, nitrofurantoin, fosfomycin, pivamecillinam, cefpodoxime proxetil, ceftibutene, cefotaxime, ceftriaxone, ceftazidime, cefepime, amoxicillin / clavulanate, piperacillin / tazobactam, gentamicin, amikacin, ertapenem, imipenem / cilastatin, meropenem, doripenem, aztreonam, gallium iron mimetic substances, and combinations thereof. In another embodiment, the “drug” administered to the patient includes attenuated bacteria / pathogens for colonizing the urogenital tract with non-pathogenic bacteria in order to prevent recurrent urinary tract infections or pyelonephritis.

[0133] In another embodiment, a patient requires treatment for renal cell carcinoma. In a particular embodiment, the treatment method includes delivering an anti-angiogenic agent, a tyrosine kinase inhibitor, an mTOR inhibitor, or a combination thereof via a drug delivery device. Non-limiting examples of specific drugs that may be used in a treatment method for renal cell carcinoma include everolimus, aldesleukine, bevacizumab, axitinib, sorafenib tosylate, pazapanib hydrochloride, aldesleukine, sunitinib malate, temsirolimus, and combinations thereof. Other treatments may be used in conjunction with the use of the devices and drug delivery devices described herein. For example, the treatment method may further include surgery, e.g., partial nephrectomy, radiation, or systemic chemotherapy.

[0134] In yet another embodiment, the patient requires treatment for upper urothelial carcinoma or transitional cell carcinoma of the renal pelvis and ureter. Non-limiting examples of specific drugs that may be used in a method for treating upper urothelial carcinoma include Bacillus Calmette-Guerin (BCG), mitomycin C, BCG / interferon, interferon (IFN)-2a, epirubicin, thiotepa, doxorubicin, gemcitabine, and combinations thereof. Other treatments may be used in conjunction with the use of drug delivery devices described herein. For example, the treatment method may further include surgery, radiation, or systemic chemotherapy.

[0135] In another embodiment, the patient requires treatment for hyperfibrinolysis. Non-limiting examples of specific drugs that may be used in a method of treating hyperfibrinolysis include tranexamic acid, aminocaproic acid, and combinations thereof.

[0136] In yet another embodiment, the treatment method may include releasing an anti-inflammatory agent, an anti-fibrotic agent, or a combination thereof from a deployed drug delivery device.

[0137] Publications cited herein and materials from which they are cited are incorporated specifically by reference.

[0138] In the descriptions provided herein, the terms “includes,” “is,” “containing,” “having,” and “comprises” are used in a non-restrictive manner and should therefore be interpreted as “including, but not limited to.” When a method, system, or apparatus is claimed or described in relation to “comprising” various components or processes, the method or system may also “essentially consist of” or “consist of” various components or processes, unless otherwise stated.

[0139] Various numerical ranges may be disclosed herein. Wherever the applicant discloses or claims any kind of range, the applicant intends to disclose or claim each possible number of such ranges that can reasonably be included, including the endpoints of the range and the endpoints of any subranges and combinations of subranges contained within that range. Furthermore, the endpoints of all numerical ranges disclosed herein are approximations. As a typical example, the applicant discloses that in one embodiment, a drug delivery device has a length of about 1.5 cm to about 3 cm when in a holding configuration. This range should be interpreted as encompassing a length of about 1.5 cm to about 3 cm, and further encompassing each of "about" 1.6 cm, 1.7 cm, 1.8 cm, 1.9 cm, 2 cm, 2.1 cm, 2.2 cm, 2.3 cm, 2.4 cm, 2.5 cm, 2.6 cm, 2.7 cm, 2.8 cm, and 2.9 cm, including any range and subranges between any of these values.

[0140] As used herein, the term "about" refers to a value within 5% of the indicated value. For example, "about 2 cm" would encompass a range of 1.9 cm to 2.1 cm.

[0141] It will become clear that many modifications and other implementations of the disclosure described herein have the benefit of the teachings presented in the foregoing description and the relevant drawings. Therefore, it should be understood that the disclosure is not limited to the specific implementation disclosed, and that modifications and other implementations are intended to be included within the scope of the appended claims. [Examples]

[0142] The present invention will be further explained by the following non-limiting embodiments.

[0143] Example 1 - Drug delivery device A gemcitabine delivery device was fabricated for in vitro testing. The system was constructed using a double-walled polyurethane tube. The drug reservoir lumen of the drug delivery device in this example contained a gemcitabine hydrochloride powder blend, including gemcitabine hydrochloride, KOLLIDON® 30 polyvinylpyrrolidone (PVP) (BASF Corp., USA), and CAB-O-SIL® fumed silica (Cabot Corp., USA).

[0144] The drug delivery device had a dual lumen structure, including a substantially circular guidewire lumen and a drug reservoir lumen having a crescent-shaped cross-section, such as the drug reservoir lumen shown in Figure 1C. The elastic body of the device was fabricated from barium sulfate-added Tecoflex polyurethane (TECOFLEX® EG-80A-B20, 20% barium sulfate added, Tecoflex polyurethane, Lubrizol Life Sciences, USA) and TECOPHILIC® TPU polyurethane (HP-60D-35, Lubrizol Life Sciences, USA). Tecoflex polyurethane is a water-permeable and drug-impermeable material with barium sulfate addition, which allowed for visualization during insertion. This material allowed water to diffuse into the drug delivery device, contributing to the dissolution of the loaded drug payload. Drug-permeable stripes were formed using TECOPHILIC® TPU polyurethane. Therefore, TECOPHILIC® TPU polyurethane is a water-permeable and drug-permeable material, allowing water to enter the drug delivery device and enabling dissolved drugs to cross the drug-permeable stripe and enter the area surrounding the drug delivery device.

[0145] A first spacer was heat-fused to the first end of the drug reservoir lumen of the drug delivery device. Then, the gemcitabine hydrochloride powder blend was filled into the drug reservoir lumen of the drug delivery device, and then a second spacer was heat-fused to the second end of the drug reservoir lumen to seal / close the drug reservoir lumen.

[0146] The drug delivery device of this embodiment is shown in Figures 4A to 4C. The drug delivery device 400 included an outer wall 406 formed of Tecoflex polyurethane, along with a drug permeability stripe 424 made of tecophilic polyurethane. Each end of the drug reservoir lumen 407 was sealed with spacers 420, and the drug payload 416, a gemcitabine powder blend, was loaded into the drug reservoir lumen. The drug permeability stripe 424 extended along the length of the drug delivery device, as indicated by the arrow passing through the drug permeability stripe 424 in Figure 4C, providing a pathway for drug release by transwall diffusion. Figure 4C also shows a guidewire lumen 412 defined between the outer wall 406 and the inner wall 408.

