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

Abstract

A drug delivery device and system are provided for delivering a drug to the upper urinary tract of a patient in need thereof. The drug delivery device (100) may be deployed directly into the renal pelvis via the patient's ureter, bladder, and urethra, and the drug delivery device may be retained entirely therein for localized, continuous, controlled release of the drug over an extended period of time.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 62 / 757,798, filed November 9, 2018, which is incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present disclosure relates generally to in vivo deployable drug delivery devices for the controlled localized delivery of therapeutic and prophylactic agents to the upper urinary tract of a patient in need thereof, and more specifically to drug delivery devices and methods for administering drugs locally to the renal pelvis of a patient over an extended period of time. [Background technology]

[0003] Implantable drug delivery devices are known for targeted, e.g., local or regional, drug delivery to avoid one or more problems associated with systemic drug delivery. However, targeted drug delivery to some tissue sites has room for significant improvement. Such sites include the kidney and ureter.

[0004] Currently available drug delivery device-based therapies are invasive and / or can only deliver drugs while a delivery catheter extends from outside the patient's body into the body. Some such systems, such as the BENEPHIT™ Renal Infusion System, deliver therapeutic agents directly to the kidney via the renal artery through a catheter system, but require arterial puncture, which is undesirable in interventional or surgical procedures. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains 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 extended periods of time, preferably continuously and while the patient is ambulatory. [Means for solving the problem]

[0006] Improved drug delivery devices and systems, as well as methods of drug delivery, are provided herein. The drug delivery device may be deployed directly into the renal pelvis via a natural lumen of the patient's body, i.e., via the ureter, bladder, and urethra, and the drug delivery device may be retained entirely therein for drug delivery over an extended period of time, e.g., days or weeks, without relying on a catheter extending into the body during external supply and administration of the drug. In some embodiments, the drug delivery device is configured to be inserted into the renal pelvis and deliver drug therein continuously, preferably providing a zero-order release rate of a therapeutically effective amount of the drug.

[0007] In one aspect, a drug delivery device configured to be deployed within a patient's renal pelvis is provided. In embodiments, the device includes (i) an elongated elastic body, the 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 including a drug, the drug delivery device being elastically deformable between (a) a deployed configuration configured to pass the drug delivery device through the ureter and into the patient's renal pelvis, and (b) a retained configuration configured to mitigate migration of the device from the renal pelvis. In some preferred embodiments, the retained configuration is helical. In some embodiments, the elastic body includes (i) an outer tube including an elongated outer wall; and (ii) an elongated, arcuate inner wall located within the outer tube, the arcuate inner wall being integrally connected to an inner surface of the outer wall along two opposing edges of the arcuate inner wall, the outer wall and inner wall together defining (a) a guidewire lumen on a concave side of the inner wall, and (b) a drug reservoir lumen on opposing convex sides of the inner wall, the drug reservoir lumen being closed at its opposing ends.

[0008] In another aspect, a system is provided for 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 within the renal pelvis, the guidewire deployment system including (i) a guidewire and (ii) a plunger device for pushing the drug delivery device over the guidewire.

[0009] In yet another aspect, a method is provided for administering a drug to a patient in need thereof, in some embodiments, the method includes deploying a drug delivery device within the renal pelvis of the patient and continuously releasing a drug from the deployed drug delivery device into urine within the renal pelvis over a chronic treatment period of at least 24 hours, the drug delivery device being entirely contained within the renal pelvis with the optional exception of a retrieval string extending into at least the patient's ureter. [Brief description of the drawings]

[0010] The detailed description is described with reference to the accompanying drawings. Use of the same reference numbers 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. 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] FIG. 1 is a perspective view of one embodiment of a drug delivery device having a helical retention configuration as disclosed herein. [Figure 1B] FIG. 1B is a perspective view of the drug delivery device of FIG. 1A in a straightened, deployed configuration. [Figure 1C] 1C is a cross-sectional view of the drug delivery device shown in FIG. 1B along section line CC in FIG. 1B. [Diagram 2] FIG. 1 is a perspective view of one embodiment of a drug delivery device having a single coil retention configuration as disclosed herein. [Diagram 3]FIG. 1 is a cross-sectional view of one embodiment of a drug delivery device having a triple lumen design as disclosed herein. [Figure 4A] FIG. 1 is a plan cross-sectional view of one embodiment of a drug delivery device as disclosed herein in a straightened configuration, with the cross-sectional plane extending longitudinally through the end of the device and the drug reservoir lumen. [Figure 4B] FIG. 4B is a plan view of the drug delivery device shown in FIG. 4A. [Figure 4C] FIG. 4B is a side cross-sectional view of the drug delivery device shown in FIG. 4A, with the cross-sectional plane extending longitudinally through the end of the device and through the drug reservoir and guidewire lumens. [Figure 5A] FIG. 1 is a plan cross-sectional view of another embodiment of a drug delivery device disclosed herein in a straightened configuration, with the cross-sectional plane extending longitudinally through the end of the device and the drug reservoir lumen. [Figure 5B] FIG. 5B is a plan view of the drug delivery device shown in FIG. 5A. [Figure 5C] FIG. 5B is a side cross-sectional view of the drug delivery device shown in FIG. 5A, with the cross-sectional plane extending longitudinally through the end of the device and through the drug reservoir and guidewire lumens. [Figure 6] FIG. 1 is a perspective view of one embodiment of a drug delivery device having a helical retention profile and straight ends. [Figure 7] FIG. 13 is a perspective view of another embodiment of a drug delivery device having a helical retention profile and straight ends. [Figure 8] FIG. 1 is a perspective view of one embodiment of a drug delivery device having a helical retention shape with two relatively straight intermediate sections. [Figure 9] FIG. 1 is a perspective view of one embodiment of a drug delivery device having a helical retention geometry with a single relatively straight intermediate section. [Figure 10A] FIG. 1 is a perspective view of a portion of an embodiment of a drug delivery device having a tapered end. [Figure 10B]FIG. 2 is a side cross-sectional view of another embodiment of a drug delivery device having a tapered end in a straightened configuration, with the cross-sectional plane extending longitudinally through the end of the device and through the drug reservoir lumen and the guidewire lumen. [Figure 11] 1 is a graph of in vitro drug release rates from drug delivery devices according to two different embodiments described herein. [Figure 12] 1 is a graph of in vitro drug release rates from drug delivery devices according to two different embodiments described herein. [Figure 13] 1A-1D show perspective and front views of one embodiment of a crescent shaped pharmaceutical tablet as disclosed herein. [Figure 14A] FIG. 1 is a perspective view of one embodiment of a deployment system for deploying a drug delivery device, for example, within the renal pelvis of a patient, as disclosed herein. [Figure 14B] FIG. 14B is a perspective view of the deployment system shown in FIG. 14A following advancement of the drug delivery device along the guidewire. [Figure 15] FIG. 1 is a side cross-sectional view of one embodiment of a drug delivery device in a straightened configuration, with the cross-sectional plane extending longitudinally through the end of the device and through the drug reservoir lumen and guidewire lumen, showing one embodiment of a connected retrieval string. [Figure 16] FIG. 1 is a side cross-sectional view of one embodiment of a drug delivery device in a straightened configuration, with the cross-sectional plane extending longitudinally through the end of the device and through the drug reservoir lumen and guidewire lumen, showing another embodiment of a connected retrieval string. [Figure 17] FIG. 2 is a cross-sectional plan view of a spacer for insertion into the end of a lumen of one embodiment of a drug delivery device as described herein, the spacer including a transverse through hole through which a retrieval string is secured. [Figure 18] 1 is a block diagram of one embodiment of a method for deploying a drug delivery device as described herein within a patient's body, for example within the patient's renal pelvis. [Figure 19]1 illustrates one embodiment of a drug delivery device as described herein in a helical retention configuration and positioned in a deployed position within the renal pelvis, with an attached retrieval string extending from the drug delivery device, through the ureter, and into the bladder. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Provided herein are drug delivery devices, systems, and methods that can be used to treat one or more conditions of the upper urinary tract. The one or more conditions of the upper urinary tract can include kidney cancer, ureteral cancer, or other diseases affecting the kidney and / or ureter. The drug delivery devices described herein can be deployed in the upper urinary tract, for example, in the renal pelvis. The drug delivery devices can release drugs in the upper urinary tract over an extended period of time.

[0012] Once deployed, the device can advantageously continuously release drug locally into the renal pelvis for days or weeks without the use or need for external pumps, ureteral stents, or transurethral catheters, i.e., the entire drug payload and the means to beneficially control drug release are contained within the renal pelvis.

[0013] In some embodiments, a drug delivery device for deployment within a patient's renal pelvis includes (i) an elongated elastic body, the 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 including a drug, the drug delivery device being elastically deformable between (a) a deployed shape configured to pass the drug delivery device through the ureter and into the patient's renal pelvis, and (b) a retention shape configured to mitigate migration of the device from the renal pelvis. In some preferred embodiments, the retention shape is helical. In some embodiments, the helical retention shape has between 2 and 10 turns.

[0014] The device is (i) thermally shaped to have a retained shape, and / or (ii) biased into the retained shape when the guidewire is not inserted within the guidewire lumen by an elastic body further comprising 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 the retained shape.

[0015] In some embodiments, the drug delivery device includes a retrieval string attached, typically at an end, to an elongated elastic body, the retrieval string having a sufficient length such that an end of the retrieval string resides within the patient's bladder when the drug delivery device is deployed within the renal pelvis.

[0016] The drug payload may be in any suitable form, but in some preferred embodiments, the drug payload is in the form of a powder or multiple tablets. In some embodiments, the elongated elastic body includes a water-permeable wall configured to allow urine to diffuse into the drug reservoir lumen and contact the drug payload. In some embodiments, the elongated elastic body includes a drug-permeable wall adjacent the drug reservoir lumen, the drug-permeable wall configured to allow the drug to diffuse out of the device in solution. The elongated elastic body may further include a drug-impermeable wall adjacent the drug reservoir lumen, for example, to limit the area available for transmural 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 the length of the elastic body.

[0017] The opposing ends of the drug reservoir lumen are typically each sealed by an end spacer, while the guidewire lumen is left open at both ends to allow passage of a guidewire.

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

[0019] In some embodiments, the drug reservoir lumen has a crescent cross-sectional shape 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 including an elongated outer wall; and (ii) an arcuate, elongated inner wall located within the outer tube, the arcuate, elongated inner wall integrally connected to an 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 guidewire lumen on a concave side of the inner wall and (b) a drug reservoir lumen on opposing convex sides of the inner wall, the drug reservoir lumen being closed at its opposing ends.

[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 disposed between the opposing end portions of the elastic body.

[0022] In some embodiments, the outer tube of the drug delivery device comprises two different materials of construction, a first material that is permeable to water but impermeable to the drug when the drug is in solution, and a second material that 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" refers to a material that is substantially impermeable to the drug such that essentially the drug is not released through the material over a therapeutic release period. In some embodiments, the drug delivery device is operable in vivo to allow water to diffuse through the first material and the second material into the drug reservoir lumen, solubilizing the drug payload and controllably releasing the solubilized drug from the drug delivery device through the second material. In one example, 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, the walls are laterally connected to one another such that they are directly bounded by each other and together define a drug reservoir within the device, in some cases this means that the walls together define an annulus.

[0023] In some alternative embodiments, the first material is both water-impermeable and drug-impermeable, and 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-1C. Figure 1A shows a drug delivery device 100 including 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 retained configuration. Figure 1B shows the device 100 in a straightened deployed configuration. As shown in Figures 1B-1C, the elastic body 102 includes a guidewire lumen 112 extending therethrough and a separate drug reservoir lumen 114 extending within the elastic body 102. A drug payload 116 is disposed 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 elastomeric body 102 includes an outer tube 104 including an elongated outer wall 106, and an elongated arcuate inner wall 108 located within the outer tube and integrally connected to a surface of the outer wall along opposing edges of the arcuate inner wall 108. A drug reservoir lumen 114 is defined longitudinally on a convex side of the inner wall 108, and a guidewire lumen 112 is defined longitudinally on an opposing concave side of the inner wall 108. Opposing ends of the drug reservoir lumen 114 are sealed with end spacers 120, respectively.

