System and method for sustained release of agents in the bladder

Abstract

Embodiments include systems and methods for treating diseases of the bladder, kidneys and urinary tract. Drug products can be administered through the urethra in a compact form. Within the bladder, the products can expand or conform to a larger size which resists passage into the urethra over a desired residence period. After a treatment period, at least a portion of the products can dissolve or degrade so that individual particles are voided in the urine. Embodiments also include drug particle delivery devices and methods of intravesical administration. A delivery device can use a straw-shaped cartridge packed with rod-shaped products that are administered into the bladder of a patient by a pressure source or actuation of a piston. The distal end of the barrel can connect to a vesical sheath or a soft tip in order to plunge directly into a patient's urethra.

Description

SYSTEM AND METHOD FOR SUSTAINED RELEASE OF AGENTS IN THE BLADDER RELATED APPLICATIONS

[0001] The present application claims priority to U.S. provisional patent application No.63 / 524,229 filed June 30, 2023 and U.S. provisional patent application No. 63 / 541,493 filed September 29, 2023. The contents of these applications are incorporated herein by reference. FIELD OF THE INVENTION

[0002] The invention relates generally to the medical devices, and, more particularly, to devices and methods for intravesical administration of a pharmacologically active agent to treat or prevent a disorder of the urinary system. BACKGROUND

[0003] A urinary tract infection (“UTI”) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (i.e., cystitis) and when it affects the upper urinary tract it is known as a kidney infection (i.e., pyelonephritis). Symptoms from a lower urinary tract infection include pain with urination, frequent urination, and feeling the need to urinate despite having an empty bladder. The most common cause of UTI is Escherichia coli, though other bacteria or fungi can also be the cause. Risk factors include female anatomy, sexual intercourse, diabetes, obesity, and family history. In uncomplicated cases, UTIs are treated with a short course of antibiotics (e.g., nitrofurantoin). Nearly one in five adults develops a UTI, and many of these individuals are at risk for a recurring infection.

[0004] The prevalence of UTI risk increases with age. They are particularly common in older adults who use catheters or live in a nursing home or other full-time care facilities. Other conditions common in older adults (e.g., Alzheimer’s disease, Parkinson’s disease and diabetes) can lead to urinary retention or neurogenic bladder which increases the risk of UTIs. More than 10 percent of women over age 65 reportPATENT WM1-006WO having a UTI within the past year. That number increases to almost 30 percent in women over 85. Men also tend to experience more UTIs as they age. According to a recent study, more than one-third of all infections in people in nursing homes are UTIs. In many cases, chronic urinary tract infections can require continuous medication, which leads to progressive levels of resistance to antibiotics and ultimately to kidney problems.

[0005] If not treated timely or properly, an infection from a UTI can spread. A UTI can ultimately lead to a bladder infection. This presents the risk of the infection spreading to the kidney via the ureter which can lead to more serious consequences including kidney failure and sepsis (i.e., urosepsis). This occurs frequently in elderly patients. In many cases, elderly patients do not present typical signs of infection until they’ve become septic at which point hospitalization is needed.

[0006] UTIs and complications caused by UTIs are also expensive to treat as they often require hospitalization. In many cases, a UTI is only treated after the infection has developed and becomes symptomatic. Current treatments aimed at preventing the formation of UTIs require continuous prophylactic oral medication that have side-effects common with long–term medication. Further, long term consumption of antibiotics can lead to drug resistant bacteria. In many cases, UTIs reduce the quality of life, in particular when kidney damage leads to kidney failure requiring dialysis or implantation of a donor kidney.

[0007] Conventionally, UTIs are treated with oral antibiotics. A high dose of antibiotics is needed so that an effective amount reaches the urinary tract. With systemic delivery of drugs to treat UTIs, the volume of distribution of the therapy is equal to the total amount of urine that enters the bladder. Therefore, the therapy is voided with each emptying of the bladder and requires constant replenishment. In other cases, the drug target can be limited (i.e., the bladder wall) but cannot practically be reached without raising the concentration of the drug in the urine to the desired therapeutic concentration.PATENT WM1-006WO

[0008] Intravesical therapy refers to a treatment wherein a therapeutic is put directly into the bladder (e.g., through a catheter or similar device) rather than being given orally or injected into a vein. Intravesical therapy is an attractive option for treating UTIs because it allows local delivery of a medicament while minimizing side effects. Intravesical administration of pharmaceutically active agents can also be beneficial for treating other diseases of the bladder / urinary tract such as interstitial cystitis, overactive bladder and cancers.

[0009] Efforts at treating UTIs via intravesical therapy have had limited success. Antibiotics injected into the bladder are generally voided before they can induce a significant therapeutic effect. Implantable devices require surgical procedures for their implantation and removal. Recent improvements include implantable devices that gradually dissolve or degrade as an active agent is released. For example, WO2022216287A1 describes a controlled release pharmaceutical formulation that is administered into the bladder of a patient. The formulation includes particles that are buoyant in urine and can remain in a patient's bladder for a course of antibiotic treatment. However, the formulation is limited to small particles that can be administered through the urethra. Moreover, the particles are prone to being expelled prematurely during urination. The particles are also administered using a conventional syringe which can be problematic.

[0010] Conventional syringes are designed for injecting fluid and can easily become blocked or clogged. Further, they can cause and exacerbate patient discomfort. Even relatively large catheters may be ineffective in delivering solid drug products to the bladder. Therefore, an unmet need exists for a device that delivers solid drug products (e.g., spheres, rods, or other shapes) reliably through the urethra without damaging the products or causing discomfort to the patient. There is also a need for small particles that can expand within the bladder so that they are not prematurely expelled in the urine.

[0011] The compositions and methods described herein satisfy these objectivesPATENT WM1-006WO and can especially benefit patients at risk of a UTI such as the elderly or incapacitated. The system and methods described herein can also be used to treat other ailments of the bladder / urethra / kidneys such as, for example, cancer, overactive bladder and cystitis. SUMMARY OF THE INVENTION

[0012] The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this brief summary. The inventions described and claimed herein are not limited to, or by, the features or embodiments identified in this summary, which is included for purposes of illustration only and not restriction.

[0013] Embodiments of the invention include devices and methods for intravesical delivery of therapeutic agents into the bladder. A plurality of buoyant (or semi-buoyant) drug products can be temporarily implanted inside the bladder and float within fluid inside the bladder. The drug products can release a therapeutic agent or drug within the bladder by direct absorption, passive or active dissolution, mechanical fracture or other means.

[0014] In aspects, the drug products release multiple active agents (e.g., to treat multiple ailments or to target drug-resistant bacteria). In aspects the drug products are homogenous with one another. In aspects, the drug products are not homogenous (e.g., they contain different excipients, have different physical qualities, different active agents and / or different sizes / shapes).

[0015] In aspects, the drug products are passively released (i.e., without requiring a removal procedure) from the bladder after a retention period.

[0016] In aspects, the drug products include a linker material that dissolves and rods detach be either (a) chemical adhesion or (b) degradation. Chemical adhesionPATENT WM1-006WO refers to adhesion strength weakening over time to releases the rods. For example, 2- octyl cyanoacrylates are highly adhesive materials that lose their strength over time in moisture. Degradation can entail hydrolysis of ester linkages in PLGA (Poly(lactic-co- glycolic acid) family of copolymers. The rate of hydrolysis can vary based on molecular weight (MW) of polymer chains, ratio of lactic to glycolic, and ester or acid endcap, etc.

[0017] In aspects, the linker material swells and pushes out the rods. The linker materials can swell (either due to heat deformation or water absorption) and forces the rods out of the sockets. Poly(methyl methacrylate), poly(acrylic acid), Carbopol, hydroxypropyl methyl cellulose are types of materials that will swell to 10x size and push out the rod. The rate of swelling can be controlled via type of hydrophilic swellable polymers, their MW, salt or acetic acid blend, blend of hydrophilic swellable polymers with non-swellable hydrophobic materials, and enteric coatings.

[0018] Accordingly, embodiments include systems and methods of treating an ailment such as a urinary system disorder. In aspects, the systems and methods include a pharmaceutical formulation for intravesical administration of an active agent. The formulation can include particles, each having an excipient portion and an active agent. The formulation can be administered by transurethral delivery using a drug delivery device as described herein.

[0019] In aspects, particles can be attached to one another (i.e., each package includes a first particle joined to a second particle by a tether). The particles can be administered into the urinary bladder of the subject in a stacked arrangement (i.e., with a small diameter). An active agent can be released during a retention phase. Thereafter, the tethers can degrade so that individual particles are separated from one another. The individual particles can be excreted during urination.

[0020] In aspects, two particles can be attached or joined to one another. The particles can be administered into the urinary bladder of the subject in a stacked arrangement. Thereafter, the particles can transform into a second configuration forPATENT WM1-006WO retainment. An active agent can be released during this retention phase. Thereafter, at least a portion of the particles can degrade (e.g., the cylinders, cap, linker or hinge) so that individual particles are separated from one another. The individual particles can be excreted during urination.

[0021] In aspects, particles have a cross-sectional diameter less than or equal to 4 mm for insertion, undergo a conformational change post bladder insertion to a cross- sectional diameter of 10 mm or more for retention, and then reduce to a cross-sectional diameter less than or equal to 4 mm for elimination.

[0022] In aspects, particles can be attached to one another in a first confirmation that is conducive to transurethral administration. After the particles enter the urinary bladder of the subject, they can expand to a second confirmation that is larger and resistant to excretion. During a retention phase, an active agent can be released from the particles into the bladder. Thereafter, the particles can gradually separate from one another so that they are excreted during urination.

[0023] Also disclosed herein are insertable drug delivery devices including catheter assemblies and methods that allow intravesical administration or medicaments, drug products, gels, devices, etc. Accordingly, embodiments include drug delivery devices for administering drug products through the urethra into the bladder. The devices can include (a) an insertion tip, (b) a body, (c) a pressure source and (d) a loading funnel. In aspects, an intravesical formulation passes from the loading funnel through the body and out of the insertion tip into a bladder.

[0024] Embodiments also include methods of delivering a substance or formulation into the bladder of a patient. The methods can include steps of (a) inserting a distal end of a lumen device through a patient's urethra and into the patient's bladder, wherein an opposing proximal end of the lumen device remains outside of the patient; (b) securing the distal end of the lumen device; (c) driving a plurality of particles out of a lumen in the distal end of the lumen device and into the bladder and out of the lumen; (d) removingPATENT WM1-006WO the lumen device from the patient's urethra; and (e) allowing the particles to release a drug from the drug delivery device into the patient's bladder. In aspects, the patient suffers from an ailment of the bladder, urinary tract and / or kidney. The method can also include treating the patient for the ailment. In aspects, the ailment is a urinary tract infection (UTI), bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis. The method can also include a step of adjusting the number of particles that are administered based on a desired dose of active agent.