[0147] Alternative designs for the device were also fabricated, including the addition of a spacer in the middle of the drug reservoir lumen. This design was particularly useful when the intermediate and end spacers contained radiopaque material, allowing for three-point visualization of the device when deployed in vivo. In such embodiments, it is not necessary to include radiopaque material within the material forming the elastic body. Examples of such drug delivery devices are shown in Figures 5A–5C. The drug delivery device 500 included an outer wall 506 formed of Tecoflex polyurethane, along with a drug-permeable stripe 524 of tecophilic polyurethane. Each end of the drug reservoir lumen 507 was sealed with Tecoflex polyurethane spacers 520. The drug reservoir lumen housed the drug payload 516 (gemcitabine powder blend) and the Tecoflex polyurethane spacer 550, which was positioned approximately midway between the end spacers 520. The assembly process included (i) filling the drug reservoir lumen with approximately half of the gemcitabine powder formulation after the placement of the first spacer, (ii) inserting the intermediate spacer into the drug reservoir lumen, (iii) filling the drug reservoir lumen with the remainder of the drug payload, and then (iv) installing the second end spacer. The end spacer was heat-fused to the end of the drug reservoir lumen. The drug permeable stripe 524 extended along the length of the drug delivery device, as indicated by the arrow passing through the drug permeable stripe 524 in Figure 5C, providing a pathway for drug release by transwall diffusion. Figure 5C also shows the guidewire lumen 512 defined between the outer wall 506 and the inner wall 508.

[0148] After assembling the drug delivery device, a heat setting process was used to apply the holding shape to the device. The drug delivery device was elastically deformed into the holding shape and then placed in a 90°C oven for 10 minutes. The drug delivery device was cooled to room temperature while maintaining its holding shape. A single coil-shaped and helical holding shape was generated.

[0149] After the drug delivery device was given a retaining shape, a retrieval string was attached to the end of the drug delivery device. The retrieval string was a monofilament nylon material added to assist in the placement, removal, or both of the drug delivery device. Alternatively, a monofilament polyethylene material may be used as the retrieval string due to its ability to maintain its mechanical properties in vivo. The retrieval string penetrates from the guidewire lumen of the drug delivery device (at a distance of 2.5 mm from the end of the drug delivery device) through the [1] first spacer in the drug reservoir lumen and [2] the outer wall facing the drug reservoir lumen. The retrieval string was then pulled until it was twice its length and then tied together. The retrieval string was set to a length such that its end could be located in the bladder of the test animal (described below) for easy grasping and removal at the end of the procedure.

[0150] Example 2 - In vivo testing of a drug delivery device The movement of two drug delivery devices with different retention shapes was evaluated using in vivo studies.

[0151] Single-coil designs (e.g., those in Figure 2) with lengths of 4 cm and 6 cm (when in a substantially straight configuration) were deployed at the poles of the renal pelvis in the kidneys of Yorkshire pigs. Autopsies revealed that the drug delivery devices had moved, and that smaller drug delivery devices were more easily moved than larger ones. Furthermore, the single-coil drug delivery devices were shorter in length to fit the available renal pelvis space, which limited the drug payload.

[0152] Single-coil drug delivery devices were placed at the upper and lower poles of the four kidneys of four domestic Yorkshire pigs. Two small (i.e., 4 cm) single-coil drug delivery devices were deployed in two animals (all four small drug delivery devices) for 10 days, and two large drug delivery devices (i.e., 6 cm) were deployed in one animal for 10 days. Due to the small geometric shape of the renal pelvis, one large drug delivery device (i.e., 6 cm) was deployed in the remaining animal for 10 days. At necropsy, one of the four small drug delivery devices had migrated to the proximal ureter, two had migrated subcutaneously into the kidney, and the remaining small drug delivery devices remained within the kidney. Three large drug delivery devices were found within the kidney at necropsy. Thus, it was observed that smaller drug delivery devices are more easily migrated than larger drug delivery devices.

[0153] Helical (multi-coil) drug delivery devices with lengths of 6 cm and 8 cm (when in a relatively linearized deployment configuration) and an inner coil diameter of 0.5 cm, and helical drug delivery devices with lengths of 10 cm and 12 cm and an inner coil diameter of 1 cm were deployed within the pole of the renal pelvis of the kidney. Autopsy revealed that none of the drug delivery devices of any size exhibited significant mobility, demonstrating an improvement in retention force between the helical design and the coil design. In addition, longer systems were found to be safer than shorter systems after deployment. Due to their three-dimensional shape, the multi-coil drug delivery devices made contact with the renal pelvis wall in all directions, thereby improving retention force. Furthermore, the relative complexity of this shape reduced the likelihood of these drug delivery devices retracting from and descending the ureter. The longer the length of the multi-coil drug delivery device, the larger the drug payload that could be used.

[0154] The spiral design was deployed for 7 days on the upper poles of eight kidneys in four livestock Yorkshire pigs. The deployment of the spiral design in this embodiment is provided in the table below.

[0155] [Table 1]

[0156] Seven days later, one of the eight helical-design drug delivery devices had migrated to the ureter. The migrated drug delivery device may have been removed, at least partially, during the attempt to remove the string fixation device. Helical-design drug delivery devices of all sizes (length and coil diameter) did not exhibit significant mobility and showed an overall improvement in retention force.

[0157] Example 3 - Modified shape of drug delivery device A drug delivery device, as shown in Figure 6, was manufactured using a helical section with three turns and a straight end extending almost perpendicularly to the helical section of the device. The straight end was formed by heat setting and aligned diagonally to the device. The outer coil diameter was 12 mm.

[0158] As shown in Figure 7, a drug delivery device was manufactured having six turns of a helical section and straight ends formed by heat setting. The external coil diameter of the device was 8 mm. The non-coiled length of the device was 120 mm.

[0159] A drug delivery device was manufactured in which three coils were separated by two intermediate straight sections, as shown in Figure 8. The non-coiled length of the device was 85 mm.

[0160] A drug delivery device was fabricated in which two coils were separated by a single intermediate straight section, as shown in Figure 9. The non-coiled length of the device was 75 mm.

[0161] A drug delivery device with eight turns and straight ends was also manufactured. This device had an external coil diameter of 7 mm.

[0162] The tip of each of these devices was thermoformed to provide a tapered end, as shown in Figure 10A.

[0163] Example 4 - In vitro release of drug In vitro release tests of gemcitabine were performed on several embodiments of the drug delivery device of Example 1. The different embodiments tested in this example included drug delivery devices having [1] drug permeability stripes of different arc angles, [2] fabricated using different recovery string attachment methods, [3] having different lengths, and [4] having different heat-set shapes.

[0164] Each drug delivery device was placed in 300 g of deionized water at 37°C, and time-lapse samples were collected at predetermined points in time to construct an in vitro release profile.

[0165] a. Stripe angle Two drug delivery devices with different stripe arc angles were tested. The first drug delivery device had a stripe arc angle of 60°, and the second drug delivery device had a stripe arc angle of 120°.

[0166] A smaller stripe arc angle (i.e., 60°) resulted in a longer release duration. Drug delivery devices with a 120° stripe arc angle had a release profile that lasted for 4 days, while drug delivery devices with a 60° stripe arc angle had a release profile that lasted for 7 days.