[0025] In the embodiment shown in Figures 1A-1C, the elastic body is formed of two constituent materials, one that forms the drug impermeable wall 122 and one that forms the 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 disposed within the drug reservoir lumen 114. The material that forms the drug impermeable wall 122 may also form the arcuate inner wall 108 and the remainder of the outer tube 104, i.e., excluding the stripe of drug permeable material 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 blunt, i.e., not tapered, and the terminal portion of the elastic body is helical when in the helical retained configuration.

[0026] The drug-permeable walls (stripes) 124 provide a pathway for drug release across the entire length of the drug delivery device 100. The width of the drug-permeable stripes may be selected to tailor the effective rate of transmural diffusion of the drug therethrough. Because the outer tube 104 has a circular cross-section, the width of the drug-permeable stripes may be characterized by the arc angle of the stripes. In the embodiment shown in FIG. 1C, the arc angle α is about 60°. However, the angle and / or length and / or shape of the drug-permeable stripes may be varied to alter the drug release rate.

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

[0028] FIG. 3 illustrates another embodiment of a 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 therethrough and a separate crescent-shaped drug reservoir lumen 314 that extends the length of the elastic body 302 and contains a drug payload 316 disposed 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 disposed. In this illustrated embodiment, the retaining frame lumen 330 is defined near the intersection of the edges of the arcuate inner wall 308 and outer wall 306. Similar to the configuration of the drug delivery device 100, the outer wall 306 may be formed via a dual-material polyurethane extrusion, with the drug reservoir lumen being defined at least in part by a stripe 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 helical retention shape as shown in FIG. 1A.

[0029] FIG. 6 illustrates an embodiment of a drug delivery device 600 in which the elastic body has a middle helical portion 674 and opposing straight end portions 672. The straight end portions 672 include tapered ends 676. The straight end portions 672 extend in a direction generally perpendicular to the plane of winding 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 shape-set. Although these end portions are referred to as "straight", it is understood that they do not have to literally coincide with a single straight line. As is evident in FIG. 6, the straight end portions 672 have a slight curvature, but are relatively straight compared to the helical portion 674, and are different from the helical end portions of the device 100 of FIG. 1A. The straight end portions 672 extend from either side of the helical portion 674 such that when the device is in the retained configuration, one straight end portion 672 (e.g., the leading end) is substantially aligned (diagonally relative to the device) with the other straight end portion 672 (e.g., the trailing end). This configuration advantageously (i) facilitates loading and deployment of the drug delivery device over the guidewire, (ii) can improve retention within the renal pelvis, and (iii) aids in accurate placement of the device within the renal pelvis because the leading straight terminal portion substantially maintains its position when pushed off the guidewire (because it is not coiled).

[0030] Another variation 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 diagonally relative to the drug delivery device, but instead is generally disposed on the same side of the helical portion 774 and aligned along a line that is generally 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 elongate body of the drug delivery device has one or more intermediate straight sections disposed between the 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 particular renal pelvic anatomy and / or size. For example, the intermediate straight section may be preferably positioned within the pinch point area of ​​the renal pelvis of smaller kidneys and provide retention without applying undue pressure to the pinch point tissue. As with the straight end sections, the intermediate straight section may have a slight curvature, but is more clearly straight than the turns or coils in the helical section described above.

[0032] Figure 8 shows an embodiment of a drug delivery device 800 in which the elongated body includes three loops 874 separated by two intermediate straight portions 878. The device includes a tapered end 876. Figure 9 shows an embodiment of a drug delivery device 900 in which the elongated body includes two loops 974 separated by a single intermediate straight portion 978. The device includes a tapered end 976.

[0033] The size, number, and arrangement of the intermediate straight and coiled sections may be selected to accommodate both the various drug payload volumes required for different patients and the anatomical characteristics of the renal pelvis. The overall size and deployability of the device may also influence the selected design of the drug delivery device. For example, the drug delivery device may have a shorter uncoiled length by using fewer turns in the helical section. Alternatively, the coil outer diameter may be reduced to a tighter coil. Drug delivery devices with coil outer diameters as small as about 8 mm, or even 7 mm, may be an effective retention size for smaller kidneys, while drug delivery devices with coil outer diameters as small as 12 mm or more may be an effective retention size for larger kidneys. The coil outer diameter may be reduced to 7 mm or less, but it may be more difficult to load the device onto a guidewire and deploy it.

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

[0035] In some embodiments, the elastic body has an outer shape that is generally a long, thin tube, and in the retained shape, is wound on itself, for example in a helical shape. The lumen that runs the length of the elastic body may have essentially any size or shape that allows for the loading of a sufficient drug payload volume and may accommodate a guidewire of sufficient diameter to effect deployment of the device within the renal cavity. The wall that bounds / defines the lumen must have a thickness that allows the device to be flexible yet retain adequate mechanical robustness during deployment, use, and retrieval, while still making the device small enough to fit within the renal pelvis and providing that the wall thickness and area are sized to achieve the desired water permeability and drug release kinetics.

[0036] The elastic body may be formed of any one or more materials that are sufficiently flexible to allow the drug delivery device described herein to be deformable and thus assume the deployed and retained shapes. In particular, the material may be a biocompatible elastomer, such as a thermoplastic elastomer, known in the art. The device is typically biased to the retained shape, such that in the absence of a load (e.g., a load effective to elastically deform toward / to the straightened or deployed shape), the device has the retained shape. The load may be imparted by the presence of a guidewire extending through a guidewire lumen within the elastic body.

[0037] In some embodiments, the outer tube of the drug delivery device comprises two different materials of construction, a first material that is impermeable to the drug when the drug is in solution and a second material that 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 loaded on the drug delivery device may contact at least a portion of the second material before, during, and / or after dissolution of the drug.

[0038] In some embodiments, the drug delivery devices described herein include a drug-permeable stripe of a second material. The drug-permeable stripe, in some embodiments, traverses about 50%-100%, about 80%-100%, about 90%-100%, or 100% of the longitudinal length of the outer tube. In some embodiments, the drug delivery devices described herein include an outer tube having two or more distinct portions formed from a second material. The one or more distinct portions may have any suitable size or dimension.

[0039] When the drug delivery devices described herein include a drug-permeable stripe of a second material, the drug-permeable stripe may have an arc angle of about 30° to about 120°, about 40° to about 120°, about 45° to about 120°, about 55° to about 120°, about 60° to about 120°, about 60° to about 110°, about 60° to about 100°, about 60° to about 90°, or about 60° of the circumference of the outer tube 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 a first side and a second side of the drug-permeable stripe.

[0040] In some embodiments, the inner diameter of the outer tube is about 1.0 mm to about 2.3 mm. In some embodiments, the outer diameter of the outer tube is about 2.2 mm to about 2.4 mm. In some embodiments, the wall thickness (i.e., the difference between the outer diameter and the inner diameter) of the outer tube, first inner tube, and / or second inner tube is about 0.1 mm to about 1.4 mm, or about 0.15 mm to about 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 the drug delivery device described herein may be made of any one or more materials that provide the drug delivery device with sufficient flexibility to allow the drug delivery device to be deformed between a retained shape and a deployed shape. When the elastic body includes 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, the 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 material and the second material 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™ TSPU (DSM), other thermoplastic polyurethanes (TPUs) including aliphatic and aromatic polycarbonate-based thermoplastic polyurethanes, such as CARBOTHANE™ TPU, TECOFLEX™ TPU, TECOTHANE™ TPU, PELLETHANE™ TPU, and TECOPHILIC™ TPU, and 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 grades are aliphatic polycarbonate-based and ALE grades are aliphatic polyether-based hydrophilic polyurethanes), HYDROMED™ (AdvanSource Biomaterials Corp.), or DRYFLEX™ (HEXPOL TPE). Another hydrophilic polymer that can be selected for the second material is the 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 to form an elongated body that includes two parallel lumens and is comprised of (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 comprises a TECOFLEX polyurethane and the second material comprises a TECOPHILIC polyurethane. In some embodiments, the TECOFLEX polyurethane comprises TECOFLEX™ EG-80A-B20, a TECOFLEX polyurethane with 20% barium sulfate (Lubrizol Life Sciences, USA). In some embodiments, the TECOFLEX polyurethane comprises TECOFLEX™ EG-100A-B20, a TECOFLEX polyurethane with 20% barium sulfate (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, the TECOPHILIC polyurethane comprises a drug-impermeable material with a barium sulfate loading, which may allow visualization during insertion or withdrawal of the device. In some embodiments for a particular drug, TECOPHILIC™ TPU is a water-permeable and drug-permeable material, allowing water to enter the drug delivery device and allowing solubilized or liquid drug to cross 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 (i.e., easily bendable and soft to the touch) to avoid or reduce discomfort and irritation to the patient, but not so conformable that it easily and unintentionally migrates from the renal pelvis into the calyx or ureter, e.g., carried into the ureter with the urine flow. Thus, the durometer of the first and second materials of construction 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 conformability within the renal pelvis. For example, TECOPHILIC™ thermoplastic polyurethane (Lubrizol Corp.) may have a Shore hardness greater than 70A, e.g., 80A to 65D, while other drug-impermeable thermoplastic polyurethanes may have a lower or higher Shore hardness than TECOPHILIC™, e.g., less than 90A. Thus, rather than making the entire device out of a water-swellable hydrophilic, drug-permeable second material, it may be advantageous to utilize a combination of two different polymeric materials to obtain the desired mechanical properties of the device.

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

[0048] FIG. 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 that may be placed therein prior to forming the end 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., thinned, rounded) in the process of forming the taper toward the end of the drug delivery device, but the process of forming the tapered end should not narrow or collapse the guidewire lumen 1012 at all, or at least to any extent that would prevent the passage of the guidewire. This may result in the tapered end portion being asymmetric about the central longitudinal axis of the device, as shown in FIG. 10B.

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

[0050] In some embodiments, the elastic body has a length, when in a relatively straightened deployed configuration, of about 5 cm to about 15 cm, about 5 cm to about 12 cm, about 6 cm to about 12 cm, about 7 cm to about 12 cm, about 8 cm to about 12 cm, about 10 cm to about 12 cm, about 10 cm, or about 12 cm.

[0051] In some embodiments, the elastic body of the drug delivery device described herein can be made to be fully or partially biodegradable such that retrieval of the drug delivery device is not required after release of the drug. In some embodiments, the drug delivery device is partially biodegradable such that upon partial erosion, it breaks down into non-erodible pieces small enough to be excreted from the upper urinary tract. As used herein, the term "biodegradable" means that the drug delivery device or a portion thereof breaks down in vivo by dissolution, enzymatic hydrolysis, erosion, absorption, or a combination thereof. In some embodiments, this degradation occurs at a time 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 erodible and the release of the drug is controlled, at least in part, by the degradation or erosion characteristics of the erodible 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 by and between (i) at least a portion of an elongated outer wall of the elastic body and (ii) at least a portion of an arcuate elongated inner wall of the elastic body. The outer wall and the inner wall may be a single monolithic structure, e.g., an elastomeric structure, formed, e.g., by an extrusion process. The elongated drug reservoir lumen, in some embodiments, is closed at its opposing 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 lumens having crescent cross-sectional shapes are shown in Figures 1B and 1C. Other cross-sectional shapes are envisioned depending, for example, 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 the retaining frame lumen, if present.

[0054] Each end of the drug reservoir lumen of the drug delivery devices described herein is typically sealed to contain the drug payload within the drug reservoir lumen. The drug reservoir lumen may be sealed thermally and / or with an adhesive (such as 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 disposed at the first end and the second end 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) into a fixed, sealed position within the drug reservoir lumen. In some other embodiments, the spacers may be retained within the drug reservoir lumen by friction, adhesive, mechanical features (such as tabs or other locking mechanisms), or a combination thereof. For example, the spacers may have dimensions that exceed the cross-sectional dimensions of the drug reservoir lumen such that the spacers are retained by friction.

[0055] In some embodiments, the spacer includes a radiopaque filler material, hi some embodiments, the material used to form the spacer is a barium loaded material, which may allow the spacer to act as a visualization 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 by and between (i) at least a portion of an elongated outer wall of the elastic body and (ii) at least a portion of an arcuate elongated inner wall of the elastic body. The guidewire lumen and the drug reservoir lumen are on either side of the inner wall. The outer wall and the inner wall may be a single monolithic structure, e.g., an elastomeric structure, formed, e.g., 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 travel over a guidewire suitable for renal pelvis deployment. In some embodiments, the guidewire lumen has a substantially circular cross-sectional shape. However, other cross-sectional shapes are envisioned, including, but not limited to, polygonal, e.g., hexagonal, octagonal, etc., or non-polygonal, e.g., oval, elliptical, etc., cross-sectional shapes.