[0025] Additional embodiments include methods of treating or preventing urinary tract infection (UTI) by administering formulations and drug products are described herein. In aspects, the methods are used with patients who are at risk of UTI and / or have a history of UTIs.

[0026] In aspects, the methods include a step of diagnostic imaging. In aspects, the methods include a step of observing a color change in excreted urine over at least a portion of the period of the retention phase (i.e., via addition of a color indicator to the drug product).

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG.1 is a graph showing the percentage of buoyant particles for three types (beta, beta prime and alpha) over the course of five days.

[0029] FIG.2A depicts a cylindrically shaped particle according to embodiments.

[0030] FIG.2B depicts a horseshoe shaped particle according to embodiments.PATENT WM1-006WO

[0031] FIG.2C is an image of a horseshoe shaped particle.

[0032] FIG.2D depicts a bowstring shaped particle according to embodiments.

[0033] FIG.2E is an image of a bowstring shaped particle.

[0034] FIG.2F depicts an elbow shaped particle according to embodiments.

[0035] FIG.2G is an image of an elbow shaped particle.

[0036] FIG.3A depicts the geometry of a particle in three configurations (i.e., small for insertion, large for retention and small for elimination).

[0037] FIG.3B depicts components of a particle along with its geometry including the angle between individual drug products.

[0038] FIG.3C depicts the particle of FIG.3B in a retention configuration and an elimination configuration.

[0039] FIG.3D depicts a particle in a retention configuration and three components (i.e., a linker, a hinge and an API embedded cylindrical rod).

[0040] FIG.3E is a flowchart that depicts a particle in three phases (i.e., implantation, drug delivery and disassembly for elimination).

[0041] FIG.3F depicts different mechanisms of particle separation according to embodiments.

[0042] FIG.3G depicts an embodiment in which the cylinders (or a portion) swell upon exposure to liquid to release the rods.PATENT WM1-006WO

[0043] FIG.3H depicts an embodiment in which the outer layer of rods includes a layer that reduces water movement / absorption.

[0044] FIG.3I shows the results of a comparison of different coatings (i.e., percent of rods retained over time).

[0045] FIG.3J depicts approaches toward adjusting the retention time of hinged rods including using a dissolving hinge, a push out rod, a weaken hinge, a release rod and a disassemble hinge.

[0046] FIG.4A depicts a pair of particles joined by a tether along with three configurations: (a) stacked for administration, (b) tethered for retainment in the bladder and (c) separated for voiding in the urine.

[0047] FIG.4B depicts a pair of particles joined by a linkage along with three configurations: (a) stacked for administration, (b) linked for retainment in the bladder and (c) separated for voiding in the urine.

[0048] FIG.4C depicts a pair of particles joined by a linkage along with three configurations: (a) stacked for administration, (b) linked for retainment in the bladder and (c) degraded for voiding in the urine.

[0049] FIG.5A is an image of particles (e.g., two cylinders) joined by a tether.

[0050] FIG.5B is an image of particles joined by a hinge connection.

[0051] FIG.5C depicts an embodiment in which a drug product includes filamentous extensions (e.g., sutures) that promote retention of a drug product in the bladder.PATENT WM1-006WO

[0052] FIG.6 depicts three confirmational arrangements of a plurality of particles: (a) stacked for administration, (b) joined for retention in the bladder and (c) separated for voiding in the urine.

[0053] FIG.7A depicts an embodiment in which multiple drug products (i.e., cylinders) are joined to form a circular configuration with a large size for retention in the bladder.

[0054] FIG.7B depicts an embodiment in which multiple drug products (i.e., spheres) are joined to form a circular configuration with a large size for retention in the bladder.

[0055] FIG.7C depicts a heterogenous grouping of drug products.

[0056] FIG.8 depicts a side-view of a handheld delivery device according to an embodiment of the invention.

[0057] FIG.9 depicts an overhead view of a depth-locking soft catheter.

[0058] FIG.10 depicts a side-view of a static sheath according to an embodiment of the invention.

[0059] FIG.11A depicts a static sheath with an internal flexible sheath, further equipped with a lock ring.

[0060] FIG.11B depicts an alternative design of a delivery apparatus of cotton or similar material that is inserted into the urethra (i.e., “tampon-like).

[0061] FIG.12 depicts a catheter with grapple members extending from the distal end.PATENT WM1-006WO

[0062] FIG.13A depicts a first-person view of the chamber of a handheld delivery apparatus according to an embodiment of the invention.

[0063] FIG.13B depicts a top-down view of the chamber of a handheld delivery apparatus.

[0064] FIG.13C depicts a side-view of the chamber of a handheld delivery apparatus.

[0065] FIG.14 depicts the intravesical delivery of particles through the lumen of a device of the present invention.

[0066] FIG.15 depicts a trocar inserted into the bladder of a patient.

[0067] FIG. 16A depicts a magazine that is pre-loaded with particles.

[0068] FIG.16B depicts an obturator for use with a magazine that is pre-loaded with particles.

[0069] FIG. 17 depicts an obturator that is pre-loaded with particles. LIST OF REFERENCE NUMBERS 5 Delivery Device 10 Body of Delivery Device 15 Barrel 20 Insertion Tip 25 Funnel Region 27 Drug Product (e.g., capsules or cylinders) 30 Pressure Source 40 Trigger 50 Depth-locking Soft Catheter 55 Distal End (of Depth-locking Soft Catheter) 60 Proximal End (of Depth-locking Soft Catheter) 65 Fender Washer (spinnable)PATENT WM1-006WO 70 Convex Locking Nut 75 Concave Locking Nut 80 Multi-Lumen Static Sheath 85 Inner Tubular Member 90 Outer Tubular Member 95 Distal End (of Multi-Lumen Static Sheath) 100 Outer Lock-Ring 105 Soft Grapple Member 110 Drug Product Delivery Chamber 112 Trocar 115 Threaded Piston and Plunger 120 Loading Pin 125 Unloading Pin 130 Loaded Straw Bay 135 Empty Straw Bay 140 Screw Piston 145 Magazine Spring 155 One-way Valve 160 Magazine Fairing 165 Obturator Fairing 170 Thumb Catches 175 Tether 180 Filamentous Extension 185 Cap 190 Connection 195 Bridge DEFINITIONS

[0070] Reference in this specification to "one embodiment / aspect" or "an embodiment / aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the disclosure. The use of the phrase "in one embodiment / aspect" or "in another embodiment / aspect" in various places in the specification are not necessarily all referring to the same embodiment / aspect, nor are separate or alternative embodiments / aspects mutually exclusive of other embodiments / aspects. Moreover, various features are described which may be exhibited by some embodiments / aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments / aspectsPATENT WM1-006WO but not other embodiments / aspects. Embodiment and aspect can be in certain instances be used interchangeably.

[0071] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.

[0072] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.

[0073] Without intent to further limit the scope of the disclosure, examples of instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the case of conflict, the present document, including definitions, will control.

[0074] The term “over-active bladder” or “OAB” refers to a group of urinary symptoms (rather than a disease). The most common symptom is a sudden, uncontrolled need or urge to urinate. Some people will leak urine when they feel thisPATENT WM1-006WO urge. Another symptom is the need to pass urine many times during the day and night. OAB can be described as a constant urge to urgently urinate. Leaking urine is called "incontinence.”

[0075] The term “stress urinary incontinence” or “SUI” refers to another common bladder problem. Subjects with SUI leak urine while sneezing, laughing or doing other physical activities.

[0076] The term “interstitial cystitis,” “IC” or “bladder pain syndrome” refers to a chronic, or long-lasting, condition that causes painful urinary symptoms. Symptoms of IC can be different from person to person. For example, some people feel mild discomfort, pressure, or tenderness in the pelvic area. Others may have intense pain in the bladder or struggle with urinary urgency, the sudden need to urinate, or frequency, the need to urinate more often. Health care professionals diagnose IC by ruling out other conditions with similar symptoms.

[0077] The term “immunomodulator” or “immunomodulating agent” refers to a drug that can support the immune function by modifying, in a beneficial way, the immune system’s response to a threat. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

[0078] The term “chronic inflammatory disease” refers to a disease that causes the body to overreact and, in some cases, attack itself. For example, in multiple sclerosis, the body's immune system attacks nerve coatings. Chronic inflammation is not a specific disease but a mechanistic process. The diseases associated with chronic inflammation are multiple and include CVD, diabetes, malignancy, auto-immune disease, chronic hepatic and renal disease, etc.

[0079] The term “catheter” refers to a flexible tube that can be inserted through several points of entry and into a patient or subject’s body cavity, duct, vessel, brain,PATENT WM1-006WO skin or adipose tissue. Catheters perform several functions including allowing drainage of body fluids, administration of substances and materials into a patient or subject and enabling access by surgical instruments to a patient or subject.

[0080] The term “Foley catheter” refers to a flexible tube that a clinician passes through the urethra and into the bladder to drain urine.

[0081] An “indwelling catheter” is a catheter typically retained in a fixed position by means of an inflated balloon attached to the outer body of the catheter.

[0082] A “vesical sheath” refers to a hollow tube which functions as a conduit for introducing surgical instruments, substances, and other media to the urinary system of a subject or patient. As used herein, the sheath refers to the middle section of the device between the distal balloon tip and the proximal lock ring assembly. The main length of the primary lumen is in the middle sheath portion, but the primary lumen is open from end to end for delivery of product through the entire device. The sheath should have low friction on the outside and in the primary lumen so that it can be installed with minimal distress to the patient and so that the product can slide through it easily. Materials can be, for example, silicone coated fibers, spring, or struts (for a combination of strength and flexibility in a thin material), coating with PTFE for low friction, or metal for strength in a thin material.

[0083] The term “active agent,” “active ingredient” or “active pharmaceutical ingredient” or “API” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of thePATENT WM1-006WO composition is attributed.

[0084] The term “drug product” refers to any substance, device, particle or product suitable for delivery into a subject or patient for the treatment of a disease, condition, malady or disorder, and may further include excipients, adjuvants, carriers, placebos, powders, foams, gels, liquids, capsules, coatings, time-release mechanisms, delayed- release mechanisms, robotic medicaments, computer-programmed drug products, products driven or guided by artificial intelligence or machine learning, transmitters, or any substance, device or product known in the art that is suitable for delivery to a patient or subject.

[0085] The term "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition as provided herein and not cause any substantial undesirable biological effects or interact in a deleterious manner with any of the other components of the composition. When the term "pharmaceutically acceptable" is used to refer to a solid or semi-solid carrier, liquid vehicle, or other excipient, i.e., to any inactive ingredient herein, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing and / or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration and designated "Generally Regarded as Safe" ("GRAS").