[0167] b. Attachment of the retrieval string The method of attaching the retrieval string described in Example 1 did not result in any leakage and was the simplest attachment method tested.

[0168] c. Length of drug delivery device Drug delivery devices with a relatively linearized deployment shape, coil-holding or helical-holding shape, and lengths of 4 cm (coil-holding shape), 8 cm (coil-holding shape), 10 cm (helical-holding shape), and 12 cm (helical-holding shape) were tested. However, drug delivery devices with lengths of 4 cm and 8 cm experienced undesirable movement after deployment. Drug delivery devices with lengths of 10 cm or 12 cm did not experience undesirable movement after deployment, and the change in length (from 4 cm or 8 cm) did not affect the release duration of the drug delivery device, although this change increased the peak release rate.

[0169] d. Heat set configuration The change to a heatset configuration did not have a significant impact on the drug delivery device's release profile.

[0170] Figure 11 shows the release profiles of two different drug delivery devices in this embodiment. The first drug delivery device has a stripe with an arc angle of 60°, a length of 10 cm when in a relatively linearized configuration, and a helical heat-set configuration. The second drug delivery device was identical to the first, except that its length was 12 cm. The plots in Figure 11 show that the release rates achieved by the two drug delivery devices were similar, but the device with the longer length (device 2) released a larger amount of drug on each of the days from 1 to 9.

[0171] e. Stripe angle Changes in the stripe angle did not significantly affect the release profile of drug delivery devices tested when devices with smaller stripe angles had larger drug payloads.

[0172] Figure 12 shows the release profiles of two different drug delivery device configurations. The first configuration of the drug delivery device was fabricated using EG-100A-B20 as the base material, and the second configuration of the drug delivery device was fabricated using EG-80A-B20 as the base material. EG-100A-B20 is a highly rigid material that increases the column strength of the drug delivery device and reduces the collapse of the drug delivery device when it is pushed along the guidewire. The first configuration of the drug delivery device had an outer diameter of 9Fr and a higher drug payload capacity, while the second configuration had an outer diameter of 8Fr. The drug permeability stripe of both drug delivery devices was fabricated with HP-60D-35. The stripe angle of the second configuration was 60°. Because the first configuration has a higher drug payload capacity, the stripe angle was reduced to 55° to maintain the peak release of the drug profile. As seen in Figure 12, despite the modification of the drug delivery device to fabricate the second configuration, both configurations had very similar drug release profiles and maintained peak release.

[0173] Example 5 - Crescent-shaped tablets Crescent-shaped tablets were manufactured, including those corresponding to the dimensions of the drug reservoir lumen of the drug delivery device of Example 1. A single-station automated press and a placebo blend were used to manufacture the crescent-shaped tablets. The crescent-shaped tablets were similar to those shown in Figure 13.

[0174] Exemplary Embodiments Embodiment 1. A drug delivery device for deployment in the renal pelvis of a patient, wherein the drug delivery device is an elastic body, the elastic body comprising (i) an outer tube including an elongated outer wall, and (ii) an elongated arc-shaped inner wall located within the outer tube, integrally connected to the inner surface of the outer wall along two opposing edges of the arc-shaped inner wall, wherein the outer wall and the inner wall together define (a) a guidewire lumen on the concave side of the inner wall and (b) a drug reservoir lumen on the opposing convex side of the inner wall, the drug reservoir lumen being closed at its opposing end, and the drug delivery device comprising a drug payload disposed within the drug reservoir lumen, the drug payload containing at least one drug, the drug delivery device being elastically deformable between a deployment shape for passage of the drug delivery device into the renal pelvis of a patient via the ureter and a retaining shape configured to reduce movement of the device from the renal pelvis.

[0175] Embodiment 2. The drug delivery device according to Embodiment 1, wherein the device is biased to hold the guidewire in place when the guidewire is not inserted into the lumen of the guidewire.

[0176] Embodiment 3. The drug delivery device according to Embodiment 1 or 2, wherein the holding shape is spiral.

[0177] Embodiment 4. The drug delivery device according to Embodiment 3, wherein the spiral retaining shape includes 2 to 10 turns.

[0178] Embodiment 5. A drug delivery device according to any one of Embodiments 1 to 4, wherein the outer tube comprises two different constituent materials, the first of which is impermeable to the drug when the drug is in a solution, and the second of which is permeable to the drug when the drug is in a solution, and the second of which is adjacent to the drug payload.

[0179] Embodiment 6. The drug delivery device according to Embodiment 5, wherein the second material is in the form of a drug-permeable stripe extending along the length of the elongated outer wall.

[0180] Embodiment 7. The drug delivery device according to Embodiment 6, wherein the outer wall is cylindrical and the drug-permeable stripe has an arc angle of approximately 30° to approximately 120° on the outer circumference of the outer wall within the cross-section.

[0181] Embodiment 8. The drug delivery device according to Embodiment 7, wherein the drug-permeable stripe has an arc angle of approximately 60° to approximately 120° on the outer periphery of the outer wall within the cross-section.

[0182] Embodiment 9. A drug delivery device according to any one of Embodiments 1 to 8, wherein the lumen of the drug reservoir has a crescent-shaped cross-section.

[0183] Embodiment 10. A drug delivery device according to any one of Embodiments 1 to 9, wherein the guidewire lumen has a circular cross-sectional shape.

[0184] Embodiment 11. A drug delivery device according to any one of Embodiments 1 to 10, further comprising a retaining frame lumen and a retaining frame disposed within the retaining frame lumen, wherein the retaining frame is an elastic wire configured to bias the drug delivery device into a retaining shape.

[0185] Embodiment 12. A drug delivery device according to any one of Embodiments 1 to 11, wherein the holding shape is spiral, and the drug delivery device has a length of about 5 cm to about 15 cm, about 8 cm to about 12 cm, or about 10 cm to about 12 cm when in the deployed shape.

[0186] Embodiment 13. The drug delivery device according to Embodiment 12, wherein the drug delivery device has a maximum width of approximately 0.5 cm to approximately 1.4 cm, approximately 0.5 cm to approximately 1 cm, or approximately 0.5 cm to approximately 1 cm.

[0187] Embodiment 14. A drug delivery device according to Embodiment 12 or 13, wherein the drug delivery device has a length of approximately 0.8 cm to approximately 2 cm, or approximately 0.8 cm to approximately 1.8 cm, or approximately 0.8 cm to approximately 1.4 cm when in a holding position.

[0188] Embodiment 15. A drug delivery device according to any one of Embodiments 1 to 14, wherein each of the opposing ends of the lumen of the drug reservoir is sealed by a spacer.

[0189] Embodiment 16. A drug delivery device according to any one of Embodiments 1 to 15, further comprising at least one intermediate spacer positioned between opposing ends within the lumen of a drug reservoir.