[0058] Retention and deployment configuration The drug delivery devices described herein are elastically deformable between a relatively straightened shape suitable for insertion through a lumen into a patient's renal pelvis and a retained shape suitable for retaining the device within the renal pelvis. In some embodiments, the drug delivery device may naturally assume the retained shape and may be deformed into the relatively straightened shape manually or with the aid of an external device for insertion into the body. After deployment, the device may spontaneously or naturally return to the initial retained shape for retention within the body upon removal of a corrective force, for example, that is imparted by the presence of a guidewire extending through a guidewire lumen within the device body.

[0059] As used herein, the phrase "retention shape" generally refers to any shape suitable for retaining a drug delivery device described herein within the renal pelvis.

[0060] Similarly, the phrase "deployed configuration" generally refers to any shape suitable for deploying a drug delivery device described herein through a patient's urethra, bladder, and ureters into the renal pelvis.

[0061] In some embodiments, the elastic body itself is configured to provide the retention feature of the drug delivery device. That is, the elastic body may be formed of a suitable material (e.g., high durometer silicone) and sized to provide the requisite elasticity and spring constant required by the drug delivery device. In some embodiments, the drug delivery device includes a retention frame to provide the retention feature of the drug delivery device.

[0062] The elastic body of the retention shape may have essentially any shape and size that fits within the renal pelvis and contacts the walls of the renal pelvis polylaterally or laterally, i.e., in multiple directions, thereby resisting migration and promoting device retention. In addition, this shape may promote drug delivery to many different tissue surfaces within the kidney, and when treating tumors, may advantageously obscure drug delivery relative to the location of the tumor. Examples of such shapes include coils, spirals, and other configurations in which a long, narrow tube may be wound back and forth or on itself to form an overall 3D shape with substantially circular features, e.g., spherical, cylindrical. In these embodiments, the device may be elastically shaped into an essentially linear shape for deployment over / through a guidewire or other deployment instrument.

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

[0064]

number

[0065] In some embodiments, the retention shape comprises a coil. As used herein, the term "coil" generally refers to a single loop formed in the elastic body of the drug delivery device. An embodiment of a drug delivery device having a coil retention shape is shown in FIG.

[0066] In some embodiments, the retention shape comprises a helix. As used herein, the term "helix" generally refers to an elastic body that forms two or more coils having the same or different coil diameters, at least a portion of the elastic body resembling a corkscrew or a helical spring. In some embodiments, a drug delivery device having a helical retention shape comprises 2, 3, 4, 5, 6, 7, 8, 9, or 10 turns. Each turn (coil) of the drug delivery device may or may not contact 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 retained configuration, the drug delivery device for an adult patient may have dimensions selected to retain the drug delivery device within the renal pelvis. For example, when the drug delivery device has a helical retained 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 straightened deployed configuration. When in a helical retained 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 retained configuration, the "length" of the drug delivery device is measured along the axis circumscribed by two or more coils. When in a helical retained 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 that 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 ranges define the "maximum width" of some embodiments of the drug delivery device described herein.

[0068] As a further example, when the drug delivery device has a coiled retained configuration, the length of the drug delivery device when in a relatively straightened deployed configuration may be from about 4 cm to about 8 cm, or from about 4 cm to about 6 cm. A drug delivery device having a coiled retained configuration may have a maximum width when in the retained configuration of from about 1 cm to about 3 cm, or from about 1.5 cm to about 3 cm. Again, the elastic may form a loop that is not substantially circular when the drug delivery device has a coiled retained configuration, and thus the "maximum width" is provided by the ranges set forth above.

[0069] For pediatric patients, the dimensions of the drug delivery device may be smaller, e.g., proportional, based on, e.g., anatomical size differences and / or differences in drug dosage between adult and pediatric patients. In addition to allowing insertion, the relatively small size of the drug delivery device may 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 the retained configuration, although mobility, if any, is preferably minimized to prevent the ends of the device from becoming entrapped in and flowing into the urine. Movement of the drug delivery device may promote uniform drug delivery throughout the renal pelvis.

[0070] Holding frame In some embodiments, the drug delivery device may include an additional elongate lumen separate from the guidewire lumen and the drug reservoir lumen. This additional lumen may be a retaining frame lumen in which the retaining frame is disposed. The retaining frame lumen may be closed at its ends.

[0071] The retention frame lumen includes an elastically deformable retention frame disposed therein. The retention frame serves to bias the elastic body of the drug delivery device into a retention shape. The retention frame may be an elastic wire. It may be formed of any elastic material effective to impart a suitable elastic modulus or spring constant to the elastic body, and thus to the drug delivery device. In some embodiments, the retention 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 retention shape.

[0072] Drug delivery devices and deployment systems In one aspect, a drug delivery system, or kit, is provided, hi 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 that includes (i) a guidewire and (ii) a plunger device for pushing the drug delivery device over the guidewire. The guidewire may have a cross-sectional area sized and shaped 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 a driving force applied to the handle to the plunger, and an internal bore for receiving a guidewire, thereby allowing the plunger device to move over the guidewire.

[0075] In some embodiments, the drug delivery device 100 of Figures 1A-1C may be deployed into the renal pelvis using a specialized guidewire deployment system. Figures 14A-14B show an embodiment of such a guidewire deployment system 1400 for deploying a drug delivery device into 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, such that when the guidewire 1402 is positioned in the urethra, its proximal end extends out of the urethra while 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 a handle 1408 via a sheath 1410. The sheath 1410 is sufficiently rigid to transmit a driving force from the handle 1408 to the plunger 1406. The plunger 1406 and sheath 1410 have an internal bore suitable for threading the plunger device 1404 over the guidewire 1402. When the plunger device 1404 is so threaded, the handle 1408 is positioned at the proximal end of the guidewire 1402, the plunger 1406 is positioned on the guidewire 1402 behind its distal end, and the rigid sheath 1410 extends from the handle 1408 to the plunger 1406, whereby a driving force applied to the handle 1408 can be transmitted to the plunger 1406.

[0077] In use, the guidewire 1402 may be positioned within the ureter such that its distal end is located within the renal pelvis and its proximal end is exposed outside the patient's body. The drug delivery device 100 may be threaded over the guidewire 1402 with the guidewire 1402 passing through the guidewire lumen 112 as shown in FIGS. 1A and 1B. The plunger device 1404 may be threaded over the guidewire 1402 and the handle 1408 may be advanced such that the rigid sheath 1410 moves along the guidewire 1402 to advance the plunger 1406 until the drug delivery device 100 is pushed off 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 FIG.

[0078] In some embodiments, the plunger device 1404 further includes a stop 1412. The stop 1412 is positioned at an appropriate location on the plunger device 1404 such that when the drug delivery device 100 is separated from the guidewire 1402, the stop 1412 contacts the patient's body. In this manner, the user is informed that the drug delivery device 100 has been deployed in vivo, so that the user can cease advancing the handle 1408 forward. In some embodiments, the stop 1412 may be adjustable to account for differences in anatomical size. The user can adjust the stop 1412, if necessary, before advancing the plunger device 1404.

[0079] The guidewire 1402 may facilitate straightening of the drug delivery device 100 from a retained configuration suitable for retaining the drug delivery device 100 in the renal pelvis to a deployed configuration 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 threaded through the deployment catheter, although other configurations are 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 provided together in a package.

[0080] In some embodiments, any of the deployment instruments described herein with reference to FIGS. 14A-14B may be provided as part of a kit. The kit may include a package housing 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 prior to the deployment procedure. For example, the components may be sterilized together and transported and stored together in the package until needed for use. In such embodiments, the drug delivery device described herein may be preloaded 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 inadvertently dropping or damaging the drug delivery device during loading. However, the drug delivery device need not be preloaded. Instead, the drug delivery device may be provided with the deployment instrument or packaged separately. Also, the stylet may be either packaged with the deployment instrument, packaged separately, or omitted entirely. Regardless of which components are packaged together, the package may be sterilized, such as using gamma irradiation or ethylene oxide sterilization.

[0081] 19 shows an embodiment of a drug delivery device 1900 as described herein in a helical retention configuration and in a deployed position within the renal pelvis 1920 of a kidney 1910, with an attached retrieval string 1902 extending from the drug delivery device, through the ureter 1940, and into the bladder 1930. In this embodiment, the drug delivery device 1900 provides localized drug delivery to a tumor 1950, e.g., renal cell carcinoma. However, in other cases, the drug delivery device can be used to treat other diseases and disorders other than cancer involving the kidney.

[0082] Drug Payload and Drugs Generally, the drug delivery devices provided herein include a drug payload disposed within the drug reservoir lumen. The drug payload includes 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), 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 the elastomer to have a uniform size and shape that is selectively imparted, and then the solid units are loaded into the drug reservoir lumen. In certain embodiments, the units have a longest dimension configured to retain the orientation of the solid units (loaded) within the drug reservoir lumen, while keeping that dimension short enough to have sufficient gaps (between adjacent units) to allow the loaded device to elastically deform along its length. In some embodiments, the drug payload includes multiple solid tablets aligned end-to-end in the drug reservoir lumen.

[0083] The solid units may be made by direct powder compression or tableting processes, molding processes, or other processes known in the pharmaceutical art. In some embodiments, crescent-shaped tablets may be made by a modified tableting process in which a powder mixture is loaded into a specially shaped die 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 workable form and then cured / solidified therein.

[0084] The drug payload may include a formulation comprising at least one drug and at least one excipient. In some embodiments, the drug comprises one or more active active ingredients (APIs) and the excipient comprises one or more pharma- ceutically acceptable excipients. The formulation may include essentially any therapeutic, prophylactic, or diagnostic agent, such as those useful for localized delivery to the renal pelvis. The drug payload may consist of only the API or may include one or more excipients. As used herein, the term "drug" referring to any particular drug described herein includes salt forms, free acid forms, free base forms, and alternative forms thereof, such as hydrates. The term "excipient" is known in the art, and representative examples of excipients useful in the present formulations may include components such as binders, lubricants, glidants, disintegrants, colorants, fillers, diluents, coatings, or preservatives, as well as other inactive ingredients to facilitate the manufacture, stability, dispersibility, wettability, and / or release kinetics of the drug, or administration of the formulation. The drug may be a small molecule, a macromolecule, a biologic, 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 includes a high weight fraction of the drug or API and a reduced or low weight fraction of excipients as required for manufacturing the solid drug unit and for manufacturing and use considerations of the drug delivery device assembly. For purposes of this disclosure, terms such as "weight fraction," "weight percentage," and "percentage by weight" with respect to a drug or API refer to the form of the drug or API used, such as a salt form, a free acid form, a free base form, or a 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 greater than 50% by weight of the drug. In some embodiments, 75% by weight or more of the drug payload is drug, with the remaining weight comprising excipients such as lubricants and binders that facilitate fabrication of the solid drug unit. For purposes of this disclosure, the term "high weight fraction" with respect to a drug or API means that 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 content comprises about 75% or more of the weight of the drug payload. More specifically, the drug may comprise about 80% or more of the weight of the drug payload. For example, the drug may comprise about 85% to about 99.9% of the weight of the solid drug unit. In some embodiments, the excipient content may be omitted entirely.

[0087] In some embodiments, the drug and excipient(s) are selected such that the solid drug form is water soluble, such that the solid drug form may be solubilized and release the solubilized drug when the drug delivery device is positioned within the renal pelvis.

[0088] The individual solid drug units may have essentially any selected shape and size that fits within the drug reservoir lumen of the drug delivery device described herein. In some embodiments, the solid drug units are sized and shaped such that the drug reservoir lumen is substantially filled with a selected number of the 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, the drug unit may have an extruded crescent shape for positioning within a drug reservoir lumen having a crescent cross-sectional shape. The solid drug units, once loaded, may, in some embodiments, substantially fill the drug reservoir lumen.

[0089] In some embodiments, the solid drug units are shaped to be aligned in a line within the drug reservoir lumen of the device. For example, each solid drug unit may have a cross-sectional shape that corresponds to the cross-sectional shape of the drug reservoir lumen, and each solid drug unit may have an end shape that corresponds to the end face of an adjacent solid drug unit. The gaps or breaks between the solid drug units may allow the individual drug units to retain their solid form while accommodating deformation or movement of the drug delivery device, such as during deployment. Thus, the drug delivery device may be relatively flexible or deformable even when loaded with solid drug, since each drug unit may be able to move relative to adjacent drug units.