[0086] The term “controlled-release” or “CR” refers to a medication, carrier or other platform that releases an active ingredient at a specific rate to keep constant medication levels in a patient’s body for a specific time period. This allows medication levels to remain at an effective level for a duration of time. Unlike sustained release (SR) forms, CR medications can precisely control the amount of medication in your body at a given time, not just its release. Administration of a controlled-release active agent-containing formulation or fraction thereof does not result in the immediate release of 100% of the active agent. The term is used interchangeably with "nonimmediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA:PATENT WM1-006WO Mack Publishing Company, 1995). In general, the term "controlled release" as used herein includes sustained release, modified release, pulsatile release, and delayed release formulations, as well as formulations that combine two or more types of release profiles, such as immediate release of a bolus dose followed by pulsatile release or sustained release thereafter. "Sustained release” (synonymous with "extended release”) refers to a formulation that provides for gradual release of an active agent over an extended period of time, and that preferably, although not necessarily, results in substantially constant levels of an agent in a volume of distribution (e.g., urine, bladder, total body water, etc.), and is normally referred to as "zero order" release. "Controlled release” also includes "delayed release," indicating a formulation that, following administration to a patient, provides for a measurable time delay before the active agent is released from the formulation into the patient's body. Controlled release dosage forms herein, however, are generally of the sustained release dosage type.

[0087] The term “particles" or "microparticles" refers to a carrier or controlled release carrier described herein that is formulated so as to contain a pharmacologically active agent. The particles can be substantially spherical, cylindrical or rod-shaped or have some other shape. Particle size is given as the mean particle diameter in a population of particles. The particle size distribution in a population of particles is relatively narrow (i.e., the specified mean particle size is associated with a fairly low standard of deviation, typically less than 30%), for example, less than 20% or less than 15%. Particles within a formulation may or may not have substantially the same shape and size. The terms “particles” and “microparticles” may be used interchangeably with the term “drug product” and is also a form of drug product with the term drug product being utilized as an umbrella term that includes both particles and microparticles.

[0088] The terms “intravesical delivery particle grouping,” “solid drug product grouping,” “drug product capsule grouping,” “drug product carpule grouping,” “delivery particle grouping,” “coupled drug product grouping,” “connected drug product grouping,” “drug product grouping,” “hinged drug product grouping” or “particle grouping” are interchangeable and refer to a connection of separate drug particles or drug products orPATENT WM1-006WO structures via a tether or other equivalent connective structure.

[0089] The term “intravesical administration” or “intravesical therapy” refers to a treatment wherein a therapeutic is put directly into the bladder (i.e., through a catheter) rather than being given orally or injected into a vein. Similarly, an intravesical drug is directly administered into the urinary bladder via a urethral catheter.

[0090] The term “enteric coating” refers to a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment. As used herein, a cylinder pellet made of a swellable material can be coated in a slow- degrading adhesive material. This can be placed in the socket that joins the cylinders. In this design, the adhesive coating helps keep the cylinders together while the drug payload is delivered. Thereafter, as the coating degraded / dissolves over time, water can diffuse through accessing the swellable material cause swelling of the material (e.g., to 10x size) which pushes out the rod. In aspects, the rate of swelling is adjusted by changing the rate that water diffuses in the socket by modifying the silicone hinge. This includes, for example, 1) changing length of the hinge and its thickness, 2) slits on the side, 3) hole(s) of varying diameter on the caps of the hinge and / or combinations.

[0091] The term “mucoadhesion” refers to the adhesion between two materials, one of which is a mucosal surface. Mucoadhesive drug delivery systems prolong the residence time of the dosage form at the site of application or absorption. Mucoadhesive drug delivery systems interact with the mucus layer covering the mucosal epithelial surface, and mucin molecules and increase the residence time of the dosage form at the site of absorption.

[0092] The term "spherical" herein refers to a precisely spherical particle or, more generally, to a particle or object with a rounded surface that may or may not be substantially spherical.

[0093] The terms "mean diameter," "mean longest dimension," and "particle size"PATENT WM1-006WO are used interchangeably herein. As used herein, the particle size is given by mean diameter for spherical particles and mean longest dimension for non-spherical particles. It should be noted that the term "mean diameter" technically corresponds to substantially spherical particles; however, other particle shapes can also be incorporated into the particulate formulation, providing that the particles have at least one dimension (i.e., at least one mean dimension, in the overall population of particles) greater than 2.0 mm, e.g., in the range of 2.0 mm to about 12.0 mm, e.g., about 2.5 mm to about 6.5 mm, e.g., about 2.5 mm to about 6.0 mm, about 2.5 mm to about 5.5 mm, about 2.5 mm to 5.0 mm, etc., as before. An elongated particle, e.g., a cylindrical or rod-shaped particle, could, for example, have a length of about 9.0 mm and yet be narrow enough to pass through a urethral catheter and the urethral opening.

[0094] The terms "effective amount" and "therapeutically effective amount" of an active agent, an active agent combination, or a pharmaceutical formulation refer to an amount or concentration that is nontoxic but sufficient for producing a desired result. The exact amount required will vary from subject to subject, depending on factors such as the age, weight and general condition of the subject, the particular condition being treated, the severity of the condition, the specific active agent, and the judgment of the clinician.

[0095] The term "urinary system" is used in the conventional sense to refer to the lower urinary tract as well as the upper urinary tract, and thus includes the bladder, urethra, kidneys, and ureters.

[0096] The term "disorder" refers to a physiological condition of clinical relevance and thus includes symptomatic or asymptomatic conditions regardless of etiology. Disorders thus include adverse conditions resulting from disease or injury. The disorders addressed with the present invention are disorders of the urinary system.

[0097] A "drug delivery time period" refers to a period of time during which a pharmacologically active agent is released from a formulation or fraction thereof,PATENT WM1-006WO generally an extended time period.

[0098] The term “subject” or "patient" refers to any single animal, more preferably a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. Most preferably, the patient herein is a human.

[0099] The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0100] The term “pharmaceutically acceptable composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0101] The term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. arresting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease.

[0102] The term “specific gravity” refers to the ratio of a material's density with that of water at 4 °C. It is therefore a relative quantity with no units. The specific gravity of urine refers to the electrolytes and urine osmolality. The normal range for urine specific gravity is 1.005 to 1.030. Specific gravity, in the context of clinical pathology, is aPATENT WM1-006WO urinalysis parameter commonly used in the evaluation of kidney function and can aid in the diagnosis of various renal diseases.

[0103] The term “hygroscopic material” refers to a substance that absorbs water and expands. Many engineering polymers are hygroscopic, including nylon, ABS, polycarbonate, cellulose, carboxymethyl cellulose, and poly(methyl methacrylate) (PMMA, plexiglas, perspex).

[0104] The term “Amikacin” refers to an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections (UTIs). It is also used for the treatment of multidrug-resistant tuberculosis. It is typically used by injection into a vein using an IV or into a muscle.

[0105] The term “excipient” refers to pharmacologically inert ingredients added intentionally to a drug product for various functional roles, such as to enhance dosage form volume or size, disintegration of solid dosage forms, binding of particulates, lubrication during processing, taste masking or modifying drug release.

[0106] The term “zero-order” refers to a delivery system that releases a drug at a constant rate (i.e., the release rate is independent of the concentration or the amount of drug that remains in the delivery system). Drug release kinetics is said to be zero-order kinetics when a constant amount of drug is eliminated per unit time but the rate is independent of the concentration of the drug. Zero-order drug delivery systems (DDS) can overcome the issues faced by immediate-release and first-order systems by releasing the drug at a constant rate, thereby maintaining drug concentrations within the therapeutic window for an extended period.

[0107] The term “first-order” refers to a drug release rate that is directly proportional to the concentration gradient and is a function of the amount of drug remaining in the dosage form. Similarly, “sustained release” refers to the slow release of a drug over anPATENT WM1-006WO extended period after administration of a single dose.

[0108] The terms “therapeutic index,” “TI” or “therapeutic ratio” refer to a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. A therapeutic window or safety window refers to the range of doses that optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side effects or toxicity. TI is calculated from the ratio of the dose of a drug that causes adverse effects at an incidence / severity not compatible with the targeted indication (e.g., toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g., efficacious dose in 50% of subjects, ED50).

[0109] With respect to “proximal,” a “proximal portion” or a “proximal-end portion” of, for example, a catheter disclosed herein includes a portion of the catheter intended to be near a clinician when the catheter is used on a patient. Likewise, a “proximal length” of, for example, the catheter includes a length of the catheter intended to be near the clinician when the catheter is used on the patient. A “proximal end” of, for example, the catheter includes an end of the catheter intended to be near the clinician when the catheter is used on the patient. The proximal portion, the proximal-end portion, or the proximal length of the catheter can include the proximal end of the catheter; however, the proximal portion, the proximal-end portion, or the proximal length of the catheter need not include the proximal end of the catheter. That is, unless context suggests otherwise, the proximal portion, the proximal-end portion, or the proximal length of the catheter is not a terminal portion or terminal length of the catheter.

[0110] With respect to “distal,” a “distal portion” or a “distal-end portion” of, for example, a catheter disclosed herein includes a portion of the catheter intended to be near or in a patient when the catheter is used on the patient. Likewise, a “distal length” of, for example, the catheter includes a length of the catheter intended to be near or in the patient when the catheter is used on the patient. A “distal end” of, for example, thePATENT WM1-006WO catheter includes an end of the catheter intended to be near or in the patient when the catheter is used on the patient. The distal portion, the distal-end portion, or the distal length of the catheter can include the distal end of the catheter; however, the distal portion, the distal-end portion, or the distal length of the catheter need not include the distal end of the catheter. That is, unless context suggests otherwise, the distal portion, the distal-end portion, or the distal length of the catheter is not a terminal portion or terminal length of the catheter.

[0111] The term “pain” refers to a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." The terms “pain” and “discomfort” can be used interchangeably. The visual analogue scale (VAS) and numeric rating scale (NRS) are most commonly used to assess the present intensity of acute pain.

[0112] The term “trocar” refers to a medical or veterinary device used in minimally invasive surgery, typically made up of an awl (which may be a metal or plastic with a pointed or tapered tip), a cannula (essentially a rigid hollow tube) and often a seal, and some trocars also include a valve mechanism to allow for insufflation. Trocars are designed for placement through the chest and abdominal walls during thoracoscopic and laparoscopic surgery, and each trocar functions as a portal for the subsequent insertion of other endoscopic instruments such as grasper, scissors, stapler, electrocautery, suction tip, etc. — hence the more commonly used colloquial jargon "port." Trocars also allow passive evacuation of excess gas or fluid from organs within the body.

[0113] The term “obturator” or “obturator rod” refers to a thin, rigid (and sometimes curved) rod that passes through a hollow passage or lumen to aid in the insertion of medical devices and other medical implements within a patient or subject.