[0190] Embodiment 17. A drug delivery device according to Embodiment 15 or 16, wherein the elastic body, end spacers, and / or at least one intermediate spacer comprises a radiopaque filler material.

[0191] Embodiment 18. A drug delivery device according to any one of Embodiments 1 to 17, wherein the outer tube comprises two different constituent materials, the first of which comprises Tecoflex polyurethane which is impermeable to the drug when the drug is in a solution, and the second material which is permeable to the drug when the drug is in a solution, and the second material is adjacent to the drug payload.

[0192] Embodiment 19. The drug delivery device according to Embodiment 18, wherein the first material further comprises a radiopaque filler.

[0193] Embodiment 20. A drug delivery device according to Embodiment 18 or 19, wherein the second material comprises tecophilic polyurethane.

[0194] Embodiment 21. A drug delivery device according to any one of Embodiments 1 to 20, further comprising a retrieval string having a first end attached to the drug delivery device.

[0195] Embodiment 22. The drug delivery device according to Embodiment 21, wherein the retrieval string is of sufficient length for the second end of the retrieval string to be in the patient's bladder when the drug delivery device is deployed in the renal pelvis.

[0196] Embodiment 23. A drug delivery device according to any one of embodiments 1 to 22, further comprising a tab fixed to the end portion of an elastic body and configured to be grasped by forceps.

[0197] Embodiment 24. A drug delivery device according to any one of Embodiments 1 to 23, wherein the drug payload is in a solid or semi-solid form.

[0198] Embodiment 25. The drug delivery device according to Embodiment 24, wherein the drug payload is in the form of a powder or a plurality of tablets.

[0199] Embodiment 26. The drug delivery device according to Embodiment 24, wherein the drug payload is in the form of a plurality of tablets having a crescent-shaped cross-section.

[0200] Embodiment 27. A drug delivery device according to any one of Embodiments 1 to 26, wherein the outer tube and inner wall are formed together by a co-extrusion process.

[0201] Embodiment 28. A drug delivery device according to any one of Embodiments 1 to 27, wherein the elastic body is thermally shaped to have a retaining shape.

[0202] Embodiment 29. A system for administering a drug to a patient in need of a drug, the system comprising a drug delivery device according to any one of Embodiments 1 to 28, and a guidewire deployment system for deploying the drug delivery device into the renal pelvis of a patient, the guidewire deployment system comprising (i) a guidewire configured to be operably associated with the drug delivery device and having a distal end portion capable of extending into the renal pelvis while an opposing proximal end portion extends out of the patient's urethra, and (ii) a plunger device for pushing the drug delivery device into the renal pelvis from the distal end along the guidewire.

[0203] Embodiment 30. The system according to Embodiment 29, wherein the guidewire has a cross-sectional area sized to pass through the lumen of the guidewire of the drug delivery device.

[0204] Embodiment 31. The plunger device is the system according to Embodiment 29 or 30, comprising a plunger, a handle, a sheath extending between the plunger and the handle, the sheath transmitting a driving force applied to the handle to the plunger, and an internal bore for receiving a guide wire so that the plunger device can move along the guide wire.

[0205] Embodiment 32. The system according to Embodiment 31, wherein the plunger further includes a stopper configured to indicate that the drug delivery device is separated from the guidewire.

[0206] Embodiment 33. A method for administering a drug to a patient in need of a drug, the method comprising deploying a drug delivery device according to any one of Embodiments 1 to 28 in the renal pelvis of the patient, wherein the drug delivery device is fully housed in the patient's renal pelvis, with the optional exception of a recovery string configured to extend into the patient's bladder, or through the bladder into the patient's urethra, or through the patient's urethra; and releasing the drug from the drug delivery device into the renal pelvis.

[0207] Embodiment 34. The method according to Embodiment 33, wherein the drug is released via transwall diffusion through at least a portion of the outer wall.

[0208] Embodiment 35. The method according to Embodiment 34, wherein the outer wall comprises two different constituent materials, the first of which is impermeable to the drug when the drug is in solution, and the second material is permeable to the drug when the drug is in solution, the second material is adjacent to the drug payload, and the drug is released by transwall diffusion through the second material.

[0209] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein deploying a drug delivery device includes elastically deforming the drug delivery device into a deployed shape, inserting the drug delivery device through the patient's urethra, bladder, and ureters, and releasing the drug delivery device into the patient's renal pelvis so that the drug delivery device elastically deforms into a retaining shape.

[0210] Embodiment 37. The method according to any one of Embodiments 33 to 36, wherein deploying the drug delivery device comprises inserting the distal end of a guidewire into the patient's renal pelvis through the patient's urethra, bladder, and ureter; advancing the drug delivery device along the guidewire toward the distal end of the guidewire and toward the proximal end of the guidewire, wherein the guidewire is positioned within the lumen of the guidewire until the drug delivery device is positioned within the renal pelvis; and then withdrawing the guidewire from the lumen of the guidewire and from the patient.

[0211] Embodiment 38. The method according to Embodiment 37, wherein the drug delivery device is elastically deformable between a coiled or helical holding shape and a relatively straightened insertion shape, and during the step of advancing the drug delivery device along a guidewire, the guidewire located within the lumen of the guidewire applies a load to the drug delivery device, biasing the drug delivery device into the relatively straightened insertion shape, and after the step of withdrawing the guidewire from the lumen of the guidewire, the drug delivery device elastically deforms into a coiled or helical holding shape suitable for holding the drug delivery device in the renal pelvis of a patient.

[0212] Embodiment 39. The method according to any one of Embodiments 33 to 38, wherein the drug delivery device comprises a radiopaque marker or drug, and the method further comprises determining the placement of the drug delivery device in the patient by X-ray imaging.

[0213] Embodiment 40. The method according to any one of Embodiments 33 to 39, wherein, following the deployment of a drug delivery device into the renal pelvis, urine diffuses into the lumen of a drug reservoir and comes into contact with the drug contained in the lumen of the drug reservoir, generating a drug solution, which is then released into the renal pelvis.

[0214] Embodiment 41. The method according to Embodiment 40, wherein the outer wall comprises two different constituent materials, the first of which is impermeable to the drug when the drug is in a solution, and the second of which is permeable to the drug when the drug is in a solution, and following the deployment of the drug delivery device into the renal pelvis, urine diffuses into the lumen of the drug reservoir by transwall diffusion through the first and / or second material, comes into contact with the drug contained in the lumen of the drug reservoir, generates a drug solution, and the solution is subsequently released into the renal pelvis by transwall diffusion through the second material.

[0215] Embodiment 42. The method according to any one of Embodiments 33 to 41, wherein the rate of drug release from the drug delivery device is essentially zero-order over a period ranging from 36 hours to 7 days.

[0216] Embodiment 43. A method for administering a drug to a patient in need of a drug, comprising deploying a drug delivery device in the patient's renal pelvis and continuously releasing the drug from the deployed drug delivery device into the urine in the renal pelvis for a long-term treatment period of at least 24 hours, wherein the drug delivery device is fully housed in the renal pelvis, with the optional exception of a retrieval string extending at least into the patient's ureter.