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

[0091] The drug reservoir lumen may hold a number of drug tablets or other solid drug units, hi some embodiments, the device holds between 4 and 400 drug tablets, e.g., between 10 and 100 drug tablets, between 5 and 50 tablets, or between 10 and 40 tablets.

[0092] In some embodiments, the pharmaceutical 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 that are connected at their ends / edges by a shorter rounded side. In other embodiments, not shown, the convex and concave sides may meet 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 pharmaceutical tablet may approximate and fit into the drug reservoir lumen of the crescent-shaped drug reservoir and fill a substantial portion of the cross-sectional area of ​​the drug reservoir lumen, e.g., 80% to 99% thereof. The crescent-shaped tablet may have flat ends.

[0093] An example of a crescent-shaped tablet is shown in FIG. 13. The tablet 1300 has a crescent-shaped cross-sectional shape including a major curved surface 1342 and a minor curved surface 1340. Although the major curved surface 1342 and the minor curved surface 1340 are rounded curves, it is envisioned that these surfaces may be or include flat surfaces (e.g., the major or minor curves of the cross section may resemble three sides of a pentagon, three sides of a hexagon, etc.). The major and minor curves may meet at a point at one or both ends of the tablet when viewed in cross section, such as when two overlapping circles form a crescent, or the major and minor curves may be connected at one or both ends of the table by a rounded portion of the table, as featured in the embodiment shown in FIG. 13. The crescent-shaped tablet may have a structure in which the distance between the major and minor curves is tapered, substantially constant, or a combination thereof. A tablet is considered to have a crescent cross-sectional shape if the maximum distance between its major and minor curves is less than or equal to 95% of the tablet's height.

[0094] The drug may be a low solubility drug. As used herein, the term "low solubility" refers to a drug having a solubility characteristic 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 of more than about 10 mg / mL in water at 37°C. For example, the approximate solubilities of certain formulations are: 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, the drug delivery device is used to treat diseases of the upper urinary tract, including upper urinary tract cancers, such as upper urinary tract urothelial carcinoma. Drugs that may be used include antiproliferative agents, cytotoxins, chemotherapeutic agents, or combinations thereof. Representative examples of drugs that may be suitable for treating upper urinary tract cancers include Bacillus Calmette-Guerin (BCG) vaccine, docetaxel, cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall-DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin (e.g., mitomycin C, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, selective estrogen receptor modulators (i.e., SERMs such as tamoxifen), botulinum toxin, and cyclophosphamide. Drugs may include monoclonal antibodies, TNF inhibitors, anti-leukins, and the like. Drugs The agent may also be an immunomodulatory agent such as a TLR agonist, including imiquimod or another TLR7 agonist. The agent may also be a kinase inhibitor, such as fibroblast growth factor receptor-3 (FGFR3), a selective tyrosine kinase inhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or a mitogen-activated protein kinase (MAPK) inhibitor, among others, or a combination thereof. Other examples include celecoxib, erolotinib, gefitinib, paclitaxel, polyphenon E, valrubicin, neocarzinostatin, apaziquone, belinostat, ingenol mebutate, urocidin (MCC), proxinium (VB4845), BC819 (BioCancell These include Lorus Therapeutics, keyhole limpet hemocyanin, LOR2040 (Lorus Therapeutics), urocanic acid, OGX427 (OncoGenex), and SCH721015 (Schering-Plough). Drug therapy may be combined with traditional radiation or surgical therapy to target cancerous tissue.

[0096] In some other embodiments, the drug delivery device may be used to treat pain, and the drug payload includes an anesthetic, an analgesic, and combinations thereof. For example, the anesthetic may be an aminoamide (e.g., lidocaine), an aminoester (e.g., benzocaine), or combinations thereof. In some embodiments, the analgesic includes 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, sulodexide), 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 promote the dissolution of the kidney stones.

[0098] In some embodiments, the drug delivery device may be used to treat urinary incontinence, including urge incontinence and neurogenic incontinence, urinary frequency or urgency, and bladder trigonitis. Drugs that may be used include anticholinergics, antispasmodics, antimuscarinics, beta-2 agonists, alpha adrenergic agonists, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, potassium channel openers, and muscle relaxants.

[0099] In some embodiments, the drug delivery device may be used to treat infections involving the kidneys, ureters, bladder, and urethra. Antibiotics, antibacterials, antifungals, antiprotozoal, antiseptics, antivirals, and other anti-infectives 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 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 procedure.

[0102] In some embodiments, the elastic body is composed of a material that includes an imaging element. The imaging element may include a radiopaque filler material, such as barium sulfate or another radiopaque material known in the art. The imaging element may include one or more radiopaque marker bands secured 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 processing of the material from which the elastic body is formed. In some embodiments, the first material from which the elastic body is formed is a barium sulfate loaded material, i.e., a material that includes barium sulfate. In some embodiments, at least one spacer of the drug delivery device includes an imaging material, including, but 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 middle spacer, all of which are disposed within the drug reservoir lumen. The drug delivery device can be imaged in vivo using ultrasound imaging or fluoroscopy. To improve visibility of the drug delivery device during insertion or otherwise, the barium sulfate concentration can be increased in the elastomer (e.g., the first material, the second material, or a combination thereof), the one or more spacers, or a combination thereof.

[0103] Recovery string The drug delivery devices described herein may further include a retrieval feature, such as a retrieval string, loop, tab, or other structure that facilitates removal of the drug delivery device from the renal pelvis. In some embodiments, the retrieval feature is a retrieval string having a distal end secured to an end of the drug delivery device and a proximal end configured to extend through the ureter into the bladder after device deployment. The device can then be removed from the renal pelvis, for example, after completion of the treatment period (e.g., after releasing some or all of the drug payload into the renal pelvis), by grasping and pulling the proximal end of the retrieval string.

[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 assume a relatively narrow or linear shape when the drug delivery device is pulled by the retrieval mechanism into the ureter and then into the urethra. The retrieval string has a first end portion attached to the drug delivery device and an opposing second end portion that is engaged to pull the drug delivery device through the ureter, bladder, and urethra. The retrieval string may have a length sufficient for the second end of the retrieval string to reside in the bladder when the drug delivery device is deployed in the renal pelvis, as shown in FIG. 19. The retrieval string is generally formed from a biocompatible woven or nonwoven material. In some embodiments, the retrieval string is composed of suture materials known in the art, such as silk, nylon, polyester, PVDF, and polypropylene. The retrieval string may be attached to any portion of the drug delivery device, including the end or middle portions of the elongated body of the drug delivery device. In some embodiments, the drug delivery device comprises 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 of connecting these components. For example, Figures 15-16 show two different embodiments in which the retrieval string is secured to the end of the drug delivery device, and Figure 17 shows another embodiment of the retrieval string secured to an end spacer prior to placing the assembly within the lumen of the 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 bound (i) a drug reservoir lumen 1507 that contains a drug payload 1590 and (ii) a guidewire lumen 1512. A spacer 1520 is secured within the drug reservoir lumen and is closed at its ends. The outer wall 1506 includes a hole 1586 through which a retrieval string 1580 passes. The retrieval string 1580 forms a loop on itself, with a first portion of the retrieval string secured 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 tied to the first portion of the retrieval string (strong) with a knot 1582. Alternatively, or in addition to the knot, the retrieval string 1580 may be held in place either by friction between the spacer 1520 and an inner portion of the outer wall 1506, and / or with the aid of an adhesive. In a variation of this embodiment (not shown), the hole extends into the spacer and the retrieval string passes through both a hole in the outer wall and a hole in the spacer such that a first portion of the retrieval string is secured 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 with an outer wall 1606 and an inner wall 1608 that bound (i) a drug reservoir lumen 1607 that contains a drug payload 1690 and (ii) a guidewire lumen 1612. A spacer 1620 is fixed within the drug reservoir lumen and is closed at its ends. One of the outer wall 1606, the inner wall 1608, and the spacer 1620 both have a hole 1686 through which they extend. A retrieval string 1580 passes through the hole 1686 and forms a loop on 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 a second portion of the retrieval string (strong) with a knot 1682. Alternatively, or in addition to the knot, the retrieval string 1680 may be held in place with the aid of an adhesive. In one variation (not shown), the holes in the spacer are offset from the holes in the outer and inner walls (instead of being aligned with one another as in the illustrated embodiment), so that a portion of the retrieval string is captured by frictional engagement between the spacer and the inner and / or outer walls. In another variation (not shown), the holes may extend laterally through the outer wall of the device body at two points without penetrating the inner wall.

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

[0109] In yet another embodiment, the retrieval string is embedded directly into the spacer. For example, the retrieval string may be attached during formation of the spacer, e.g., incorporated with the thermoplastic material during a molding process to create the spacer. In yet another embodiment, the retrieval string is attached directly to the device body at a part and / or location that does not include the spacer. For example, the retrieval string may be adhesively tied and / or secured to the sidewall of the device body.

[0110] In some embodiments, the drug delivery device may include a retrieval tab. The retrieval tab may be part of the device body, e.g., may be integrally formed therewith. The device may be removed from the renal pelvis by grasping or otherwise engaging the retrieval tab with forceps or another instrument 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 an instrument through the urethra, bladder, and ureter into the renal pelvis to reach the device. The drug delivery device may be configured to assume a relatively narrow or linear shape when the drug delivery device is pulled by the tab into the urethra or ureter.

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

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

[0113] Release may occur, for example, via transmural 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 that includes (i) a first material that is impermeable to the drug, and (ii) a second material that is permeable to the drug, with the drug diffusing (by transmural diffusion) only through the second material. The drug delivery device may include any feature or combination of features described herein.

[0114] In some embodiments, urine diffuses into the drug reservoir lumen by transmural diffusion through the first material, the second material, or a combination thereof, and contacts the drug contained within the drug reservoir lumen to form a solution of the drug, which then diffuses by transmural diffusion through the second material into the renal pelvis.

[0115] In some embodiments, the deployed drug delivery device remains within the renal pelvis for a predetermined treatment period and controllably releases the drug over the predetermined treatment period. After its deployment, the drug delivery device may deliver the drug for a treatment period of days, weeks, months, or longer.

[0116] Once deployed, the drug delivery device releases a desired amount of drug for a desired, predetermined period of time. In preferred embodiments, the drug delivery device may continuously deliver a desired dosage of drug for 24 hours or more, e.g., 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 rate of delivery and dosage of the drug may be selected depending on the drug being delivered and the disease or condition being treated. In some embodiments, the release rate of the drug from the drug delivery device is substantially zero order for at least 36 hours. In some embodiments, the release rate of the drug 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 for 7 days. In other embodiments, at least 1 mg / day of gemcitabine hydrochloride is released for 7 days to 3 months.

[0118] In some embodiments, elution of the drug from the drug delivery device occurs after dissolution of the drug in the drug delivery device. For example, urine enters the drug delivery device, contacts the drug, and solubilizes the drug, and the dissolved drug is then released from the drug delivery device, for example, by diffusion and / or osmotic pumping. In some embodiments, releasing the drug from the drug delivery device includes solubilizing the drug by water absorbed through the 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 that are released at different times. The first payload may be adapted for a relatively quick release and the second payload may be adapted for a longer release. The drugs in the two payloads may be the same drug or two different drugs.

[0120] Methods for deploying and retrieving the device In general, the method includes deploying a drug delivery device as described herein into the renal pelvis of a patient, the drug delivery device being entirely contained within the renal pelvis of the patient with the optional exception of a retrieval string configured to extend into or through the patient's bladder and urethra. The drug delivery device may be retrieved from the body, such as when the drug delivery device is not resorbable or otherwise needs to be removed. In alternative embodiments, the drug delivery device is fully or partially bioerodible, resorbable, or biodegradable, and retrieval is not necessary, either because the entire drug delivery device is resorbed, or because the drug delivery device degrades sufficiently into pieces small enough to be excreted with the urine flowing from the renal pelvis. In embodiments, the drug delivery device may not be retrieved or reabsorbed until a portion of the drug, or preferably most or all of the drug, has been released. If desired, a newly drug-loaded drug delivery device may be subsequently deployed during the same procedure as the retrieval, or at a later time.