[0114] The term "substantially" indicates the possibility of slight deviation from aPATENT WM1-006WO recited chemical or physical property and allows for a difference of at most about 20%, or at most about 10%, or at most about 5%, between an actual chemical or physical property and the recited chemical or physical property. The term "substantially homogeneous," for example, refers to a material in the form of a mixture of two or more components in which the material is substantially uniform throughout, with any two discrete regions within the material differing by at most about 20%, or at most about 10%, or at most about 5%, with respect to a chemical or physical property of the material, such as the presence or absence of a component, the concentration of a component, the degree of hydrophilicity or lipophilicity, density, crystallinity, or the like. Similarly, the term "approximately" or "about" in any context is intended to connote a possible variation of at most about 20%. Generally, the term connotes a possible variation of at most about 10%, or at most about 5%.

[0115] Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof. DETAILED DESCRIPTION

[0116] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology as claimed. Additional features and advantages of the subject technology are set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and claims hereof.

[0117] Embodiments include drug delivery devices that can be implanted into the bladder for a retention period while a drug is released. A successful bladder implantPATENT WM1-006WO must securely retain itself within the bladder to deliver its active pharmaceutical ingredient (API) effectively throughout for the intended duration. To prevent unintentional removal during normal urinary voiding, the implant can be designed with an oversized cross-sectional area or a shape that does not allow it to pass through the urethra.

[0118] It is important that the drug delivery device remains in the bladder only as long as it is therapeutically beneficial. Conventional approaches include physically removing the device after a retention period. Active Removal can entail responsive disassembly. The implant can be designed to disassemble into smaller parts upon a specific trigger to respond to specific stimuli, such temperature, pH, salts, and enzymes. Alternatively, a procedure-based removal can be performed by a medical professional. For example, the device can be physically retrieved or disintegrated via a cystoscopy procedure. Applicants described a third approach herein that entails passive removal. The implant and / or its parts are designed to degrade or dissolve gradually, eventually passing naturally with urine flow after its therapeutic window has closed.

[0119] Embodiments of the invention include devices, systems and methods for administering solid drug products for treating ailments related to the urinary system. When administered to the bladder, “intravesical particles” or “drug products” can deliver drugs locally to the bladder / urethra. This avoids the need for oral medication and systemic administration. Low doses of antibiotics are effective and consequently there are fewer side effects. An improved therapeutic window is also possible with controlled drug release. As described below, a formulation that includes active-agent-containing particles can be administered to a subject via the intravesical route (i.e., through the urethra or via a bladder injection) using devices described herein.PATENT WM1-006WO

[0120] Embodiments also include methods of treatment that include administering a drug product into the bladder of a subject. The methods can include intravesical administration of particles using a drug delivery device described herein. Thereafter, the particles can release a therapeutic agent (or multiple agents) into the bladder for a desired course of treatment. The methods are useful for treating ailments such as infections (e.g., UTI), interstitial cystitis, overactive bladder syndrome, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis.

[0121] The shape and form of drug products of the invention can include solid drug products (e.g., particles, spheres, rods, cartridges, cylinders, tampons, straw-shaped drug products, drug products with patterned or irregular cross-sections etc.), fluidic drug products (e.g., foams, gels, coatings) or powdered or lyophilized drug products which are contained within capsules, cartridges, pellets, tablets, or any suitable encapsulation. The shape or form of drug products for use with the devices of the invention can further include connected forms, connected shapes, coupled forms and coupled shapes.

[0122] Examples of coupled and connected forms and coupled and connected shapes are shown in the figures and can include multiple drug products or structures that are connected (e.g., by a tether, suture or other linkage). The drug products can include one or more active agents (i.e., pharmaceutically active portions) applied as coatings on or along the particles and / or within the particles. In aspects, the drug products (or portions thereof) degrade or dissolve in the bladder of a patient.

[0123] The drug products described herein can be administered directly into the bladder through the urethra (i.e., transurethral administration). In aspects, the drug products are retained in the bladder for an intended duration of time (i.e., a retention period). During the retention period, one or more active agents can be released into the bladder and urinary system. After the retention period, the products can be expelled from the bladder by urination (i.e., elimination phase). As can be appreciated, the size of the particles and diameter of the urethra are relevant to each of these phases.PATENT WM1-006WO

[0124] Though there is variation among humans, the urethra has a normal cross- sectional diameter of about 6 mm with a maximum diameter of about 10 mm. Applicants have demonstrated that a 4 mm object (in length) can pass the urethra with minimal irritation. Whereas objects of 5 mm or greater typically cause discomfort and / or complications when expelled. Therefore, Applicants propose that the optimum cross- sectional diameter of an object introduced into the bladder through the urethra is less than or equal to 4 mm. In aspects, the objects are cylindrically shaped with a diameter of about 4 mm (as depicted in FIG.3A). The length of the objects can be, for example, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, about 20 mm or longer.

[0125] FIG.2A depicts the structure of an individual cylinder-shaped particle showing its length (L) and diameter (D). From human experiments, Applicants have demonstrated that a 4 mm cross-sectional object (D) is not retained in the bladder. Rather, it is voided in the urine with a short (or negligible) retention phase. A 5 mm object can have a longer retention period in the bladder but is also expelled. Reviewing objects in the bladder that are not easily expelled indicates a 10 mm cross-sectional diameter cutoff for retention. Though drug products of this size have a long retention phase, they are not easily administered and must be removed surgically or significantly degraded within the bladder.

[0126] It is also worth considering that objects in the bladder are rotated into their minimum cross-sectional diameter by the mechanics of voiding when there is a gradient of flow velocity towards the bladder outlet (i.e., urethra). This means that taking an object that has a cross-sectional diameter (D) of 4 mm and increasing its length (L) (e.g., to 10 mm, 20 mm or 30 mm) has minimal effect on its rate of retention. Because of fluid dynamics, the urethra “sees” it is a 4 mm object during the voiding phase. Hence, drug products of 4 mm diameter with lengths of 10 mm have similar properties to drug products with longer lengths (e.g., 4 mm x 30 mm).PATENT WM1-006WO

[0127] Accordingly, embodiments include drug products of different shapes that resist premature voiding from the bladder. FIG.2B depicts a “horseshoe” shaped particle. FIG.2C depicts a “bowstring” shaped particle according to embodiments. An image is shown in FIG.2C. In other aspects, multiple drug products are joined to one another. The drug products can be joined with an absorbable suture (e.g., a suture joining bowstring or a suture joining hinge). In aspects, the absorbable suture can dissolve to release the individual drug products from one another. FIG.2D depicts a bowstring particle. An image is shown in FIG.2E. A greater angle (i.e., about 90°) can increase the relative size and retention of the drug product. FIG.2F depicts an elbow- shaped particle. An image is shown in FIG.2G.

[0128] Applicants further discovered that drug products can be joined with filamentous structures (e.g., sutures) that prevent premature voiding of the drug product. The filamentous structures can degrade after a desired retention period at which time the drug products are excreted in the urine. Accordingly, embodiments include a drug-releasing rod with three or more filamentous extensions (e.g., sutures) protruding from the main body as shown in FIG.5C. In aspects, each drug product has three filaments that are 120 degrees from each other and at least 8 mm in length. In aspects, rugae (i.e., folds in the bladder wall) impede excretion of the drug products.

[0129] The filamentous structures can be collapsible so that the drug products are easily inserted through the urethra and expand upon entry into the patient’s bladder. The expansion of the filamentous structures allows the drug product to remain within the bladder through the course of a treatment. In aspects, the filamentous structures can be bioabsorbable and dissolve after a predetermined time period or a predetermined number of voiding cycles. Confirmational Changing Drug Products

[0130] Applicants describe herein drug products that are easily administered (i.e., through the urethra), retained in the bladder and subsequently excreted when the bladder is voided. In embodiments, the drug products undergo one or morePATENT WM1-006WO confirmational changes. FIG.3A depicts a drug product that is relatively small for insertion, larger for retention and small again for elimination. This allows the products to be administered when small and expand so that they are retained in the bladder for a desired period of time (i.e., a retention period). In aspects, particles have a cross- sectional diameter less than or equal to 4 mm for insertion, undergo a conformational change post bladder insertion to a cross-sectional diameter of 10 mm or more for retention, and then reduce to a cross-sectional diameter less than or equal to 4 mm for elimination.

[0131] In aspects, the first confirmational change (i.e., from 4 mm to 10 mm) occurs after insertion and before the first voiding event (i.e., the first urination). In aspects, the second confirmational change (i.e., from 10 mm to 4 mm) occurs after the course of treatment or gradually during the course of treatment. This allows the drug products to remain in the larger confirmation for the term of a drug treatment (i.e., during administration of an active agent). As can be appreciated, the drug products can include materials known to expand when exposed to a liquid (i.e., hygroscopic materials).

[0132] In aspects, the conformational change (post-insertion) occurs mechanically through a bend or articulation of the object as shown in FIG.3A. In other aspects, the confirmational change occurs chemically through expansion or swelling, or through accumulation of like objects to form an agglomeration (not shown).

[0133] The drug products can also include an “elbow” with a deformable shape as shown in FIG.3B. The elbow can assume a straight or bent conformation with an angle ranging from 10 to 180 degrees, allowing the cross-sectional diameter of administered drug product to vary across those positions. For example, two drug products can be joined by a hinge or elbow of polymer (e.g., silicone) at an angle between 10 and 180 degrees from each other. Upon insertion, the drug product can be parallel (i.e., at about 180 degrees from each other). After insertion, the hinge or elbow can return to a second angle for the retention phase (e.g., about 90 degrees). After a period of drugPATENT WM1-006WO release, the elbow can dissolve so that it is expelled through the urethra.

[0134] FIG.3C depicts cylindrical particles joined by a linkage. In aspects, each cylinder 27 is secured to a cap 185. A bridge portion 195 is linked to a connection 195. One or more of these components can degrade. In aspects, the bridge portion 195 degrades or dissolves to release the cylindrical particles from one another as depicted. Alternatively, one or both of the caps 185 can degrade or dissolve to release the cylindrical particles from one another (not shown). In another embodiment, one or both of the cylindrical particles 27 degrade or dissolve to cause their release from one another (not shown). In another embodiment, one or both of the cylinders swell which causes their release from the cap. Upon release from one another, the cylindrical particles are more readily expelled during urination.

[0135] When separated from one another (e.g., after degradation), the individual drug products can be excreted from the bladder. The degradable portion of the drug products can be selected based on a desired rate of degradation, such that e.g., at one week, about 25% of the product is cleared, at two weeks about 50% is cleared, etc.

[0136] The drug product can have a preferred conformation (i.e., angle) that it assumes post-insertion. The elements that hold the position can be made in whole or in part from a dissolvable polymer. As shown in FIG.3B, an angle between about 75 and 90 can provide the largest area. The components of the linker can be various materials known in the art and chosen based on, for example, dissolvability, buoyancy, stability, tear / tensile strength, moldability, elasticity, flexibility, moldability and hardness.