[0217] Embodiment 44. The method according to Embodiment 43, wherein the treatment period is 1 to 90 days.

[0218] Embodiment 45. The method according to Embodiment 43 or 44, wherein the drug is released from the drug delivery device by transwall diffusion or osmotic pressure through an opening in the wall of the drug delivery device.

[0219] Embodiment 46. The method according to any one of Embodiments 43 to 45, wherein the patient requires treatment or prevention of a urinary tract infection or pyelonephritis.

[0220] Embodiment 47. The method according to Embodiment 46, wherein the drug comprises an antibacterial agent.

[0221] Embodiment 48. The method according to Embodiment 46, wherein the drug comprises an aminoglycoside, a penetrating agent, or an iron mimetic.

[0222] Embodiment 49. The method according to Embodiment 46, wherein the drug comprises an antibiotic, antibacterial agent, antifungal agent, antiviral agent, anthelmintic agent, disinfectant, or preservative.

[0223] Embodiment 50. The method according to Embodiment 46, wherein the drug comprises attenuated bacteria / pathogens for colonizing the urogenital tract with non-pathogenic bacteria in order to prevent recurrent urinary tract infections or pyelonephritis.

[0224] Embodiment 51. An embodiment according to any one of Embodiments 43 to 45, wherein the patient requires treatment for renal cell carcinoma.

[0225] Embodiment 52. The method according to Embodiment 51, wherein the drug is selected from everolimus, aldesleukin, bevacizumab, axitinib, sorafenib tosylate, pazapanib hydrochloride, aldesleukin, sunitinib malate, temsirolimus, gemcitabine, and combinations thereof.

[0226] Embodiment 53. The method according to any one of Embodiments 43 to 45, wherein the patient requires treatment for upper urothelial carcinoma.

[0227] Embodiment 54. The method according to Embodiment 53, wherein the drug is selected from Bacillus Calmette-Guerin (BCG), mitomycin C, BCG / interferon, interferon 2α, epirubicin, doxorubicin, thiotepa, gemcitabine, and combinations thereof.

[0228] Embodiment 55. The method according to any one of Embodiments 43 to 45, wherein the patient requires treatment for hyperfibrinolysis.

[0229] Embodiment 56. The method according to Embodiment 55, wherein the drug is selected from tranexamic acid, aminocaproic acid, and combinations thereof.

[0230] Embodiment 57. The method according to any one of Embodiments 43 to 45, wherein the patient requires treatment for urinary stones.

[0231] Embodiment 58. The method according to Embodiment 57, wherein the drug delivery device into the renal pelvis is deployed after the patient has been treated with extracorporeal shock wave lithotripsy for the treatment of kidney stones in the patient.

[0232] Embodiment 59. The method according to Embodiment 57 or 58, wherein the drug is selected from antibacterial agents, alkalizing agents, acidifying agents, urease inhibitors, and combinations thereof.

[0233] Embodiment 60. The method according to any one of Embodiments 43 to 59, wherein the drug delivery device includes the device described in any one of Embodiments 1 to 28.

[0234] Embodiment 61. A drug delivery device for deployment in the renal pelvis of a patient, comprising: an elongated elastic body, the elastic body comprising a guidewire lumen and a separate drug reservoir lumen; and a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug, wherein the drug delivery device is elastically deformable between a deployment shape configured to accommodate the passage of the drug delivery device into the renal pelvis of a patient via the ureter and a helical retaining shape configured to reduce the movement of the device from the renal pelvis.

[0235] Embodiment 62. The drug delivery device according to Embodiment 61, wherein the spiral retaining shape includes 2 to 10 turns.

[0236] Embodiment 63. The drug delivery device according to Embodiment 61 or 62, wherein the device is biased to a retaining shape when a guidewire is not inserted into the guidewire lumen, and the elastic body further comprises (i) being thermally shaped to have a retaining shape and / or (ii) a retaining frame lumen and a retaining frame disposed within the retaining frame lumen, the retaining frame being an elastic wire configured to bias the drug delivery device into a retaining shape.

[0237] Embodiment 64. A drug delivery device according to any one of embodiments 61 to 63, further comprising a retrieval string having a first end attached to the terminal portion of an elongated elastic body, wherein the retrieval string is of sufficient length for the second end of the retrieval string to be in the patient's bladder when the drug delivery device is deployed in the renal pelvis.

[0238] Embodiment 65. A drug delivery device according to any one of Embodiments 61 to 64, wherein the drug payload is in the form of a powder, a plurality of tablets, or a semi-solid form such as a gel.

[0239] Embodiment 66. A drug delivery device according to any one of embodiments 61 to 65, wherein the elongated elastic body includes a water-permeable wall configured to allow urine to diffuse into the lumen of the drug reservoir and come into contact with the drug payload.

[0240] Embodiment 67. A drug delivery device according to any one of Embodiments 61 to 66, wherein the elongated elastic body includes a drug-permeable wall adjacent to the lumen of a drug reservoir, the drug-permeable wall being configured to allow the drug to diffuse from the device in solution.

[0241] Embodiment 68. The drug delivery device according to Embodiment 67, wherein the elongated elastic body further includes a drug-impermeable wall adjacent to the lumen of the drug reservoir.

[0242] Embodiment 69. The drug delivery device according to Embodiment 68, wherein the drug-permeable wall contains tecophilic polyurethane and the drug-impermeable wall contains tecoflex polyurethane.

[0243] Embodiment 70. The drug delivery device according to Embodiment 68 or 69, wherein the drug-permeable wall is in the form of a drug-permeable stripe extending over the length of the elastic body.

[0244] Embodiment 71. A drug delivery device according to any one of embodiments 61 to 70, wherein each of the opposing ends of the lumen of the drug reservoir is sealed by an end spacer.

[0245] Embodiment 72. A drug delivery device according to any one of embodiments 61 to 71, further comprising at least one intermediate spacer positioned approximately midway between the opposing ends of an elongated elastic body within the lumen of a drug reservoir.

[0246] Embodiment 73. A drug delivery device according to Embodiment 71 or 72, wherein the elastic body, end spacers, and / or at least one intermediate spacer comprises a radiopaque filler material.

[0247] Embodiment 74. A drug delivery device according to any one of Embodiments 61 to 73, wherein the lumen of the drug reservoir has a crescent-shaped cross-section, and the drug payload comprises a powder or a plurality of crescent-shaped tablets.

[0248] Embodiment 75. A drug delivery device according to any one of Embodiments 61 to 74, wherein the elastic body comprises one or more water-permeable thermoplastic polyurethanes.

[0249] Embodiment 76. A drug delivery device according to any one of Embodiments 61 to 75, wherein the holding shape has a spiral portion having one straight end.

[0250] Embodiment 77. A drug delivery device according to any one of Embodiments 61 to 75, wherein the holding shape has a spiral portion having two straight ends.