[0121] In some embodiments, deploying the drug delivery device in the patient includes inserting the drug delivery device into the renal pelvis of the patient via a deployment instrument. In some embodiments, deploying the drug delivery device in the renal pelvis of the patient includes elastically deforming the drug delivery device into a deployed shape, inserting the drug delivery device through the urethra, bladder, and ureter of the patient, and releasing the drug delivery device into the renal pelvis of the patient such that the drug delivery device assumes a retained shape suitable for preventing or reducing migration of the drug delivery device from the renal pelvis, e.g., into the ureter or calyx. In some embodiments, deploying the drug delivery device in the patient includes inserting a guidewire into the renal pelvis of the patient through the urethra, bladder, ureter, and advancing the drug delivery device along the guidewire, the guidewire being 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 retained configuration and a relatively straightened insertion configuration, and during the step of advancing the drug delivery device over the guidewire, the guidewire located within the guidewire lumen exerts a load on the drug delivery device urging it into the relatively straightened insertion configuration, and after the step of retracting the guidewire from the guidewire lumen, the drug delivery device elastically returns to the coiled or helical retained configuration suitable for retaining the drug delivery device within the patient's renal pelvis. In some embodiments, the drug delivery device includes a radiopaque marker or agent, and the deploying includes determining placement of the drug delivery device within the patient by x-ray.

[0122] 18 is a block diagram illustrating an embodiment of a method 1800 of using a drug delivery device described herein within a patient's body, for example, within the renal pelvis. In block 1802, a deployment device is inserted into the body and provides a pathway through one of the patient's urethra, bladder, and ureters to reach the renal pelvis. Inserting the deployment device generally involves inserting the deployment device into the urethra, bladder, and ureters, and driving the deployment device forward while the proximal end remains outside the body until the distal end is positioned within the renal pelvis. In an embodiment, the drug delivery device is deployed within the patient's renal pelvis in a separate procedure or in another urological procedure (e.g., lithotripsy), either before, during, or after the other procedure.

[0123] In some embodiments, the deployment instrument is inserted into the body at block 1802 in conjunction with a cystoscope or urethroscope to enable visualization of the deployment procedure. In some embodiments, inserting the deployment instrument into the body at block 1802 also includes verifying that the distal end of the deployment instrument is positioned within the renal pelvis. The position of the distal end may be verified by visualizing the distal end of the deployment instrument with a cystoscope, ultrasound, or x-ray. Also, in some embodiments, inserting the deployment instrument into the body at block 1802 also includes anchoring the distal end of the deployment instrument within the renal pelvis, such as by inflating a balloon positioned on the distal end.

[0124] In block 1804, the drug delivery device is operably associated with the deployment device. The type of association depends on the deployment device involved. If the device is an intraluminal device (e.g., cystoscope, urethroscope, catheter, etc.), the association step includes inserting the drug delivery device into the lumen of the device. If the device includes a guidewire, the association step includes inserting the guidewire into the guidewire lumen of the drug delivery device. Combinations of different deployment devices and operative associations may be used. In an exemplary embodiment, the operative association includes elastically deforming the drug delivery device from its retained shape to its deployed shape. When the deployment device and 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 preloaded on / in the deployment device before the deployment device is inserted into the body. In such cases, the order of blocks 1802 and 1804 is reversed.

[0125] At block 1806, the drug delivery device is driven into the renal pelvis. In 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, the distal end of which may remain with the deployment device), expelling the drug delivery device into the renal pelvis. In the case of an intraluminal deployment device, the drug delivery device is pushed out of an opening in the distal end portion of the device, for example, using a stylet and / or a non-compressible fluid (e.g., water, lubricant) that travels through the lumen to the rear of the drug delivery device. In the case of a guidewire-type deployment device, the drug delivery device is pushed out of the distal end of the guidewire, for example, using a plunger that rides up the guidewire. In some embodiments, following separation of the drug delivery device from the deployment device, the drug delivery device elastically returns to its retained shape, typically spontaneously, once the device is no longer subject to straightening-inducing loads from the deployment device. In some embodiments, driving the drug delivery device into the renal pelvis at block 1806 includes viewing the drug delivery device within the renal pelvis to ensure that the drug delivery device is properly deployed. For example, the drug delivery device may be viewed using a urethroscope, ultrasound, or x-ray.

[0126] At block 1808, the deployment instrument is removed from the patient's body by withdrawing the instrument from the renal pelvis, ureter, bladder, and then the urethra. If the deployment instrument includes multiple components, the components may be withdrawn simultaneously or multiple times depending on the components and the manner desired to minimize patient discomfort and / or trauma to the luminal tissue through which the deployment instrument passes. If the drug delivery device includes an attached retrieval string, the free distal end of the retrieval string may be withdrawn along with the deployment instrument and released into the desired location within the patient (e.g., within the bladder).

[0127] Thereafter, in block 1810, the drug delivery device remains deployed within the renal pelvis for a selected treatment period and releases drugs from the drug payload at a selected rate / amount over the treatment period, i.e., when deployed in vivo, the drug delivery device releases drugs 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, upon completion of the treatment period or release of all or most of the drug payload. This process may include inserting a removal instrument into the body, positioning the drug delivery device or a portion thereof, and withdrawing the drug delivery device from the body with the aid of the removal instrument. The removal instrument may include a cystoscope, catheter, or ureteroscope, and may further include forceps, a lariat, or another grasping instrument. In embodiments where the drug delivery device includes a retrieval string, a method of removing the device from the patient may include grasping a distal end portion of the retrieval string, which may be located within the patient's bladder, and then removing the drug delivery device from the patient through the ureter, bladder, and urethra by pulling the retrieval string. In some embodiments, the drug delivery device may be retracted into the distal end portion of the luminal removal instrument, causing the device to collapse or assume a deployed shape upon entering the removal instrument. In some embodiments, forceps passed through the removal instrument can be used to grasp the drug delivery device and retract the drug delivery device partially or completely into the removal instrument before withdrawing the removal instrument. In some embodiments, the removal instrument may include a magnet for magnetically coupling to a portion of the drug delivery device configured for this purpose. The magnetic coupling can advantageously be performed in a blind procedure; that is, the device does not need to be visualized in order to secure it with the removal instrument. In some other embodiments, after any portion of the drug delivery device is firmly grasped (e.g., by a retrieval string), the removal instrument is withdrawn from the patient's body and the drug delivery device follows behind it rather than within the removal instrument. In these embodiments, the drug delivery device may be retracted into a deployed shape as it enters the ureter and urethra, allowing these tissue structures to pass through while maintaining the drug delivery device in its deployed shape. In various procedures, the drug delivery device may be withdrawn from the removal instrument, which may then be removed from the body, or the drug delivery device and the removal instrument 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 the embodiment of drug delivery device 100 shown in Figures 1A-1C, and the deployment instrument 1400 may be the instrument shown in Figures 14A-14B. In one example, the drug delivery device is deployed by guiding the drug delivery device with a deployment instrument, e.g., a ureteral catheter and / or a guidewire system, and expelling the drug delivery device from the deployment instrument into the renal pelvis. In these cases, the drug delivery device may assume a retained shape (e.g., a coil or helical shape) once the drug delivery device emerges from the deployment instrument into the renal pelvis. The deployment instrument may include a guidewire deployment system described herein. In some embodiments, deploying the drug delivery device within the patient's renal pelvis includes (i) elastically deforming the drug delivery device into a deployed shape; (ii) inserting the drug delivery device through the patient's urethra, bladder, and ureter; and (iii) releasing the drug delivery device into the patient's renal pelvis such that the drug delivery device assumes a retained shape suitable to prevent unwanted migration of the device.

[0130] Treatment method The deployed drug delivery device may release one or more drugs locally to the renal pelvis of a patient for the local or regional 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 tract urothelial carcinoma, and urinary stones, such as kidney stones, ureteral stones, and bladder stones. Treatment of other diseases and conditions is also contemplated.

[0131] In one embodiment, the patient is in need of treatment and / or prevention of stones. Non-limiting examples of drugs delivered by the device include antibacterial agents, alkalinizing 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 treating the patient with extracorporeal shock wave lithotripsy (ESWL) for the treatment of kidney stones in the patient. Migration of smaller stone fragments to the lower or lower pole calyx of the kidney has been observed to occur after ESWL treatment due to gravity and anatomical configuration (Bourdoumis et al., "Lower Pole Stone Management," Med Surg Urol S1:002 (2012)). These stone fragments are relocated into the lower calyx and act as nuclei for new stone formation, causing lower pole calyx lithiasis. Thus, in embodiments of the method, drugs that inhibit stone formation are released from the deployed device into the renal pelvis. The released drug may be more concentrated and effective in these lower calyces due to gravity and anatomical configuration.

[0132] In one embodiment, the patient is in need of treatment or prevention of a urinary tract infection (UTI) or pyelonephritis. In certain embodiments, the method of treatment or prevention includes delivering an antimicrobial agent via the drug delivery device. The antimicrobial agent may be an antibiotic, antibacterial, antifungal, antiviral, antiparasitic, disinfectant, or antiseptic agent known in the art. In certain embodiments, the antimicrobial agent may be an aminoglycoside, a penetrating agent, or an iron mimetic. Non-limiting examples of specific antibacterial agents that may be used in the methods of treating or preventing UTI or pyelonephritis include trimethoprim / sulfamethoxazole, trimethoprim, ciprofloxacin, levofloxacin, norfloxacin, gatifloxacin, ofloxacin, nitrofurantoin, fosfomycin, pivamecillinam, cefpodoxime proxetil, ceftibuten, cefotaxime, ceftriaxone, ceftazidime, cefepime, amoxicillin / clavulanic acid, piperacillin / tazobactam, gentamicin, amikacin, ertapenem, imipenem / cilastatin, meropenem, doripenem, aztreonam, gallium ferrum mimetics, and combinations thereof. In another embodiment, the "medicament" administered to the patient comprises an attenuated bacterium / pathogen to colonize the genitourinary tract with non-pathogenic bacteria to prevent recurrent urinary tract infections or pyelonephritis.

[0133] In another embodiment, the patient is in need of renal cell carcinoma treatment. In certain embodiments, the treatment method includes delivering an antiangiogenic agent, a tyrosine kinase inhibitor, an mTOR inhibitor, or a combination thereof via a drug delivery device. Non-limiting examples of specific drugs that can be used in the treatment method for renal cell carcinoma include everolimus, aldesleukin, bevacizumab, axitinib, sorafenib tosylate, pazapanib hydrochloride, aldesleukin, sunitinib malate, temsirolimus, and combinations thereof. Other treatments may be used with the device, drug delivery device described herein. For example, the treatment method may further include surgery, such as partial nephrectomy, radiation, or systemic chemotherapy.

[0134] In yet another embodiment, the patient is in need of treatment for upper tract urothelial carcinoma, or transitional cell carcinoma of the renal pelvis and ureter. Non-limiting examples of specific drugs that may be used in the method of treating upper tract 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 the drug delivery device described herein. For example, the method of treatment may further include surgery, radiation, or systemic chemotherapy.

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

[0136] In yet other embodiments, the method of treatment 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 the material for which they are cited are specifically incorporated by reference.

[0138] In the description provided herein, the terms "includes," "is," "containing," "having," and "comprises" are used in an open-ended manner and should therefore be interpreted to mean "including, but not limited to." When a method, system, or apparatus is claimed or described in terms of "comprising" various components or steps, the method or system may also "consist essentially of" or "consist of" the various components or steps, unless otherwise specified.

[0139] Various numerical ranges may be disclosed herein. When applicants disclose or claim any type of range, it is the intention of the applicants to individually disclose or claim each possible number that such ranges may reasonably encompass, including the endpoints of the ranges and the endpoints of any subranges and combinations of subranges encompassed within the ranges. Moreover, all numerical endpoints of ranges disclosed herein are approximations. As a representative example, applicants disclose that in one embodiment, the drug delivery device has a length of about 1.5 cm to about 3 cm when in a retained configuration. This range should be interpreted as encompassing a length of about 1.5 cm to about 3 cm, including 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 ranges 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 1.9 cm to 2.1 cm.

[0141] Many modifications and other implementations of the disclosure set forth herein will become apparent having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the disclosure is not limited to the particular implementations disclosed, and that modifications and other implementations are intended to be included within the scope of the appended claims. EXAMPLES

[0142] The invention is further illustrated by the following non-limiting examples.