[0137] FIG.3D depicts a drug product in a retention configuration and three components (i.e., a linker, a hinge and an API embedded cylindrical rod). As shown, the free end of each cylinder is about 4 mm in diameter. The capped portion is about 5 mm in diameter. As described above, degradation of one or more of the components (i.e., linker, hinge or cylindrical rod) can trigger release of the cylinders from each other. In aspects, the linker is dissolvable, degradable or bioresorbable material; the hingePATENT WM1-006WO includes a silicone connecting piece that connects to rods and improves retention in the bladder; and the rod is embedded in a polymer matrix. In aspects, the hinge can further include a) a socket (where rod is inserted), b) a cap (flat round top of socket) and c) a connector (flexible link or joint that bridges two caps).

[0138] In embodiments, the drug products are passively expelled from the bladder in the urine. In aspects, the produces dissolve / degrade to a smaller size or pieces so that it can be naturally expelled through the urethra during urination. Alternatively, the rods could be coated with a degradable surface coating such that when the coating dissolves, the rod no longer fit in the socket and fall off thereby causing disassembly of the embodiment. Alternatively, the silicone material of the hinge can be replaced with a bioresorbable elastomer that is just as flexible and elastic as silicone and dissolves over time.

[0139] In embodiments, the drug products disassemble into separate parts for excretion in the urine. The disassembly function can be isolated to a single component of the implant that does not interfere with other functionalities. This approach allows different sections of the implant to perform distinct roles, enabling independent tuning of each component with minimal impact on the overall performance. For example, the implant can include rods made from a base material optimized for API diffusion, connectors primarily composed of flexible, non-degrading silicone, and a third component designed to ensure the connectors between the rods and the hinges fail at a predetermined rate or time. This third component, the linker, can be crucial as it connects different parts of the implant and eventually triggers its disassembly. When the implant's pieces are intact, its size or shape prevents natural expulsion during urination. Alternatively, the connector between the two hinges can be replaced from silicone to an erodible, elastic material which after erosion causes disassembly of socket with rod that can be voided out.

[0140] FIG.3E depicts the three phases of the drug product (i.e., implantation, drug delivery and disassembly for elimination). FIG.3F depicts different mechanisms ofPATENT WM1-006WO particle separation according to embodiments. In aspects, pores on the hinges allow water to enter. The cylinders gradually swell until they are released. In aspects, slits on the hinges increase freedom of movement. The cylinders are released as adhesive material loses its strength. In aspects, adhesive material in a butt joint connects the cylinders. As the adhesive material dissolves, the cylinders are released. Tethered / Linked Drug Products

[0141] In embodiments, multiple drug products are joined by a tether or similar structure. The “grouping” of drug products increases their effective size. Because of their larger size, they are more resistant to being voided from the bladder with urine. FIG.4A is depicts multiple drug products (e.g., two cylinders) joined by a tether or otherwise linked (e.g., by a hinge).

[0142] In aspects, tethered drug products are stacked upon one another for administration (i.e., insertion). Cylinder-shaped products 27 can be easily administered through a syringe or other device. After the products are administered (e.g., upon exposure to urine), they can form a “tethered grouping.” This arrangement increases the size and prevents the drug products from being expelled with urine. In aspects, an active agent is released from the drug products during this “retention phase.”

[0143] In aspects, the tether 175 gradually degrades or dissolves. The tether dissipates until the drug products are released from one another. Thereafter, the drug products can be voided when the patient urinates. In this regard, the tethered drug products can follow three phases (a) an administration phase, (b) a retaining phase and (c) a voiding phase. In aspects, the duration of the retaining phase is controlled by the size and / or composition of the tether. For example, administration of a ten-day antibiotic treatment would entail use of a tether that would take at least ten days to dissolve. A tether that dissolved more quickly (i.e., a shorter retaining phase) could be used for a shorter antibiotic treatment.PATENT WM1-006WO

[0144] In aspects, the tethered drug product (in the administration phase) has a diameter smaller than the diameter of the urethra (i.e., less than or about 5 mm). In aspects, the tethered drug product (in the retaining phase) is larger than the ureteral opening (i.e., more than or about 10 mm). Further, the diameter of individual drug products (in the voiding phase) is smaller than the diameter of the ureteral opening (i.e., less than or about 5 mm).

[0145] In aspects, the cylinder-shaped products have different compositions and / or functions. For example, a first cylinder that contains an active agent can be paired with a second cylinder that provides buoyancy. In aspects the first and second cylinder each have a different active agent.

[0146] In aspects, more than two particles are coupled or connected by tether. For example, a drug product can include three cylinder-shaped particles, four cylinder - shaped particles, five cylinder -shaped particles, six cylinder -shaped particles, seven cylinder -shaped particles, eight cylinder -shaped particles, nine cylinder -shaped particles, ten cylinder -shaped particles or more. The particles can be stacked or arranged in another compact position for transurethral administration.

[0147] In other embodiments, multiple drug products are joined by a linkage. The linkage can be flexible and / or rigid. As shown in FIG.4B, the “linked” drug products have a larger effective size. The linkage can maintain the cylinders parallel with one another for administration. After administration (i.e., upon exposure to fluid in the bladder), the linkage can create an angle between the particles. Because of this angle, the particles are more resistant to being voided from the bladder. The linkage can degrade so that the particles separate from each other.

[0148] Similarly, FIG.4C depicts multiple drug products joined by a linkage. Here, the cylinders degrade during the retention phase. Upon degradation, the individual drug products can separate for excretion from the bladder. As described above, the degradable portion can be selected based on a desired rate of degradation, such thatPATENT WM1-006WO e.g., at one week, about 25% of the product is cleared, at two weeks about 50% is cleared, etc.

[0149] FIG.5A is an image of particles (e.g., two cylinders 27) joined by a tether 175. Similarly, FIG.5B is an image of particles joined by a hinge connection. Confirmational Arrangement of Linked Drug Products

[0150] FIG.6 depicts an arrangement of six drug products. The drug products are stacked for ease of administration (i.e., insertion). This configuration is conducive to administration into the bladder using a syringe or similar device. After the products are administered (e.g., upon exposure to urine), they can form a “tethered grouping.” The cylinders can form a zig-zag arrangement as depicted. The increased area of this confirmation prevents the drug products from being expelled with urine. In aspects, an active agent is released from the drug products during this “retaining phase.” As described above, the tethered portions can gradually degrade or dissolve until individual drug products are released from one another. In aspects, the drug products are retained on a single axis (i.e., flat). Alternatively, the drug products can form a multi- axis arrangement. Further, the rods can be linked at their ends in a series as shown. The angle of this connection can be free (as in on a string) or fixed (as with a hinge). Alternatively, there can be a single connection (e.g., two rods joined at an angle) or multiple in series.

[0151] In embodiments, the tether dissolves or degrades over a period of about two days, about five days, about ten days, about two weeks, about three weeks, about one month, about two months, about three months or longer. In aspects, the tether is stable and does not dissolve.

[0152] Embodiments include other shapes and configurations of drug products. In aspects, the tether material is rigid (e.g., or semi-flexible) so that the drug products revert to a preferred shape. FIG.7A depicts cylindrical drug products that assume a circular shape. As can be appreciated, a circular shape has a greater diameter andPATENT WM1-006WO higher retention. Similarly, FIG.7B depicts spherical drug products that assume a circular shape. In other aspects, the drug products are shaped as tampons, rods, cartridges, cylinders, straw-shaped, pretzel-shaped, horseshoe-shaped, drug products with patterned or irregular cross-sections, etc.). The grouping can form various three- dimensional shapes, for example, coils, hexagons, open loops, closed-loops, etc.

[0153] As can be appreciated, the tethered portion of the drug product can determine the three-dimensional shape upon confirmational change. Thus, the material, number of hinges, tear / tensile strength, moldability, elasticity, flexibility and hardness can effect the three-dimensional arrangement. The material can be, for example, monocryl, cat gut suture material, vicryl, PDS (polydioxanone suture), etc. In aspects, the material is bioabsorbable or biodegradable.

[0154] In aspects, the drug products are linked in an orientation such that all rods are in the same plane. Alternatively, the drug products can be orientated out of plane, or alternating with or without periodicity. In these configurations, the linkage can share both a common plane and a common direction with other linkages. For example, rods connected in series via hinged linkages that all share the same plane and direction would curve so as to, in aggregate, form a coil. In another example, the linked hinges could regularly alternate between two orientations on the same plane with periodicity of two and form a zig-zag arrangement.

[0155] The linkage can be incorporated into, attached to, or hold the cylinders. The linkage can exist between cylinders or more. The linkage can take the form of two caps joined by a bridge as shown in FIG.3B. The cap 185, bridge 190, and connection between cap and bridge 195 can be made of materials varying in matter, behavior, dimension, polarity, stiffness, angle, and number.

[0156] FIG.7C depicts a heterogenous grouping of drug products. The particles can have a homogenous or heterogenous function. For example, the rods can vary by buoyancy, length, material, drug payload, drug release kinetics, drug loading,PATENT WM1-006WO degradation rate and kinetics, surface vs bulk erosion, cohesion (to each other), adhesion (to tissue), etc. In this example, cylinders are linked to spheres. The active agent can be contained within the cylinders; the spheres can provide buoyancy. For example, the spheres can be composed of a material that expands for buoyancy and degrades in the urine. Bladder Modulation

[0157] In other aspects, the entry point from the bladder to the urethra is modulated during the retention phase. Embodiments include changing the cross-sectional diameter threshold for retention in the bladder post-insertion of the therapy (not shown). In aspects, the placement of a filter over the bladder neck, the injection of bulking agents around the bladder neck to cause urethral wall apposition, or a flow limiting object within the urethra that reduces the velocity of flow and therefore is used for retention of objects within the bladder. Intravesical Drug Delivery Device

[0158] In one aspect, the device of the present invention is a hand-held administration device that includes a loading funnel which accepts solid drug products (e.g., particles, spheres, tampons, rods, cartridges, cylinders, straw-shaped drug products, drug products with patterned or irregular cross-sections, etc.). FIG.8 depicts a delivery device 5 according to embodiments. The delivery device can include a body 10 with components. In aspects, the body includes a barrel 15 that is substantially linear and an insertion tip 20. The insertion tip is passed into the urethra of a subject and secured in place. Thereafter, drug products can be passed from a funnel region 25 into the barrel 15. A source of pressure 30 (e.g., compressed water or air) can drive the drug products through the device into the bladder. In aspects, a user (e.g., health care professional) controls the delivery (e.g., rate) of the drug products using a trigger 40. For example, the user can vary the pressure that is applied to the trigger to adjust the pressure that enters the device (and resulting rate of discharge of drug products).

[0159] As can be appreciated, the size / diameter of the delivery device is important.PATENT WM1-006WO With a smaller insertion tip, a patient will experience less pain and discomfort during insertion and use of the device. Accordingly, in aspects, the barrel of the device has a length of about 1 centimeter (cm) to about 15 cm or more. The insertion tip can have an outer diameter (“OD” or largest cross-sectional dimension) of about 9 millimeters (mm) or less. In addition to the inner diameter (“ID”) of the barrel, the size / flexibility of drug products and amount of pressure exerted can affect the rate of delivery of the drug products.