[0251] Embodiment 78. A drug delivery device according to any one of embodiments 61 to 77, wherein the holding shape has a spiral portion and at least one intermediate straight portion.

[0252] Embodiment 79. The drug delivery device according to Embodiment 78, wherein the holding shape includes two or more intermediate straight sections.

[0253] Embodiment 80. A drug delivery device according to any one of Embodiments 61 to 79, wherein the device body includes a tube comprising a base material EG-100A-B20 and a stripe material HP-60D-35 having a stripe angle of approximately 55 degrees.

[0254] Embodiment 81. A drug delivery device according to any one of Embodiments 61 to 80, wherein the device body has an outer diameter of 9 Fr.

[0255] Embodiment 82. A drug delivery device according to any one of Embodiments 61 to 81, wherein the two opposing ends of the device body are linear and, when in the holding configuration, extend in a direction substantially perpendicular to the plane within the helical coil of the body.

[0256] Embodiment 83. A drug delivery device according to any one of Embodiments 61 to 82, wherein the external coil diameter is 8 mm to 12 mm and the device has 3 to 8 coils.

[0257] Embodiment 84. A drug delivery device according to any one of Embodiments 61 to 83, wherein the drug payload comprises at least 90% by weight, preferably at least 95% by weight, of the drug, and the drug payload is in the form of a filled powder or a plurality of tablets.

[0258] Embodiment 85. The drug delivery device according to claim 84, wherein the drug is gemcitabine hydrochloride.

[0259] Embodiment 86. The apparatus, system, or method according to any one of Embodiments 1 to 85, wherein the drug delivery device comprises a tapered end configured to function as a tip that facilitates the introduction of the device into the patient's renal pelvis through the urethra and ureter.

[0260] Embodiment 87. The apparatus, system, or method according to Embodiment 86, further comprising a tapered end configured to function as a terminal portion of the drug delivery device.

[0261] Embodiment 88. The drug delivery device further comprises at least one retrieval string fixed to the device, the device, system, or method according to Embodiment 86 or 87.

[0262] 〔Embodiment〕 (1) A drug delivery device for deployment within a patient's renal pelvis, the drug delivery device comprising: An elastomer, the elastomer comprising: (i) An outer tube including an elongated outer wall; and (ii) An elongated arcuate inner wall located within the outer tube, the elongated arcuate inner wall being integrally connected to the inner surface of the outer wall along two opposing edges of the arcuate inner wall, the outer wall and the inner wall together defining (a) a guide wire lumen on the concave side surface of the inner wall and (b) a drug reservoir lumen on the opposing convex side surface of the inner wall, the drug reservoir lumen being closed at its opposing ends, the elastomer; A drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug, the drug payload; The drug delivery device is elastically deformable between a deployment shape for passage of the drug delivery device through the patient's ureter to the renal pelvis and a retention shape configured to reduce movement of the device from the renal pelvis. (2) The drug delivery device according to Embodiment 1, wherein the device is biased to assume the retention shape when a guide wire is not inserted into the guide wire lumen. (3) The drug delivery device according to Embodiment 1, wherein the retention shape has a helical portion. (4) The drug delivery device according to Embodiment 3, wherein the retention shape further includes a straight terminal portion extending in the longitudinal direction of the device. (5) The drug delivery device according to Embodiment 3, wherein the helical portion includes 2 to 10 turns.

[0263] (6) The drug delivery device according to Embodiment 5, wherein at least two of the turns are separated by an intermediate straight portion. (7) The drug delivery device according to any one of Embodiments 1 to 6, wherein one or both ends of the device body are tapered. (8) The outer tube includes two different constituent materials, wherein the first material is impermeable to the drug when the drug is in solution, and the second material is permeable to the drug when the drug is in solution, and the second material is adjacent to the drug payload. The drug delivery device according to any one of Embodiments 1 to 6. (9) The drug delivery device according to Embodiment 8, wherein the second material is in the form of a drug-permeable stripe extending along the length of the elongated outer wall. (10) The drug delivery device according to Embodiment 9, wherein the outer wall is cylindrical, and the drug-permeable stripe has an arc angle of about 30° to about 120° of the outer periphery of the outer wall in the cross section.

[0264] (11) The drug delivery device according to Embodiment 10, wherein the drug-permeable stripe has an arc angle of about 55° to about 120° of the outer periphery of the outer wall in the cross section. (12) The drug delivery device according to Embodiment 9, wherein the first material includes tecoflex polyurethane. (13) The drug delivery device according to Embodiment 9, wherein the first material further includes a radiopaque filler. (14) The drug delivery device according to Embodiment 9, wherein the second material includes tecophilic polyurethane. (15) The drug delivery device according to any one of Embodiments 1 to 6, wherein the drug reservoir lumen has a crescent cross-sectional shape.

[0265] (16) The drug delivery device according to any one of Embodiments 1 to 6, wherein the guide wire lumen has a circular cross-sectional shape. (17) A drug delivery device according to any one of embodiments 1 to 6, further comprising a retaining frame lumen and a retaining frame disposed within the retaining frame lumen, wherein the retaining frame is an elastic wire configured to bias the drug delivery device into the retaining shape. (18) The drug delivery device according to any one of embodiments 1 to 6, wherein the holding shape includes a spiral portion, and the drug delivery device has a length of about 5 cm to about 15 cm when in the deployment shape. (19) The drug delivery device according to Embodiment 18, wherein the drug delivery device has a length of about 0.8 cm to about 2 cm when in the holding shape. (20) A drug delivery device according to any one of embodiments 1 to 6, wherein each of the opposing ends of the lumen of the drug reservoir is sealed by a spacer.

[0266] (21) The drug delivery device according to embodiment 20, further comprising at least one intermediate spacer positioned between the opposing ends within the lumen of the drug reservoir. (22) The drug delivery device according to Embodiment 20 or 21, wherein the elastic body, the end spacer, and / or the at least one intermediate spacer comprises a radiopaque filler material. (23) A drug delivery device according to any one of embodiments 1 to 20, further comprising a retrieval string attached to the drug delivery device. (24) The drug delivery device according to embodiment 23, wherein the retrieval string is of sufficient length so that the end of the retrieval string is located in the patient's bladder when the drug delivery device is deployed in the renal pelvis. (25) A drug delivery device according to any one of embodiments 1 to 6, wherein the drug payload is in a solid or semi-solid form.