[0143] Example 1 - Drug Delivery Device A gemcitabine release device was fabricated for in vitro testing. The system was constructed using dual-material polyurethane tubing. The drug reservoir lumen of the drug delivery device in this example contained a gemcitabine hydrochloride powder blend containing 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-sectional shape, such as the drug reservoir lumen shown in FIG. 1C. The elastic body of the device was made from barium sulfate-doped Tecoflex polyurethane (TECOFLEX™ EG-80A-B20, 20% barium sulfate doped, 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 doping, 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. TECOPHILIC™ TPU polyurethane was used to form the drug-permeable stripe. Thus, TECOPHILIC™ TPU polyurethane was a water-permeable and drug-permeable material, allowing water to enter the drug delivery device and allowing dissolved drug to traverse the drug-permeable stripe and enter the area surrounding the drug delivery device.

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

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

[0147] An alternative design of the device was also made that included adding a spacer in the middle of the drug reservoir lumen. This design was particularly useful where the middle and end spacers comprised radiopaque material, allowing for three-point visualization of the device when deployed in vivo. In such an embodiment, it is not necessary to include radiopaque material within the material forming the elastic body. An example of such a drug delivery device is shown in Figures 5A-5C. The drug delivery device 500 included an outer wall 506 formed of Tecoflex polyurethane with a drug-permeable stripe 524 of Tecophilic polyurethane. Each end of the drug reservoir lumen 507 was sealed with a Tecoflex polyurethane spacer 520. The drug reservoir lumen contained a drug payload 516 (gemcitabine powder blend) and a Tecoflex polyurethane spacer 550, located approximately midway between the end spacers 520. The assembly process included (i) loading approximately half of the gemcitabine powder formulation into the drug reservoir lumen after placement of the first spacer, (ii) inserting the middle spacer into the drug reservoir lumen, (iii) loading the remainder of the drug payload into the drug reservoir lumen, and then (iv) placing the second end spacer. The end spacers were heat fused to the ends 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 FIG. 5C, to provide a path for drug release by transmural diffusion. FIG. 5C also shows the guidewire lumen 512 defined between the outer wall 506 and the inner wall 508.

[0148] After the drug delivery device was assembled, a retained shape was applied to the device using a heat setting process. The drug delivery device was elastically deformed into the retained shape and then placed in an oven at 90° C. for 10 minutes. The drug delivery device was allowed to cool to room temperature while still in the retained shape, and the drug delivery device maintained the retained shape. Single coiled and spiral retained shapes were 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 aid in the placement of the drug delivery device, the removal of the drug delivery device, or both the placement and removal 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 [1] the 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 doubled in length, after which the string was tied together. The retrieval string was set to a length such that the end could be present 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 drug delivery devices The migration of two drug delivery devices with different retention geometries was evaluated using an in vivo study.

[0151] Single coil designs (e.g., that of FIG. 2) having lengths of 4 cm and 6 cm (when in a substantially straight deployed configuration) were deployed in the renal pelvic pole of the kidneys of domestic Yorkshire pigs. Necropsy revealed that the drug delivery devices migrated and that the smaller drug delivery devices were more prone to migration than the larger drug delivery devices. Additionally, the single coil drug delivery devices were shorter in length to fit into the available renal pelvic space, limiting the drug payload.

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

[0153] Helical (multi-coil) drug delivery devices with lengths of 6 cm and 8 cm (when in a relatively straightened deployed 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 renal pelvic pole of the kidney. Necropsy revealed that neither size of drug delivery device exhibited significant migration potential, indicating improved retention of the helical design over the coil design. In addition, longer systems were observed to be safer than shorter systems after deployment. Due to their three-dimensional shape, the multi-coil drug delivery devices contacted the renal pelvic wall in all directions, thereby improving retention. The relative complexity of this shape also made these drug delivery devices less likely to back out and down the ureter. The longer length of the multi-coil drug delivery device allowed for the use of larger drug payloads.

[0154] The spiral design was deployed in the upper poles of eight kidneys of four domestic Yorkshire pigs for a period of seven days. The deployment of the spiral design of this example is provided in the table below.

[0155] [Table 1]

[0156] After 7 days, one of eight helical design drug delivery devices had migrated into the ureter. The migrated drug delivery device may have been at least partially dislodged during attempted removal of the string fastener. All sizes (length and coil diameter) of helical design drug delivery devices did not exhibit significant migration potential, indicating an overall improvement in retention.

[0157] Example 3 - Variations in Drug Delivery Device Shape A drug delivery device as shown in Figure 6 was fabricated with three turns of the helical portion and a straight end extending approximately perpendicular to the helical portion of the device. The straight end was heat set and aligned at an angle to the device. The outer coil diameter was 12 mm.

[0158] A drug delivery device was fabricated with six turns of the helical portion and straight ends formed by heat setting, as shown in Figure 7. The external coil diameter of the device was 8 mm. The uncoiled length of the device was 120 mm.

[0159] A drug delivery device was fabricated with three coils separated by two intermediate straight sections as shown in Figure 8. The uncoiled length of the device was 85 mm.

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

[0161] A drug delivery device was also fabricated with 8 turns and a straight end. This device had an outer 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 drugs Several embodiments of the drug delivery device of Example 1 were tested for in vitro release of gemcitabine. The different embodiments tested in this example included drug delivery devices that [1] had drug permeable stripes with different arc angles, [2] were made with different withdrawal string attachment methods, [3] had different lengths, and [4] had different heat-set geometries.

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

[0165] Stripe angle Drug delivery devices with two 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] Smaller stripe arc angles (i.e., 60°) resulted in longer release duration: drug delivery devices with a stripe arc angle of 120° had a release profile that lasted for 4 days, and drug delivery devices with a stripe arc angle of 60° had a release profile that lasted for 7 days.

[0167] b. Attaching the recovery string The recovery string installation method described in Example 1 did not cause any leaks and was the simplest installation method tested.

[0168] c. Drug delivery device length Drug delivery devices with coiled or helical retention shapes in a relatively straightened deployed configuration and lengths of 4 cm (coiled retention shape), 8 cm (coiled retention shape), 10 cm (helical retention shape), and 12 cm (helical retention 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, but this change increased the peak release rate.

[0169] d. Heat set configuration The change to the heat-set configuration did not significantly affect the release profile of the drug delivery device.

[0170] Figure 11 shows the release profiles of two different drug delivery devices of this example, the first having stripes with an arc angle of 60°, a length of 10 cm when in a relatively straightened deployed 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 plot in Figure 11 shows that the release rates achieved for the two drug delivery devices were similar, but the device with the longer length (Device 2) released a greater amount of drug on each of days 1-9.

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

[0172] FIG. 12 shows the release profiles of two different drug delivery device configurations. The first configuration of the drug delivery device was made with EG-100A-B20 as the base material and the second configuration of the drug delivery device was made with EG-80A-B20 as the base material. EG-100A-B20 is a stiff 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 9 Fr and a higher drug payload potential and the second configuration had an outer diameter of 8 Fr. The drug permeable stripes of both drug delivery devices were made with HP-60D-35. The stripe angle of the second configuration was 60°. Since the first configuration has a higher drug payload potential, the stripe angle was reduced to 55° to maintain the peak release of the drug profile. As can be seen in FIG. 12, despite the modification of the drug delivery device to produce the second configuration, both configurations had very similar drug release profiles and the peak release was maintained.

[0173] Example 5 - Crescent-shaped tablets Crescent shaped tablets were produced that included dimensions corresponding to the drug reservoir lumen dimensions of the drug delivery device of Example 1. A single station automated press and a placebo blend were used to produce the crescent shaped tablets. The crescent shaped tablets were similar to those shown in FIG.

[0174] Exemplary embodiments and a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug; and a drug delivery device for deployment within a renal pelvis of a patient, the drug delivery device comprising: an elastic body comprising: (i) an outer tube including an elongated outer wall; and (ii) an elongated arcuate inner wall located within the outer tube, the arcuate inner wall being integrally connected to an 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 guidewire lumen on a concave side of the inner wall; and (b) a drug reservoir lumen on opposing convex sides of the inner wall, the drug reservoir lumen being closed at opposing ends thereof.

[0175] Embodiment 2. The drug delivery device of embodiment 1, wherein the device is biased into the retained configuration when a guidewire is not inserted within the guidewire lumen.

[0176] Embodiment 3. A drug delivery device as described in embodiment 1 or 2, wherein the retention shape is helical.

[0177] Embodiment 4. The drug delivery device of embodiment 3, wherein the helical retention shape comprises 2 to 10 turns.

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

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

[0180] Embodiment 7. A drug delivery device as described in embodiment 6, wherein the outer wall is cylindrical and the drug permeable stripe has an arc angle of about 30° to about 120° of the circumference of the outer wall in cross section.

[0181] Embodiment 8. A drug delivery device as described in embodiment 7, wherein the drug-permeable stripe has an arc angle of about 60° to about 120° of the circumference of the outer wall in cross section.

[0182] Embodiment 9. A drug delivery device described in any one of embodiments 1 to 8, wherein the drug reservoir lumen has a crescent cross-sectional shape.

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

[0184] Embodiment 11. A drug delivery device described in any one of embodiments 1 to 10, further comprising 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 retained shape.

[0185] Embodiment 12. A drug delivery device described in any one of embodiments 1 to 11, wherein the retention shape is helical 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 of embodiment 12, wherein the drug delivery device has a maximum width of about 0.5 cm to about 1.4 cm, about 0.5 cm to about 1 cm, or about 0.5 cm to about 1 cm.

[0187] Embodiment 14. A drug delivery device as described in embodiment 12 or 13, wherein the drug delivery device has a length of about 0.8 cm to about 2 cm, or about 0.8 cm to about 1.8 cm, or about 0.8 cm to about 1.4 cm when in the retained configuration.

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

[0189] Embodiment 16. A drug delivery device described in any one of embodiments 1 to 15, further comprising at least one intermediate spacer disposed within the drug reservoir lumen at a position between the opposing ends.

[0190] Embodiment 17. A drug delivery device as described in embodiment 15 or 16, wherein the elastic body, the end spacers, and / or at least one intermediate spacer comprises a radiopaque filling material.

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

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

[0193] Embodiment 20. A drug delivery device as described in embodiment 18 or 19, wherein the second material comprises a tecophilic polyurethane.

[0194] Embodiment 21. A drug delivery device described in 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. A drug delivery device as described in embodiment 21, wherein the retrieval string has a length sufficient such that a second end of the retrieval string is within the patient's bladder when the drug delivery device is deployed within the renal pelvis.

[0196] Embodiment 23. A drug delivery device described in any one of embodiments 1 to 22, further comprising a tab fixed to the end portion of the 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 solid or semi-solid form.

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

[0199] Embodiment 26 The drug delivery device of embodiment 24, wherein the drug payload is in the form of a plurality of tablets having a crescent cross-sectional shape.

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

[0201] Embodiment 28. A drug delivery device described in any one of embodiments 1 to 27, wherein the elastic body is thermally shaped to have a retained shape.

[0202] Embodiment 29. A system for administering a drug to a patient in need of the drug, comprising: a drug delivery device as described in any one of embodiments 1 to 28; and a guidewire deployment system for deploying the drug delivery device within the patient's renal pelvis, the guidewire deployment system including: (i) a guidewire configured to be operatively 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 over the guidewire from the distal end into the renal pelvis.

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

[0204] Embodiment 31. The system described in embodiment 29 or 30, wherein the plunger device includes 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 guidewire so that the plunger device can move over the guidewire.

[0205] Embodiment 32. The system described in embodiment 31, wherein the plunger further comprises a stop configured to indicate that the drug delivery device is separated from the guidewire.

[0206] Embodiment 33. A method of administering a drug to a patient in need of the drug, the method comprising: deploying a drug delivery device described in any one of embodiments 1 to 28 within the patient's renal pelvis, wherein the drug delivery device is entirely contained within the patient's renal pelvis, with the optional exception of a retrieval string configured to extend into or through the patient's bladder and into or through the patient's urethra; and releasing the drug from the drug delivery device into the renal pelvis.

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

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

[0209] Embodiment 36. The method of any one of embodiments 33 to 35, wherein deploying the drug delivery device comprises elastically deforming the drug delivery device into a deployed shape, inserting the drug delivery device through the patient's urethra, bladder, and ureter, and releasing the drug delivery device into the patient's renal pelvis such that the drug delivery device elastically deforms into a retained shape.