[0160] Accordingly, the ID of the lumen of the barrel 15 and insertion tip 20 can be determined based on the intended size of the drug product to be delivered. In aspects, the ID is between about 0.3 mm and about 2 mm. In aspects, the lumen is elastomeric so that it can be flexible / elastically deformed. In aspects, the insertion tip 20 is tapered at the distal end for insertion through the urethra. In aspects, the insertion tip is utilized for single-use and can be disposed after use.

[0161] The body 10 can be of any suitable biocompatible material to connect / house the components. In one aspect, the drug capsule body 10 is constructed from plastic or silicone. The loading funnel can have a funnel shape, but other forms are contemplated. The funnel can deliver drug products, medicaments, or any suitable substance or structure known in the art and within the purview of a practitioner of the device. In other embodiments, the funnel is a high-capacity delivery device configured to store up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 125, 135, 150, 175, 200, 250, 300, 350, 400, 500, 750, 1000 or more units of drug product. In yet other embodiments, the funnel is a rapid delivery device, capable of delivering multiple units of drug product simultaneously or in rapid succession.

[0162] The loading funnel 25 can further include grooves, ridges, obstructions, pegs, springs, switches, latches, manifolds, valves or labyrinthine structures to throttle or alter the pace of drug product / medicament / excipient delivery. In aspects, the loading funnel is an integral component of the handheld delivery device body. In aspects, thePATENT WM1-006WO loading funnel is a modular component configured for detachable attachment to the handheld delivery device body. Multiple funnels can be provided to deliver multiple drug products, excipients, medicaments or combinations thereof, or deliver drug products, excipients, or medicaments at a faster or more optimal pace of delivery. The loading funnel can be operatively attached to any contemplated device of the present invention.

[0163] The loading funnel can feed drug products into a hollow passage within a barrel operatively connected to the handheld administration device or made integral within the body of the handheld administration device. As shown in FIG.8, a desired number of drug products can be placed / poured into the loading funnel 25. In aspects, drug products in solution are fed into the loading funnel. Alternatively, a magazine or loading tray (not shown) can be used to feed drug products into the funnel. The barrel may be constructed in any known shape and of any known internal and external diameter. The barrel capacity may match that of the loading funnel or may contain a greater or lesser capacity than that of the loading funnel. The barrel may be smooth along its internal circumference, semi-smooth, partially smooth or may include ridges, notches, grooves, knurls, springs or any known geometrical projections to optimize the delivery of drug product or any other suitable substances through its hollow passage. The barrel may further be tapered, truncated, or be of a consistent diameter, an inconsistent diameter or an irregular diameter over its entire length, over substantially its entire length or over a partial or repeating stretch of its length. The barrel may also include a locking mechanism or multiple locking mechanisms to throttle, alter, and / or optimize the rate of delivery of a drug product. In aspects, the funnel is shaped (i.e., wider at the top and narrow toward the base) so that individual drug products are fed into the lumen of the barrel.

[0164] In embodiments, a “hopper mechanism” is operatively attached to the loading funnel. The hopper mechanism is constructed as a dispenser of drug particles. It can ensure that drug particles (e.g., rods) enter the barrel in the correct orientation to avoid jamming. One design is a conical-shaped hopper with a narrow opening at the bottom that leads to the barrel. The barrel can be shaped to properly fit the drugPATENT WM1-006WO product. This allows the rods to be funneled into the barrel in the correct orientation. Another design includes a series of small channels or tubes that lead from the hopper to the barrel. The channels can be angled / curved to direct the rods into the barrel in the correct orientation. In aspects, the device automatically stops dispensing after a specific dose (i.e., volume or number of particles) is administered.

[0165] In embodiments, the handheld delivery device includes a trigger for actuating the delivery of drug product from the handheld delivery device. The trigger may be spring loaded with a tension spring, compression spring, leaf spring, or any spring suitable and known within the art. The trigger can be connected to a housing of the handheld device body and may be enveloped by a hollow trigger housing. The trigger housing may be formed into any shape for housing the trigger of the handheld delivery device. In an embodiment, the trigger housing is arcuate. In other aspects, the trigger housing is substantially square shaped. In yet other aspects, the trigger housing is a low-profile hollow protrusion offering optimal clearance for the actuation of the trigger. The trigger housing is designed to provide clearance for a practitioner or user’s finger for accessing the trigger. The trigger may further include a grip or gripping surface. The grip or gripping surface may be made of any suitable material such as an elastomeric material, a plastic, a polymer, a metal, an alloy, or a blend of alloys or any aforementioned material or any suitable material known in the art. The grip of the trigger may include altered geometry to aid in gripping. The altered geometry may be in the form of a concavity, convexity, undulation, depression, protrusion or the like. The grip of the trigger may further include multiple protrusions, undulations or depressions to aid the ability of a user or practitioner to grip the trigger. Such protrusions may be in the form of raised grooves, notches, knurls, raised dots, orbs, pegs, or any other suitable gripping surfaces or geometries known in the art. Such undulations may be in the form of a wave pattern with rounded crests, pointed crests, plateaus, or any suitable form for aiding a user’s or practitioner’s grip of the trigger.

[0166] The trigger can provide automatic delivery of the drug product from the handheld delivery device, semi-automatic delivery, or delivery at any frequency knownPATENT WM1-006WO in the art. One or more units of drug product may be dispensed on a single trigger actuation, or may be dispensed at a rate of one drug product per trigger actuation, two drug products per trigger actuation, three drug products per trigger actuation, four drug products per trigger actuation, five drug products per trigger actuation, six drug products per trigger actuation, seven drug products per trigger actuation, eight drug products per trigger actuation, nine drug products per trigger actuation, ten drug products per trigger actuation, 12 drug products per trigger actuation, 15 drug products per trigger actuation, 17 drug products per trigger actuation, 20 drug products per trigger actuation, 25 drug products per trigger actuation, 30 drug products per trigger actuation, 40 drug products per trigger actuation, 50 drug products per trigger actuation, 65 drug products per trigger actuation, 75 drug products per trigger actuation, 100 drug products per trigger actuation, 125 drug products per trigger actuation, 150 drug products per trigger actuation, 200 drug products per trigger actuation, 500 drug products per trigger actuation, 1,000 drug products per trigger actuation, or more.

[0167] In further aspects, drug products may be dispensed at a rate or volume of about one drug product per trigger actuation, about two drug products per trigger actuation, about three drug products per trigger actuation, about four drug products per trigger actuation, about five drug products per trigger actuation, about six drug products per trigger actuation, about seven drug products per trigger actuation, about eight drug products per trigger actuation, about nine drug products per trigger actuation, about ten drug products per trigger actuation, about 12 drug products per trigger actuation, about 15 drug products per trigger actuation, about 17 drug products per trigger actuation, about 20 drug products per trigger actuation, about 25 drug products per trigger actuation, about 30 drug products per trigger actuation, about 40 drug products per trigger actuation, about 50 drug products per trigger actuation, about 65 drug products per trigger actuation, about 75 drug products per trigger actuation, about 100 drug products per trigger actuation, about 125 drug products per trigger actuation, about 150 drug products per trigger actuation, about 200 drug products per trigger actuation, about 250 drug products per trigger actuation, about 300 drug products per trigger actuation, about 350 drug products per trigger actuation, about 400 drug products per triggerPATENT WM1-006WO actuation, about 500 drug products per trigger actuation, about 1,000 drug products per trigger actuation, or more.

[0168] In further aspects, drug products may be dispensed at a rate or volume of no more than one drug product per trigger actuation, no more than two drug products per trigger actuation, no more than three drug products per trigger actuation, no more than four drug products per trigger actuation, no more than five drug products per trigger actuation, no more than six drug products per trigger actuation, no more than seven drug products per trigger actuation, no more than eight drug products per trigger actuation, no more than nine drug products per trigger actuation, no more than ten drug products per trigger actuation, no more than 12 drug products per trigger actuation, no more than 15 drug products per trigger actuation, no more than 17 drug products per trigger actuation, no more than 20 drug products per trigger actuation, no more than 25 drug products per trigger actuation, no more than 30 drug products per trigger actuation, no more than 40 drug products per trigger actuation, no more than 50 drug products per trigger actuation, no more than 65 drug products per trigger actuation, no more than 75 drug products per trigger actuation, no more than 100 drug products per trigger actuation, no more than 125 drug products per trigger actuation, no more than 150 drug products per trigger actuation, no more than 200 drug products per trigger actuation, no more than 250 drug products per trigger actuation, no more than 300 drug products per trigger actuation, no more than 350 drug products per trigger actuation, no more than 400 drug products per trigger actuation, or no more than 500 drug products per trigger actuation.

[0169] In further aspects, multiple drug products (i.e., differing drug products) may be administered with each trigger actuation. Multiple drug products may be administered simultaneously, sequentially, or in alternating or patterned fashion.

[0170] The handheld administration device can further include a hose or conduit connected to its proximal end for delivering compressed air or pressurized fluids from a pressure source and to propel solid drug products from an exit port of the funnel throughPATENT WM1-006WO the hollow barrel passage toward its distal end and out through its distal end opening. The hose or conduit can be constructed of any suitable material or any combinations of materials within the ambit of one of skill in the art. The hose or conduit may be elastomeric, polymeric, rubber, metallic, be composed of a combination of alloys or a combination of elastomeric or polymeric materials. The hose or conduit may also include clamps, brackets, locks, or other circumferential devices situated about its length. The pressurized fluids or compressed air fed through the hose or conduit further act to propel the solid drug products distally beyond the hollow barrel passage exit and past a gentle insertion tip affixed to the distal end of the hand-held administration device, delivering the solid drug products into an area of treatment of a patient or subject such as a urethra, bladder or kidney. The hose or conduit may be connected to a supply of compressed air or fluids, or alternatively, may be connected to a disposable device containing compressed air or fluids. The hose or conduit is further adaptable to connect to any suitable port for delivery of compressed air or fluids, including wall- mounted ports which deliver compressed air or fluids.

[0171] A pressure release valve 35 can be present on the handheld delivery device. The pressure release valve 35 may be located above the coupling of the conduit to the handheld device, below the coupling of the conduit to the handheld device, attached to the funnel of the handheld device or in any other suitable location preferred by the user or practitioner of the device as well as any location known in the art. The pressure release valve 35 acts to exhaust the built-up pressure within the handheld device during the actuation and drug product delivery process. The exhaust of the pressure may occur through a single outlet, a single port, a single perforation or a manifold of ports, outlets or perforations.