[0267] (26) The drug delivery device according to Embodiment 25, wherein the drug payload is in the form of a powder or a plurality of tablets. (27) The drug delivery device according to Embodiment 25, wherein the drug payload is in the form of a plurality of tablets having a crescent-shaped cross-section. (28) A drug delivery device according to any one of embodiments 1 to 6, wherein the outer tube and the inner wall are formed together by a co-extrusion process. (29) A drug delivery device according to any one of embodiments 1 to 6, wherein the elastic body is thermally shaped to have the holding shape. (30) A system for administering the drug to a patient who requires the drug, wherein the system is A drug delivery device according to any of Embodiments 1 to 29, A guidewire deployment system for deploying the drug delivery device within the renal pelvis of the patient, the guidewire deployment system comprising: (i) a guidewire configured to be operably associated with the drug delivery device and having a distal end portion that can extend into the renal pelvis while an opposing proximal end portion extends outward from the patient's urethra; and (ii) a plunger device for pushing the drug delivery device into the renal pelvis from the distal end along the guidewire, The system wherein the guidewire has a cross-sectional area sized to pass through the lumen of the guidewire of the drug delivery device.

[0268] (31) The plunger device Plunger and, The handlebars and A sheath extending between the plunger and the handle, the sheath transmitting the driving force applied to the handle to the plunger, The system according to embodiment 30, further comprising an internal bore for receiving the guide wire so that the plunger device can move along the guide wire. (32) The system according to embodiment 31, wherein the plunger further includes a stop portion configured to indicate that the drug delivery device is separated from the guide wire. (33) A method for administering the drug to a patient in need of the drug, wherein the method is The drug delivery device is deployed in the renal pelvis of the patient, wherein the drug delivery device is fully housed in the renal pelvis of the patient, with the optional exception of a retrieval string configured to extend into the patient's bladder, or through the bladder into the patient's urethra, or through the patient's urethra. A method comprising releasing a drug from the drug delivery device into the renal pelvis. (34) The method according to embodiment 33, wherein the drug is released via transwall diffusion through at least a portion of the outer wall of the drug delivery device. (35) The outer wall comprises two different constituent materials, the first of which is impermeable to the drug when the drug is in a solution, and the second of which is permeable to the drug when the drug is in a solution. The second material is adjacent to the payload containing the drug, The method according to embodiment 34, wherein the drug is released via transwall diffusion through the second material.

[0269] (36) The arrangement of the drug delivery device is The drug delivery device is elastically deformed into the deployed shape, The drug delivery device is inserted through the patient's urethra, bladder, and ureters. The method according to any one of embodiments 33 to 35, comprising releasing the drug delivery device into the renal pelvis of the patient such that the drug delivery device elastically deforms into a retaining shape. (37) The deployment of the drug delivery device The distal end of the guidewire is passed through the patient's urethra, bladder, and ureter and inserted into the patient's renal pelvis. The drug delivery device is advanced along the guidewire toward the distal end of the guidewire and toward the proximal end of the guidewire, wherein the guidewire is positioned within the lumen of the guidewire until the drug delivery device is positioned within the renal pelvis, and then, The method according to embodiment 33, comprising withdrawing the guide wire from the guide wire lumen and from the patient. (38) The drug delivery device is elastically deformable between a coiled or helical retention shape and a relatively linear insertion shape, During the step of advancing the drug delivery device along the guide wire, the guide wire located within the guide wire lumen applies a load on the drug delivery device to bias the drug delivery device into the relatively linear insertion shape. Following the step of withdrawing the guide wire from the guide wire lumen, the drug delivery device elastically transforms into the coiled or helical retention shape suitable for holding the drug delivery device within the renal pelvis of the patient, the method according to embodiment 37. (39) The drug delivery device includes a radiopaque marker or agent, and the method further includes determining the placement of the drug delivery device within the patient by fluoroscopy, the method according to embodiment 33. (40) Following the deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen and contacts the drug within the payload to form a solution of the drug, and then the solution is released into the renal pelvis, the method according to embodiment 33.

[0270] (41) The outer wall includes two different constituent materials, wherein the first material is impermeable to the drug when the drug is in solution, and the second material is permeable to the drug when the drug is in solution. Following the deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen by trans-wall diffusion through the first and / or the second material and contacts the drug contained within the drug reservoir lumen to form a solution of the drug, and then the solution is released into the renal pelvis by trans-wall diffusion through the second material, the method according to embodiment 40. (42) The rate of release of the drug from the drug delivery device is substantially zero-order over a period ranging from 36 hours to 7 days, the method according to embodiment 33. (43) A method of administering the drug to a patient who requires the drug, The drug delivery device is placed inside the renal pelvis of the patient, This includes continuously releasing the drug from the deployed drug delivery device into the urine in the renal pelvis for a long-term treatment period of at least 24 hours, The drug delivery device is completely housed within the renal pelvis, with the optional exception of a retrieval string extending into the patient's ureter. (44) The method according to embodiment 43, wherein the treatment period is 1 to 90 days. (45) The method according to embodiment 43, wherein the drug is released from the drug delivery device by transwall diffusion or osmotic pressure through an opening in the wall of the drug delivery device.

[0271] (46) The method according to any one of embodiments 43 to 45, wherein the patient requires treatment or prevention of a urinary tract infection or pyelonephritis. (47) The method according to any one of embodiments 43 to 45, wherein the patient requires treatment for renal cell carcinoma. (48) The method according to any one of embodiments 43 to 45, wherein the patient requires treatment for upper urothelial carcinoma. (49) The method according to any one of embodiments 43 to 45, wherein the patient requires treatment for hyperfibrinolysis. (50) The method according to any one of embodiments 43 to 45, wherein the patient requires treatment for urinary stones.

[0272] (51) The method according to embodiment 50, wherein the deployment of the drug delivery device into the renal pelvis is performed after the patient has been treated with extracorporeal shock wave lithotripsy for the treatment of kidney stones in the patient. (52) A drug delivery device for placement in the renal pelvis of a patient, wherein the drug delivery device is An elongated elastic body comprising an elongated elastic body including a guidewire lumen and a separate drug reservoir lumen, A drug payload disposed within the lumen of the drug reservoir, wherein the drug payload contains at least one drug, comprising: A drug delivery device is elastically deformable between a deployment shape configured for the passage of the drug delivery device to the renal pelvis of the patient via the ureter and a helical retaining shape configured to reduce the movement of the device from the renal pelvis. (53) The drug delivery device according to Embodiment 52, wherein the device is biased to have the retaining shape when a guide wire is not inserted into the lumen of the guide wire, and the elastic body further comprises (i) being thermally shaped to have the retaining shape and / or (ii) a lumen of a retaining frame and a retaining frame disposed within the lumen of the retaining frame, the retaining frame being an elastic wire configured to bias the drug delivery device into the retaining shape. (54) The drug delivery device according to embodiment 53, further comprising a retrieval string attached to the elongated elastic body, wherein the retrieval string is of sufficient length so that when the drug delivery device is deployed in the renal pelvis, the end of the retrieval string is located in the patient's bladder. (55) The drug delivery device according to embodiment 53, wherein the drug payload is in the form of a powder or a plurality of tablets.