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

[0211] Embodiment 38. The method of embodiment 37, wherein the drug delivery device is elastically deformable between a coiled or helical retaining shape and a relatively straightened insertion shape, and during the step of advancing the drug delivery device along the guidewire, the guidewire positioned within the guidewire lumen exerts a load on the drug delivery device, urging the drug delivery device into the relatively straightened insertion shape, and after the step of withdrawing the guidewire from the guidewire lumen, the drug delivery device elastically deforms into a coiled or helical retaining shape suitable for retaining the drug delivery device within the patient's renal pelvis.

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

[0213] Embodiment 40. The method of any one of embodiments 33-39, wherein following deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen and contacts the drug contained within the drug reservoir lumen to form a solution of the drug, which is then released into the renal pelvis.

[0214] Embodiment 41. The method of embodiment 40, wherein the outer wall comprises two different constituent materials, a first material being impermeable to the drug when the drug is in solution and a second material being permeable to the drug when the drug is in solution, and following deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen by transmural diffusion through the first and / or second material, contacts the drug contained within the drug reservoir lumen, and produces a solution of the drug, which is then released into the renal pelvis by transmural diffusion through the second material.

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

[0216] Embodiment 43. A method of administering a drug to a patient in need of the drug, comprising: deploying a drug delivery device within the patient's renal pelvis; and continuously releasing a drug from the deployed drug delivery device into urine in the renal pelvis over a chronic treatment period of at least 24 hours, wherein the drug delivery device is entirely contained within the renal pelvis, with the optional exception of a retrieval string extending into at least the patient's ureter.

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

[0218] Embodiment 45. The method of embodiment 43 or 44, wherein the drug is released from the drug delivery device through openings in the wall of the drug delivery device, by transmural diffusion or by osmotic pressure.

[0219] Embodiment 46. The method of any one of embodiments 43-45, wherein the patient is in need of treatment or prevention of a urinary tract infection or pyelonephritis.

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

[0221] Embodiment 48. The method of embodiment 46, wherein the drug comprises an aminoglycoside, an osmotic agent, or an iron mimetic.

[0222] Embodiment 49. The method of embodiment 46, wherein the drug comprises an antibiotic, antibacterial, antifungal, antiviral, antiparasitic, disinfectant, or antiseptic.

[0223] Embodiment 50. The method of embodiment 46, wherein the medicament comprises an attenuated bacterium / pathogen for colonizing the genitourinary tract with non-pathogenic bacteria to prevent recurrent urinary tract infections or pyelonephritis.

[0224] Embodiment 51. The embodiment of any one of embodiments 43-45, wherein the patient is in need of treatment for renal cell carcinoma.

[0225] Embodiment 52. The method of 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 of any one of embodiments 43-45, wherein the patient is in need of treatment for upper tract urothelial carcinoma.

[0227] Embodiment 54. The method of 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 of any one of embodiments 43-45, wherein the patient is in need of treatment for hyperfibrinolysis.

[0229] Embodiment 56. The method of embodiment 55, wherein the drug is selected from ranexamic acid, aminocaproic acid, and combinations thereof.

[0230] Embodiment 57. The method of any one of embodiments 43-45, wherein the patient is in need of treatment for urinary stones.

[0231] Embodiment 58. The method of embodiment 57, wherein the deployment of the drug delivery device into the renal pelvis occurs after treating the patient with extracorporeal shock wave lithotripsy for the treatment of the patient's kidney stones.

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

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

[0234] Embodiment 61. A drug delivery device for deployment within a patient's renal pelvis, the drug delivery device comprising: an elongated elastic body, the elastic body including 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, the drug delivery device being elastically deformable between a deployed shape configured to accommodate passage of the drug delivery device through the ureter into the patient's renal pelvis and a helical retained shape configured to reduce migration of the device from the renal pelvis.

[0235] Embodiment 62. A drug delivery device as described in embodiment 61, wherein the helical retention shape comprises 2 to 10 turns.

[0236] Embodiment 63. A drug delivery device as described in embodiment 61 or 62, wherein the device is biased into the retained shape when the guidewire is not inserted into the guidewire lumen, and the elastic body is (i) thermally shaped to have the retained shape, and / or (ii) further comprises 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 the retained shape.

[0237] Embodiment 64. A drug delivery device described in any one of embodiments 61 to 63, further comprising a retrieval string having a first end attached to an end portion of the elongated elastic body, the retrieval string being of sufficient length such that a second end of the retrieval string is present within the patient's bladder when the drug delivery device is deployed within 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 semi-solid form such as a powder, multiple tablets, or a gel.

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

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

[0241] Embodiment 68. A drug delivery device as described in embodiment 67, wherein the elongated elastic body further comprises a drug-impermeable wall adjacent to the drug reservoir lumen.

[0242] Embodiment 69. The drug delivery device of embodiment 68, wherein the drug-permeable wall comprises a tecophilic polyurethane and the drug-impermeable wall comprises a tecoflex polyurethane.

[0243] Embodiment 70. A drug delivery device as described in embodiment 68 or 69, wherein the drug-permeable wall is in the form of a drug-permeable stripe extending the length of the elastic body.

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

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

[0246] Embodiment 73. A drug delivery device as described in embodiment 71 or 72, wherein the elastic body, the end spacers, and / or at least one intermediate spacer comprises a radiopaque filling material.

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

[0248] Embodiment 75. A drug delivery device described in 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 described in any one of embodiments 61 to 75, wherein the retention shape has a spiral portion with one straight end.

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

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

[0252] Embodiment 79. A drug delivery device as described in embodiment 78, wherein the retention shape includes two or more intermediate straight sections.

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

[0254] Embodiment 81. A drug delivery device described in 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 described in any one of embodiments 61 to 81, wherein the two opposing ends of the device body are straight and extend in a direction approximately perpendicular to the plane within the helical coil of the body when in the retained shape.

[0256] Embodiment 83. A drug delivery device described in 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 described in 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 loaded powder or multiple tablets.

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

[0259] Embodiment 86. A device, system, or method described in any one of embodiments 1 to 85, wherein the drug delivery device has a tapered end configured to function as a tip to facilitate introduction of the device through the urethra and ureter into the patient's renal pelvis.

[0260] Embodiment 87. The device, system, or method of embodiment 86, wherein the drug delivery device further comprises a tapered end configured to function as an end piece.

[0261] Embodiment 88. A device, system, or method as described in embodiment 86 or 87, wherein the drug delivery device further comprises at least one withdrawal string fixed to the device.

[0262] [Embodiment] (1) A drug delivery device for deployment within a renal pelvis of a patient, the drug delivery device comprising: An elastic body, the elastic body comprising: (i) an outer tube including an elongated outer wall; (ii) an elongated, arcuate inner wall located within the outer tube, the arcuate inner wall being integrally connected to an inner surface of the outer wall along two opposing edges of the inner wall, the outer wall and the inner wall together defining: (a) a guidewire lumen on a concave side of the inner wall; and (b) a drug reservoir lumen on opposing convex sides of the inner wall, the drug reservoir lumen being closed at opposing ends thereof; a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug; The drug delivery device is elastically deformable between a deployed configuration for passage of the drug delivery device via the ureter to the renal pelvis of the patient and a retained configuration configured to reduce migration of the device from the renal pelvis. (2) A drug delivery device as described in embodiment 1, wherein the device is biased to the retained shape when a guidewire is not inserted within the guidewire lumen. (3) The drug delivery device of embodiment 1, wherein the retention shape has a spiral portion. (4) The drug delivery device of embodiment 3, wherein the retention shape further comprises a straight terminal portion extending longitudinally of the device. (5) The drug delivery device of embodiment 3, wherein the spiral portion comprises 2 to 10 turns.

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

[0264] (11) The drug delivery device of claim 10, wherein the drug-permeable stripe has an arc angle of about 55° to about 120° about the circumference of the outer wall in the cross section. (12) The drug delivery device of embodiment 9, wherein the first material comprises tecoflex polyurethane. (13) The drug delivery device of embodiment 9, wherein the first material further comprises a radiopaque filler. (14) The drug delivery device of embodiment 9, wherein the second material comprises a tecophilic polyurethane. (15) The drug delivery device of 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 guidewire lumen has a circular cross-sectional shape. (17) A drug delivery device described in any of embodiments 1 to 6, further comprising 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 the retained shape. (18) The drug delivery device of any one of embodiments 1 to 6, wherein the retention configuration includes a helical portion, and the drug delivery device has a length of about 5 cm to about 15 cm when in the deployed configuration. (19) The drug delivery device of embodiment 18, wherein the drug delivery device has a length of about 0.8 cm to about 2 cm when in the retained configuration. (20) The drug delivery device of any one of embodiments 1 to 6, wherein each of the opposing ends of the drug reservoir lumen is sealed by a spacer.

[0266] (21) The drug delivery device of embodiment 20, further comprising at least one intermediate spacer disposed within the drug reservoir lumen at a position between the opposing ends. (22) The drug delivery device of any one of claims 20 to 21, wherein the elastic body, the end spacers, and / or the at least one intermediate spacer comprise a radiopaque filling material. (23) The drug delivery device of any one of embodiments 1 to 20, further comprising a retrieval string attached to the drug delivery device. (24) The drug delivery device of embodiment 23, wherein the retrieval string has a length sufficient to allow an end of the retrieval string to reside within the patient's bladder when the drug delivery device is deployed within the renal pelvis. (25) The drug delivery device of any one of embodiments 1 to 6, wherein the drug payload is in solid or semi-solid form.

[0267] (26) The drug delivery device of embodiment 25, wherein the drug payload is in the form of a powder or multiple tablets. (27) The drug delivery device of embodiment 25, wherein the drug payload is in the form of a plurality of tablets having a crescent cross-sectional shape. (28) The drug delivery device of any one of embodiments 1 to 6, wherein the outer tube and the inner wall are formed together by a coextrusion process. (29) The drug delivery device according to any one of embodiments 1 to 6, wherein the elastic body is thermally shaped to have the retained shape. (30) A system for administering a drug to a patient in need of the drug, the system comprising: A drug delivery device according to any one 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 operatively 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 urethra of the patient; and (ii) a plunger device for pushing the drug delivery device over the guidewire from the distal end into the renal pelvis; The system, wherein the guidewire has a cross-sectional area sized to pass through the guidewire lumen of the drug delivery device.

[0268] (31) The plunger device A plunger; A handle and a sheath extending between the plunger and the handle, the sheath transmitting a driving force applied to the handle to the plunger; 31. The system of embodiment 30, further comprising an internal bore for receiving the guidewire so that the plunger device can be moved over the guidewire. (32) The system of embodiment 31, wherein the plunger further comprises a stop configured to indicate that the drug delivery device is separated from the guidewire. (33) A method of administering a drug to a patient in need thereof, the method comprising: deploying a drug delivery device within 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 or through the patient's bladder and into or through the patient's urethra; and releasing a drug from the drug delivery device into the renal pelvis. (34) The method of embodiment 33, wherein the drug is released through at least a portion of the outer wall of the drug delivery device via transmural diffusion. (35) The outer wall comprises two different construction materials, a first material being impermeable to the drug when the drug is in solution and a second material being permeable to the drug when the drug is in solution; the second material is adjacent to the drug-containing payload; 35. The method of embodiment 34, wherein the drug is released via transmural diffusion through the second material.

[0269] (36) The deployment of the drug delivery device, elastically deforming the drug delivery device to a deployed configuration; inserting the drug delivery device through the patient's urethra, bladder, and ureter; A method according to any 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 retained shape. (37) Deploying the drug delivery device comprises: inserting a distal end of a guidewire through the patient's urethra, bladder, ureter and into the patient's renal pelvis; advancing the drug delivery device along the guidewire toward the distal end of the guidewire, away from the proximal end of the guidewire, the guidewire being positioned within the guidewire lumen until the drug delivery device is positioned within the renal pelvis; and then and withdrawing the guidewire from the guidewire lumen and from the patient. (38) The drug delivery device is elastically deformable between a coiled or helical retained configuration and a relatively straightened insertion configuration; during the step of advancing the drug delivery device along the guidewire, the guidewire positioned within the guidewire lumen exerts a load on the drug delivery device, urging the drug delivery device into the relatively straightened insertion configuration; 38. The method of claim 37, wherein following the step of withdrawing the guidewire from the guidewire lumen, the drug delivery device elastically deforms into the coiled or spiral retained shape suitable for retaining the drug delivery device within the renal pelvis of the patient. (39) The method of embodiment 33, wherein the drug delivery device comprises a radiopaque marker or agent, and the method further comprises determining the placement of the drug delivery device within the patient by X-ray imaging. (40) The method of embodiment 33, wherein following the deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen and contacts the drug in the payload, forming a solution of the drug, which is then released into the renal pelvis.