[0172] The form and shape of drug products suitable for delivery through the devices of the present invention include straw-shaped cartridges packed with rod- shaped drug products or other drug and medicament products that fit within the straw- shaped cartridges such that the straw-shaped cartridges fit into the hollow barrel passage of the present invention. Other forms and shapes include, for example,PATENT WM1-006WO spheres, cubes, pyramids, polyhedrons, rails, cylinders, truncated cylinders, irregular cylinders, flat-faced spheres, tear drops, spikes, pretzel-shapes, horseshoe-shapes and any known suitable shape or form in the art. Combined forms, combined shapes, coupled forms and coupled shapes are also contemplated. Examples of combined and coupled forms and combined and coupled shapes include two or more cylindrical drug products or structures connected by a tether, two or more rod-shaped drug products connected by a tether, two or more spherical drug products connected by a tether, two or more cubed drug products connected by a tether, two or more ellipsoidal drug products connected by a tether, two or more prism-shaped (prismatic) drug products connected by a tether, two or more pyramidal-shaped drug products connected by a tether, two or more cylindrical drug products or structures connected by a hinge, two or more rod-shaped drug products connected by a hinge, two or more spherical drug products connected by a hinge, two or more cubed drug products connected by a hinge, two or more ellipsoidal drug products connected by a hinge, two or more prism-shaped (prismatic) drug products connected by a hinge, two or more pyramidal-shaped drug products connected by a hinge, two or more cylindrical drug products or structures connected by a suture, two or more rod-shaped drug products connected by a suture, two or more spherical drug products connected by a suture, two or more cubed drug products connected by a suture, two or more ellipsoidal drug products connected by a suture, two or more prism-shaped (prismatic) drug products connected by a suture, two or more pyramidal-shaped drug products connected by a suture and the like. The aforementioned forms and shapes are further contemplated to store an active agent and excipient, or any permutation or combination thereof. Further, the combined and coupled forms of drug product may be connected via a bioabsorbable polymer or other suitable bioabsorbable material (e.g., suture) which dissolves at a predetermined rate or after a predetermined number of voiding cycles.

[0173] In aspects, the point of entry for the barrel of the device (i.e., insertion tip 20) is made of flexible materials (e.g., silicone) which are more comfortable for the patient. These materials can allow for greater flexibility in the design of the device and can be molded into different shapes to fit different patients. The pressure for delivery can bePATENT WM1-006WO determined to deliver the drug product efficiently while avoiding patient discomfort.

[0174] The insertion tip 20 affixed to the distal end of the barrel may be a vesical sheath, a lubricious tip, a Luer lock or taper provided for connection to a medicament delivery device, or any known insertion device or coupling device known in the art. The gentle insertion tip may also be rigid, disposable, dissolvable, bioabsorbable, single-use or the like. The gentle insertion tip may also be in the form of a catheter, cannula or needle and is affixable to the distal end of the barrel or any other component of the devices of the present invention. The insertion tip may be made of a single material, multiple materials, or a mixture of materials. In further aspects, the insertion tip is composed of different materials along its length, composed of a repeating pattern of materials or composed of an irregular pattern of materials along its length. The insertion tip may further be configured for attachment to an adaptor, or to an additional tip for purposes of versatility and functionality. The insertion tip may be a modular component, detachably attachable to the distal end of the barrel or any other component of the devices of the invention. The insertion tip may also be integral with the devices of the present invention, affixed or enjoined to the distal tip of the barrel or to any component of the devices of the present invention. Depth-Locking Soft Catheter

[0175] In aspects, the insertion tip 20 includes an anchoring mechanism. Anchoring mechanisms have been used with conventional catheters. One example of such a device is a foley catheter. Conventional foley catheters often have a balloon that prevents the inside tip from slipping out once it has been inserted to proper depth. However, these catheters are not designed to deliver any product, and therefore, their lumina (i.e., channels) are narrow and have relatively high resistant friction because they are made of a certain grade of silicone.

[0176] In an embodiment, the delivery device includes a depth-locking soft catheter 50 with an anchoring mechanism to reduce / prevent movement of the tip after it is inserted into the urethra. FIG.9 depicts a catheter 50 with a distal end 55 that includesPATENT WM1-006WO an anchoring mechanism (e.g., a balloon) and the proximal end 60 that includes a locking mechanism (e.g., thread and nuts). In aspects, the threaded portion extends for more length than the lock ring assembly needs so that the assembly can be fastened variably at different depths along the longer threaded portion. In aspects, the lock ring assembly is made of one relatively wide fender washer 65 that rests against the patient’s skin and two lock nuts that tighten onto each other at exactly the desired depth outside of the fender washer (70, 75). The lock nuts can have a high surface area (one is convex and the other concave) so that they can be tightened to one another with friction helping prevent disassembly. In aspects, the lock nuts are large enough that they can easily be separated by hand, but they are less wide in comparison to the fender washer. The most proximal piece of the device can be a connector (such as a screw lock or Luer slip lock) so that other devices can attach while the vesical sheath is stationary between parts of the procedure. The inner diameter (ID) of the lumen of the catheter can be, for example, about 1 mm to about 9 mm wide or smaller / larger depending on the size of the particles that are administered. In aspects, the length of the catheter is determined by the gender of the patient (i.e., male or female).

[0177] As shown, the catheter can include a balloon or other structure which protrudes from the distal end 55. The balloon can be inflated or expanded by any suitable medium including, for example, fluid, air, gas, or any mixture of the aforementioned. The catheter can be a modular component that is detachably attachable to any component of the device of the present invention. Alternatively, the catheter can be an integral component forming a unitary device and operatively associated with a component of the device.

[0178] The depth-locking soft catheter 50 can include any number of lumens. In an embodiment, the depth-locking soft catheter includes a single lumen for passage of drug products, medicaments, excipients, adjuvants, carriers, or any suitable substance, product, particle, mechanism or device known in the art. The depth-locking soft catheter and other devices may also include two lumens, three lumens, four lumens, five lumens, six lumens, seven lumens or more. The lumens may be coaxial,PATENT WM1-006WO concentric, arrayed, patterned, irregularly offset, discontinuous, fully continuous, and of any length, circumference, diameter, gradient diameter or variable diameter deemed suitable for the purposes of the present invention.

[0179] The depth-locking soft catheter can also include inner and outer portions. In aspects, the outer portion is a semi-hard plastic with threads / nuts. The outer member can include a spinnable washer 65, a clockwise convex nut (right-hand threaded) 70 and a counter-clockwise concave nut (left-hand threaded) 75. The spinnable washer, clockwise convex nut and counter-clockwise concave nut are threadedly coupled to a threaded proximal end 60 of the depth-locking soft catheter. The spinnable washer, clockwise convex nut and counter-clockwise concave nut may be coupled to the proximal end of the depth-locking soft catheter in any suitable fashion known in the art or within the ambit of a user or practitioner. The spinnable washer, clockwise convex nut and counter-clockwise concave nut can be substituted with equivalent fasteners and gaskets known in the art. Concentric Multi-Lumen Static Sheath

[0180] In another embodiment, the delivery device includes an insertion tip with a concentric multi-lumen static sheath 80 as depicted in FIG.10. The concentric multi- lumen static sheath can include an outer tubular member 90 and an inner tubular member 85 arranged concentrically and coaxially.

[0181] In aspects, the inner tubular member 85 includes a flexible portion at its distal end. The flexible portion may be inflated or deformed upon entry into a patient or subject’s urethra or bladder to act as a locking member by maintaining the position of the outer and inner tubular members. It can form a shape of a “shoe horn” and spread open at the distal end 95 to secure the catheter in place. The flexible portion can be composed of any suitable material known in the art. Inflatable and expandable materials can include, for example, polymers, elastomers, plastics, latex, paraffin, malleable metals, malleable alloys or any combination of the aforementioned. An inflation lumen, pulling wire, pulling mechanism, or actuator (not shown) can bePATENT WM1-006WO operatively connected to the flexible portion to actuate inflation or deformation of the flexible portion. The flexible portion can deform into a lobe or wing-shape which overlaps the outer tubular member and locks the inner tubular member into position within a patient and / or lock and affix the inner tubular member relative to the outer tubular member. The flexible portion can be coated or impregnated with drug product and act as a drug and medicament delivery member.

[0182] In aspects, the insertion tip includes an outer lock-ring 100 that softly screws down to a patient’s skin to lock the sheath in place as depicted in FIG.11A. The lock ring allows a universal and adjustable sheath length that can set the depth for the urethra length of a particular patient.

[0183] In an alternative design, a catheter has a “tampon-like” structure made of flexible, sterile materials as depicted in FIG.11B. The device can come loaded with drug product inside 27. The drug product inside can be of any aforementioned shape and convention, including a bowstring alignment where two drug products are connected by a bioabsorbable tether. The bowstring alignment allows two drug products to enter at an 180-degree angle relative to one another and provides a minimum diameter to easily enter a patient’s urethra. After entry, the bioabsorbable bowstring allows the drug products to assume an angle less than 180 degrees, ensuring the drug products stay within the patient’s bladder for a predetermined amount of voiding cycles. Eventually, the bioabsorbable bowstring tether slowly dissolves, allowing each formerly connected drug product to exit the patient’s bladder and urethra after a predetermined period of dissolution. A button-pressed spring mechanism on the bottom of the device can open the device outward once it is inserted into the urethra. This mechanism can hold the device comfortably in place for the duration of drug administration. It can also be used to consistently and evenly deliver the drug product. The device can have a string / wire that can be pulled after administration is complete to close the device and allow for easy and comfortable removal. Unlike a cystoscope, the device provides comfort to the patient because it is made of flexible and / or lubricious materials (e.g., rayon, a blend of rayon and cotton along with synthetic fibers or similar). In aspects, thePATENT WM1-006WO catheter is inserted with an applicator (not shown). Soft Grapple Members

[0184] In additional embodiments, the insertion tip includes one or more soft grapple members 105. FIG.12 depicts soft grapple members that can be employed as a depth setting and locking mechanism. The soft grapple member acts to hold a vesical sheath in place while setting the depth of administration of drug product. Each soft grapple member can include a longitudinal body that terminates in a bulbous end that is of greater width than the width of the longitudinal body. The bulbous end may be fashioned into any gripping member novel or known in the art, including an array of cups, a suction member, an array of suction members, a barb, an array of barbs, or the like.

[0185] The soft grapple member 105 may originate within a wall of a tubular member of the delivery device, running coaxially with or within the delivery devices and protruding distally from the distal end of the delivery devices of the present invention. The soft grapple member is generally flexible and adapted to bend into an arc or arcuate shape in order to bring the bulbous end into contact with an interior of an orifice or anatomical structure of a patient or subject, such as the interior wall of a urethra, bladder or kidney. To set the depth, the soft grapple member is deployed into the area of treatment and pulled back via a connected pulling member, pulling wire or an actuator, which deforms the distal end of the grapple member into a curved or arcuate shape, allowing the bulbous end of the grapple member to contact the interior surface of an orifice or anatomical structure of a patient or subject.