[0273] (56) The drug delivery device according to embodiment 55, wherein the elongated elastic body includes a water-permeable wall configured to allow urine to diffuse into the lumen of the drug reservoir and come into contact with the drug payload. (57) The drug delivery device according to embodiment 56, wherein the elongated elastic body includes a drug-permeable wall adjacent to the lumen of the drug reservoir, and the drug-permeable wall is configured to allow the drug to diffuse from the device in a solution. (58) The drug delivery device according to embodiment 57, wherein the drug permeable wall is in the form of a drug permeable stripe extending over the length of the elastic body. (59) The drug delivery device according to embodiment 57, wherein the elongated elastic body further includes a drug-impermeable wall adjacent to the lumen of the drug reservoir. (60) The drug delivery device according to Embodiment 58, wherein the drug-permeable wall comprises tecophilic polyurethane and the drug-impermeable wall comprises tecoflex polyurethane.

[0274] (61) The drug delivery device according to Embodiment 60, wherein the Tecoflex polyurethane is either EG-100A-B20 or EG-80A-B20. (62) The drug delivery device according to any one of embodiments 52 to 61, wherein the helical holding shape further includes a linear end portion extending in the longitudinal direction of the device. (63) The drug delivery device according to embodiment 62, wherein each of the opposing ends of the lumen of the drug reservoir is sealed by an end spacer. (64) The drug delivery device according to embodiment 63, further comprising at least one intermediate spacer positioned approximately midway between the opposing ends of the elongated elastic body within the lumen of the drug reservoir. (65) The drug delivery device according to Embodiment 64, wherein the end spacers and the at least one intermediate spacer include a radiopaque filling material.

[0275] (66) A drug delivery device according to any one of embodiments 52 to 61, wherein the lumen of the drug reservoir has a crescent-shaped cross-section, and the drug payload comprises a powder or a plurality of crescent-shaped tablets. (67) A drug tablet, Drugs and, The drug comprises one or more excipients combined with the drug, The combination of the drug and the one or more excipients is a drug tablet having a crescent-shaped cross-sectional profile. (68) The drug tablet according to embodiment 67, wherein the tablet has a flat end wall. (69) The drug tablet according to embodiment 67 or 68, wherein the drug constitutes 90% to 99% by weight of the tablet.

Claims

1. A drug delivery device, wherein the drug delivery device is An elastic body, the elastic body is (i) An outer tube including an elongated, arc-shaped outer wall, (ii) an elongated inner wall located within the outer tube, integrally connected to the inner surface of the outer wall along two opposing edges of the inner wall, wherein the outer wall and the inner wall together define (a) a guide wire lumen on one side of the inner wall, and (b) a drug reservoir lumen on a second opposing side of the inner wall, the drug reservoir lumen being closed at its opposite end, and an elastic body, A drug payload disposed within the lumen of the drug reservoir, wherein the drug payload is in a semi-solid state and contains one type of drug, comprising: The drug delivery device is elastically deformable between a deployment shape for the passage of the drug delivery device to the patient's renal pelvis via the ureter and a holding shape configured to completely hold the elastic body within the renal pelvis. A drug delivery device wherein the elastic body is (i) thermally shaped to have the retaining shape, and (ii) biased to have the retaining shape when the guidewire is not inserted into the lumen of the guidewire.

2. A drug delivery device according to claim 1, wherein the outer tube comprises at least one thermoplastic polyurethane material that is permeable to the drug when the drug is in a solution state.

3. A drug delivery device according to claim 2, wherein the at least one thermoplastic polyurethane material includes Tecoflex polyurethane.

4. A drug delivery device according to claim 3, wherein the Tecoflex polyurethane includes EG-80A or EG-100A.

5. A drug delivery device according to claim 1, wherein the lumen of the drug reservoir has a crescent-shaped cross-section, and / or the lumen of the guide wire has a circular cross-section.

6. A drug delivery device according to claim 1, wherein each opposing end of the lumen of the drug reservoir is closed by a polyurethane end spacer.

7. A drug delivery device according to claim 1, further comprising a single-fiber retrieval string attached to the elastic body.

8. A drug delivery device according to claim 7, wherein the end of the single fiber recovery string is attached to the end of the elastic body.

9. A drug delivery device according to claim 7, wherein the single-fiber retrieval string has a length sufficient to ensure that the free distal end of the single-fiber retrieval string is located in the bladder when the elastic body is deployed in the renal pelvis.

10. A drug delivery device according to claim 7, wherein the end of the single-fiber recovery string is fixed between the elastic body and an end spacer disposed within the end of the lumen of the drug reservoir.

11. A drug delivery device according to claim 1, wherein the guide wire lumen is defined on the concave side of the inner wall, and the drug reservoir lumen is defined on the opposing convex side of the inner wall.

12. A drug delivery device according to claim 1, wherein the lumen of the drug reservoir has a crescent-shaped cross-section.

13. A drug delivery device according to claim 1, wherein in the holding shape, the outer tube of the elastic body has two coils spaced apart by a single intermediate straight section.

14. A drug delivery device according to claim 1, wherein the semi-solid form includes a suspension.

15. A drug delivery device according to any one of claims 1 to 14, wherein the drug includes a kinase inhibitor.

16. A drug delivery device according to claim 15, wherein the kinase inhibitor comprises a fibroblast growth factor receptor-3 (FGFR-3) selective tyrosine kinase inhibitor.

17. A drug delivery device, An elastic body, the elastic body is (i) an outer pipe including an elongated outer wall, (ii) an elongated, arc-shaped inner wall located within the outer tube, which is integrally connected to the inner surface of the outer wall along two opposing edges of the inner wall, wherein the outer wall and the inner wall together define (a) a guide wire lumen defined on the concave side of the inner wall, and (b) a drug reservoir lumen defined on the opposing convex side of the inner wall, the drug reservoir lumen being closed at its opposite end, and an elastic body A drug payload disposed within the lumen of the drug reservoir, wherein the drug payload is in a semi-solid state and contains a drug that is a fibroblast growth factor receptor-3 (FGFR-3) selective tyrosine kinase inhibitor, The elastic body is equipped with a retrieval string attached to it, The drug delivery device is elastically deformable between a deployment shape for the passage of the drug delivery device into the patient's renal pelvis via the ureter and a holding shape configured to completely hold the drug delivery device within the renal pelvis. In the aforementioned holding shape, the outer tube of the elastic body has two coils spaced apart by a single intermediate straight section. A drug delivery device wherein the elastic body comprises at least one thermoplastic polyurethane material and (i) is thermally shaped to have the retaining shape, and (ii) is biased to have the retaining shape when the guidewire is not inserted into the lumen of the guidewire.

18. A drug delivery device according to claim 17, wherein the retrieval string is a single fiber and has a length sufficient to ensure that the free distal end of the retrieval string is located in the bladder when the elastic body is deployed in the renal pelvis.

19. A drug delivery device according to claim 17, wherein the semi-solid form includes a suspension.

20. A drug delivery device according to any one of claims 17 to 19, wherein the at least one thermoplastic polyurethane material includes Tecoflex polyurethane.

21. A drug delivery device according to claim 20, wherein the Tecoflex polyurethane includes EG-80A.

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