[0270] (41) The outer wall comprises two different construction materials, a first material being impermeable to the drug when the drug is in solution, and a second material being permeable to the drug when the drug is in solution; The method of embodiment 40, wherein following the deployment of the drug delivery device into the renal pelvis, urine diffuses into the drug reservoir lumen by transmural diffusion through the first and / or second material, contacts the drug contained within the drug reservoir lumen, and produces a solution of the drug, which is then released into the renal pelvis by transmural diffusion through the second material. (42) The method of embodiment 33, wherein the rate of release of the drug from the drug delivery device is essentially zero order over a period ranging from 36 hours to 7 days. (43) A method of administering a drug to a patient in need thereof, comprising: deploying a drug delivery device within the patient's renal pelvis; and continuously releasing a drug from the deployed drug delivery device into the urine in the renal pelvis over a chronic treatment period of at least 24 hours. A method wherein the drug delivery device is contained entirely within the renal pelvis, with the optional exception of a retrieval string extending at least into the patient's ureter. (44) The method according to embodiment 43, wherein the treatment period is 1 to 90 days. (45) The method of embodiment 43, wherein the drug is released from the drug delivery device through openings in the wall of the drug delivery device, by transmural diffusion or by osmotic pressure.

[0271] (46) The method according to any one of embodiments 43 to 45, wherein the patient is in need of 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 is in need of treatment for renal cell carcinoma. (48) The method according to any one of embodiments 43 to 45, wherein the patient is in need of treatment for upper tract urothelial carcinoma. (49) The method according to any one of embodiments 43 to 45, wherein the patient is in need of treatment for hyperfibrinolysis. (50) The method according to any one of embodiments 43 to 45, wherein the patient is in need of treatment for urinary stones.

[0272] (51) The method of embodiment 50, wherein the deployment of the drug delivery device into the renal pelvis occurs after treating the patient with extracorporeal shock wave lithotripsy for the treatment of kidney stones in the patient. (52) A drug delivery device for deployment within a renal pelvis of a patient, the drug delivery device comprising: an elongated elastic body, the elongated elastic body including a guidewire lumen and a separate drug reservoir lumen; a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug; The drug delivery device is elastically deformable between a deployed shape configured for passage of the drug delivery device via the ureter to the renal pelvis of the patient and a helical retained shape configured to reduce migration of the device from the renal pelvis. (53) The drug delivery device of embodiment 52, wherein the device is biased into the retained shape when a guidewire is not inserted into the guidewire lumen, and the elastic body (i) is thermally shaped to have the retained shape, and / or (ii) further comprises 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 the retained shape. (54) The drug delivery device of embodiment 53, further comprising a retrieval string attached to the elongated elastic body, the retrieval string having a length sufficient such that an end of the retrieval string resides within the patient's bladder when the drug delivery device is deployed within the renal pelvis. (55) The drug delivery device of embodiment 53, wherein the drug payload is in the form of a powder or multiple tablets.

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

[0274] (61) The drug delivery device of embodiment 60, wherein the Tecoflex polyurethane is either EG-100A-B20 or EG-80A-B20. (62) The drug delivery device of any one of embodiments 52 to 61, wherein the helical retention shape further comprises a straight terminal portion extending longitudinally of the device. (63) The drug delivery device of embodiment 62, wherein each of the opposing ends of the drug reservoir lumen is sealed by an end spacer. (64) The drug delivery device of embodiment 63, further comprising at least one intermediate spacer disposed within the drug reservoir lumen at a position approximately midway between opposing ends of the elongated elastic body. (65) The drug delivery device of embodiment 64, wherein the end spacers and the at least one intermediate spacer comprise a radiopaque filling material.

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

Claims

1. 1. A drug delivery device for deployment within a renal pelvis of a patient, the drug delivery device comprising: An elastic body, the elastic body comprising: (i) an outer tube including an elongated outer wall; (ii) an elongated, arcuate inner wall located within the outer tube, the arcuate inner wall being integrally connected to an inner surface of the outer wall along two opposing edges thereof, the outer wall and the inner wall together defining: (a) a guidewire lumen on the concave side of the inner wall; (b) an elastomeric body defining a drug reservoir lumen on opposing convex sides of the inner wall, the drug reservoir lumen being closed at opposing ends thereof; a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug; the drug delivery device includes a retrieval string extending into at least the patient's urethra, and is elastically deformable between a deployed configuration for passage of the drug delivery device via the ureter to the renal pelvis of the patient and a retained configuration configured to mitigate migration of the drug delivery device from the renal pelvis, the drug delivery device being configured such that all but the retrieval string is contained within the renal pelvis. Drug delivery devices.

2. The drug delivery device of claim 1 , wherein the drug delivery device is biased into the retained configuration when a guidewire is not inserted within the guidewire lumen.

3. The drug delivery device of claim 1 , wherein the retention feature comprises a helical portion.

4. The drug delivery device of claim 3 , wherein the retention feature further comprises a straight terminal portion extending longitudinally of the device.

5. The drug delivery device of claim 3 , wherein the helical portion comprises 2 to 10 turns.

6. The drug delivery device of claim 5 , wherein at least two of the turns are separated by an intermediate straight portion.

7. A drug delivery device according to any one of claims 1 to 6, wherein one or both ends of the elastic body are tapered.

8. 7. The drug delivery device of claim 1, wherein the outer tube comprises two different construction materials, a first material that is impermeable to the drug when the drug is in solution and a second material that is permeable to the drug when the drug is in solution, the second material being adjacent to the drug payload.

9. 9. The drug delivery device of claim 8, wherein the second material is in the form of a drug-permeable stripe extending the length of the elongated outer wall.

10. 10. The drug delivery device of claim 9, wherein the outer wall is cylindrical and the drug-permeable stripe has an arc angle of about 30 degrees to about 120 degrees of the circumference of a cross section of the outer wall.

11. The drug delivery device of claim 10, wherein the drug-permeable stripe has an arc angle of about 55° to about 120° about the circumference of the cross section of the outer wall.

12. The drug delivery device of claim 9 , wherein the first material comprises Tecoflex polyurethane.

13. The drug delivery device of claim 9 , wherein the first material further comprises a radiopaque filler.

14. The drug delivery device of claim 9 , wherein the second material comprises a tecophilic polyurethane.

15. The drug delivery device of any one of claims 1 to 6, wherein the drug reservoir lumen has a crescent cross-sectional shape.

16. The drug delivery device of any one of claims 1 to 6, wherein the guidewire lumen has a circular cross-sectional shape.

17. The drug delivery device of any one of claims 1 to 6, further comprising a retaining frame lumen and a retaining frame disposed within the retaining frame lumen, the retaining frame being an elastic wire configured to urge the drug delivery device into the retained shape.

18. The drug delivery device of any one of claims 1 to 6, wherein the retention configuration comprises a helical portion, and the drug delivery device has a length of about 5 cm to about 15 cm when in the deployed configuration.

19. The drug delivery device of claim 18, wherein the drug delivery device has a length of about 0.8 cm to about 2 cm when in the retained configuration.

20. A drug delivery device according to any preceding claim, wherein each of the opposing ends of the drug reservoir lumen is sealed by a spacer.

21. 21. The drug delivery device of claim 20, further comprising at least one intermediate spacer disposed within the drug reservoir lumen at a location between the opposing ends.

22. 22. The drug delivery device of claim 20 or 21, wherein the elastic body, the spacer, and / or the at least one intermediate spacer comprise a radiopaque filling material.

23. 2. The drug delivery device of claim 1, wherein the retrieval string has a length sufficient such that an end of the retrieval string resides within the patient's bladder when the drug delivery device is deployed within the renal pelvis.

24. The drug delivery device according to any one of claims 1 to 6, wherein the drug payload is in solid or semi-solid form.

25. 25. The drug delivery device of claim 24, wherein the drug payload is in the form of a powder or multiple tablets.

26. 25. The drug delivery device of claim 24, wherein the drug payload is in the form of a plurality of tablets having a crescent cross-sectional shape.

27. The drug delivery device of any one of claims 1 to 6, wherein the outer tube and the inner wall are formed together by a co-extrusion process.

28. The drug delivery device according to any one of claims 1 to 6, wherein the elastic body is thermally shaped to have the retained shape.

29. 1. A system for administering a drug to a patient in need of the drug, the system comprising: A drug delivery device according to any one of claims 1 to 28; 1. A guidewire deployment system for deploying the drug delivery device within the patient's renal pelvis, the guidewire deployment system comprising: (i) a guidewire configured to be operatively 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 over the guidewire from the distal end portion into the renal pelvis; The system, wherein the guidewire has a cross-sectional area sized to pass through the guidewire lumen of the drug delivery device.

30. The plunger device comprises: A plunger; A handle and a sheath extending between the plunger and the handle, the sheath transmitting a driving force applied to the handle to the plunger; 30. The system of claim 29, further comprising: an internal bore for receiving the guidewire such that the plunger device can be moved over the guidewire.

31. 31. The system of claim 30, wherein the plunger further comprises a stop configured to indicate that the drug delivery device is separated from the guidewire.

32. 1. A drug delivery device for deployment within a renal pelvis of a patient, the drug delivery device comprising: an elongated elastic body, the elongated elastic body including a guidewire lumen and a separate drug reservoir lumen; a drug payload disposed within the drug reservoir lumen, the drug payload comprising at least one drug; the drug delivery device includes a retrieval string extending into at least the patient's urethra and is elastically deformable between a deployed configuration configured for passage of the drug delivery device via the ureter to the renal pelvis of the patient and a helical retained configuration configured to mitigate migration of the drug delivery device from the renal pelvis, the drug delivery device being configured to be entirely contained within the renal pelvis except for the retrieval string. Drug delivery devices.

33. 33. The drug delivery device of claim 32, wherein the drug delivery device is biased into the retained shape when a guidewire is not inserted into the guidewire lumen, and the elastic body (i) is thermally shaped to have the retained shape, and / or (ii) further comprises 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 the retained shape.

34. The drug delivery device of claim 33, wherein the retrieval string has a length sufficient to ensure that an end of the retrieval string is present within the patient's bladder when the drug delivery device is deployed within the renal pelvis.

35. 34. The drug delivery device of claim 33, wherein the drug payload is in the form of a powder or multiple tablets.

36. 36. The drug delivery device of claim 35, wherein the elongated elastic body includes a water-permeable wall configured to allow urine to diffuse into the drug reservoir lumen and contact the drug payload.

37. 37. The drug delivery device of claim 36, wherein the elongated elastic body includes a drug-permeable wall adjacent the drug reservoir lumen, the drug-permeable wall configured to allow the drug to diffuse out of the drug delivery device in solution.

38. 38. The drug delivery device of claim 37, wherein the drug-permeable wall is in the form of a drug-permeable stripe extending the length of the elongated elastic body.

39. 38. The drug delivery device of claim 37, wherein the elongated elastic body further comprises a drug-impermeable wall adjacent the drug reservoir lumen.

40. 40. The drug delivery device of claim 39, wherein the drug-permeable wall comprises a tecophilic polyurethane and the drug-impermeable wall comprises a tecoflex polyurethane.

41. 41. The drug delivery device of claim 40, wherein the Tecoflex polyurethane is either EG-100A-B20 or EG-80A-B20.

42. A drug delivery device according to any one of claims 32 to 41, wherein the helical retention feature further comprises a straight terminal portion extending longitudinally of the drug delivery device.

43. 43. The drug delivery device of claim 42, wherein each of the opposing ends of the drug reservoir lumen is sealed by an end spacer.

44. 44. The drug delivery device of claim 43, further comprising at least one intermediate spacer disposed within the drug reservoir lumen at a location approximately midway between opposing ends of the elongated elastic body.

45. 45. The drug delivery device of claim 44, wherein the end spacers and the at least one intermediate spacer comprise a radiopaque filler material.

46. 42. The drug delivery device of any one of claims 32 to 41, wherein the drug reservoir lumen has a crescent cross-sectional shape and the drug payload comprises a powder or a plurality of crescent shaped tablets.

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