[0186] In embodiments, the soft grapple member is part of a soft grapple member array. The soft grapple member array may include two or more soft grapple members connected to two or more pulling members or pulling means. The soft grapple member array may include equidistantly spaced soft grapple members or randomly spaced and assorted soft grapple members. The devices of the present invention may include any number of soft grapple members or soft grapple member arrays. The soft grapplePATENT WM1-006WO member may further be contemplated as a filamentous element such as a suture, and may include an array of sutures which serve to grip the inside of the patient’s bladder wall.

[0187] The soft grapple member may be composed of any suitable material such as an elastomeric material, a polymeric material, a plastic, metal, metal alloy, or a combination of any or all of the aforementioned. The material construction of the soft grapple member may be uniform, patterned, or composed of alternating and differentiable materials. The flexural modulus of the soft grapple member may vary along the length of the soft grapple member. For example, the soft grapple member may be composed of a more rigid material at its base and a more flexible material at its distal tip. Any arrangement of flexural modulus or intensity of flexural modulus that is well known in the art and / or within the ambit of a practitioner or user may be employed. Delivery Device with Ratchet Mechanism

[0188] In further embodiments, the delivery device is a handheld delivery device that includes a drug product loading bay, a receptacle bay, a drug product delivery chamber and an actuation mechanism which includes a piston, plunger and threaded coupling member. The drug product loading bay, receptacle bay and drug product delivery chamber may be designed to conform to any suitable dimensions and are capable of handling different types of drug products. FIG.13A, 13B and 13C depict different views of a loading mechanism (i.e., a first-person view, top-down view and side-view respectively).

[0189] The drug product delivery chamber 110 can be dimensioned to any size and shape suitable for an intended use and to any size and shape known in the art. In embodiments, the drug product delivery chamber 110 is sized and shaped to accept a threaded piston and plunger 115 that is threadedly connected to a threaded throttling device within the drug product delivery chamber. In aspects, the threaded throttling device accepts the piston in a threaded connection and is located at the proximal end of the interior of the drug product delivery chamber. In other aspects, the threadedPATENT WM1-006WO throttling device is located in other portions of the drug product delivery chamber, such as the midpoint of the chamber, near the midpoint of the chamber, outside the proximal end of the chamber, in any location a user or practitioner deems fit or in any location suitable for the purposes of the present invention and / or known in the art.

[0190] The drug product delivery chamber can also include a soft-pull trigger 40 which is connected to a swivel and spring-loaded ratchet mechanism. The spring- loaded ratchet mechanism can be operably connected to a loading pin 120 and an unloading pin 125. When a practitioner pulls or actuates the trigger 40, the trigger acts upon both pins and releases a drug product unit from a loading area (loaded straw bay) 130 into the receptacle bay (empty straw bay) 135. The trigger and pins subsequently return to their original position via retraction of the spring and hold the next successive drug product unit in place.

[0191] In embodiments, the receptacle bay is positioned opposite from the drug product loading bay and operatively connected to the drug product delivery chamber. The receptacle bay can accept cartridges, empty carpules, empty capsules, empty pellets, empty cartridges that are coupled or connected by a tether, empty carpules that are coupled or connected by a tether, empty capsules that are coupled or connected by a tether, empty pellets that are coupled or connected by a tether, empty structures that are coupled or connected by a tether or the equivalent by action of an unloading pin which is operatively connected to the trigger of the handheld delivery device. Upon actuation of the trigger, the unloading pin displaces, allowing empty drug products to enter the receptacle bay after being ejected from the drug product delivery chamber. The manner of connection between the unloading pin and trigger of the handheld delivery device are subject to variations in design. The unloading pin and trigger may be connected directly, indirectly, via a spring, via a tension member, via a pulling mechanism, via a pushing mechanism, or through any suitable means known in the art. The unloading pin may be electronically coupled to the trigger and in further aspects may not be physically connected, but instead tethered through near field communication, wireless communication, RFID, Bluetooth, Wi-Fi, or any suitablePATENT WM1-006WO equivalent which allows the trigger to communicate with the unloading pin and act upon the unloading pin.

[0192] The magazine spring 145 of the drug product loading bay can both retract to accept drug product units and expand to eject drug product units into the drug product delivery chamber. The drug product delivery chamber is operably attached to the drug product loading bay and accepts the ejected drug product units for delivery to a patient or subject by action of an actuation mechanism. The actuation mechanism can be any form of actuator known in the art, including a piston, a piston coupled to a plunger, a threaded piston, a threaded piston coupled to a plunger, an obturator rod, a stylet, a threaded stylet, a threaded rod, a pneumatic actuator, a spring-loaded actuator, a piezoelectric actuator, an electronic actuator, or the like.

[0193] FIG.13B depicts a top-down view of a drug product delivery chamber. The chamber can be attached to a catheter 50. When the trigger is pulled, a drug product unit is released from the loading area (loaded straw bay) 130 into the empty straw bay 135. A screw piston 140 directs the drug product through a connector and into the catheter region. Similarly, FIG.13C depicts a side-view of the drug product delivery chamber which shows the screw piston 140 and plunger 115 which directs drug products to a connector / catheter.

[0194] The drug product loading bay may be manufactured, designed and engineered for different capacities. In embodiments, up to one drug product unit, up to two drug product units, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, up to 10, up to 12, up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 60, up to 75, up to 100, up to 125, up to 150, up to 175, up to 200, up to 250, up to 300, up to 350, up to 400, up to 450, up to 500 or more drug product units may be loaded into the drug product loading bay at any one time.

[0195] In other embodiments, no more than 5 drug product units, no more than 10 drug product units, no more than 15, no more than 20, no more than 25, no more thanPATENT WM1-006WO 30, no more than 35, no more than 40, no more than 50, no more than 60, no more than 75, no more than 100, no more than 125, no more than 150, no more than 175, no more than 200, no more than 250, no more than 300, no more than 350, no more than 400, no more than 450, or no more than 500 drug product units may be loaded into the drug product delivery bay.

[0196] In other aspects, about two drug product units, about three drug product units, about four drug product units, about five, about seven, about 10, about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 75, about 90, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 400, about 450, about 500, about 750, or about 1000 drug product units may be loaded into the drug product loading bay at any one time.

[0197] The receptacle bay may be manufactured, designed and engineered for myriad capacities. In embodiments, up to one drug product unit, up to two drug product units, up to three, up to four, up to five, up to six, up to seven, up to eight, up to nine, up to 10, up to 12, up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 60, up to 75, up to 100, up to 125, up to 150, up to 175, up to 200, up to 250, up to 300, up to 350, up to 400, up to 450, up to 500 or more drug product units may be accepted into the drug receptacle bay at any one time.

[0198] In other embodiments, no more than 5 drug product units, no more than 10 drug product units, no more than 15, no more than 20, no more than 25, no more than 30, no more than 35, no more than 40, no more than 50, no more than 60, no more than 75, no more than 100, no more than 125, no more than 150, no more than 175, no more than 200, no more than 250, no more than 300, no more than 350, no more than 400, no more than 450, or no more than 500 drug product units may be accepted into the receptacle bay.

[0199] In other aspects, about two drug product units, about three drug productPATENT WM1-006WO units, about four drug product units, about five, about seven, about 10, about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 60, about 75, about 90, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 400, about 450, about 500, about 750, or about 1000 drug product units may be accepted into the receptacle bay.

[0200] In further aspects, at least one drug product unit, at least two drug product units, at least three drug product units, at least four drug product units, at least five drug product units, at least seven drug product units, at least nine drug product units, at least 10, at least 12, at least 15, at least 17, at least 20, at least 23, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 70, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 700, at least 800, at least 900, at least 1000 or more drug product units may be accepted into the receptacle bay. Valved Tubular Delivery Device

[0201] In further aspects, the delivery devices of the present invention may also include valves at both the entry and exit ports of the delivery device bodies. The delivery devices may terminate in a blunt distal end which is sealed by a valve when not actuated or not in use. An obturator rod, stylet, piston, or other insertion device may be employed to open the valve seal at the distal end of the devices indirectly by pushing drug product against the interior surface of the distal valve and acting to open the valve as the drug product is pushed past it. A proximal valve may also be present and seal the proximal opening of the delivery devices of the present invention. The proximal valve may be opened by action of an obturator rod, stylet, piston or other insertion device as the obturator rod, stylet, piston or other insertion device is inserted into the passage of the delivery devices of the present invention.

[0202] In another embodiment, a tubular member is provided which includes anPATENT WM1-006WO open proximal end and an open distal end and is loaded with multiple units of drug product in a hollow passage extending therebetween. A valve is affixed to the proximal end of the tubular member and envelops the open proximal end. A second valve is affixed to the distal end of the tubular member and envelops the open proximal end. An obturator rod, stylet or the like is provided as a drug product advancement and ejection tool, capable of entering the proximal opening of the tubular member through the first valve, advancing a queued amount of drug product units or particles through the hollow passage and ejecting the drug product units through the second valve and out of the open distal end of the tubular member. In aspects, the valves may be alternatively opened or activated through a push-button spring mechanism attached at the distal end of the tubular member. In other aspects, the push-button spring mechanism may be attached along the length of the tubular member, on the underside of the tubular member, or at any location that one of ordinary skill in the art would see fit. The drug product for use with the valved tubular delivery device can be of any aforementioned shape and convention, including a bowstring alignment where two drug products are connected by a bioabsorbable tether. The bowstring alignment allows two drug products to enter at an 180-degree angle relative to one another and provides a minimum diameter to easily enter a patient’s urethra. After entry, the bioabsorbable bowstring allows the drug products to assume an angle less than 180 degrees, ensuring the drug products stay within the patient’s bladder for a predetermined amount of voiding cycles. Eventually, the bowstring tether slowly dissolves, allowing each formerly connected drug product to exit the patient’s bladder and urethra after a predetermined period of dissolution.

[0203] A marking member or marking indicia may be provided along an outer wall of the tubular member for purposes of establishing proper or correct orientation of the device during use. The marking member may be in the form of a colored line extending along the length of an outer wall of the tubular member. The marking member may also be in the form of a phrase indicating proper placement of the tubular member within a subject or patient. The marking member may also be in the form of marking indicia, provided as numbers, letters, symbols, colors, words, arrows, coded indicators or otherPATENT WM1-006WO known indicia for signifying proper placement of the tubular member during usage of the device.

[0204] In aspects, the type of particles or drug products used (e.g., size, shape, composition and method produced) can be chosen based on a proposed treatment. For example, a two-millimeter-long cylinder-shaped particle (with an antibiotic active agent) may be optimal for treating a female patient with a UTI. These relatively large particles (wherein 2 mm is the mean longest dimension) can be retained within the bladder in three ways. First, the majority of the particles in the formulation (i.e., more than about 90%) are buoyant in urine. This buoyancy keeps the particles away from the urethral opening during the first half of the voiding cycle when the urethral opening is at its largest. Second, as the bladder empties and the urethral opening gradually narrows, the particle diameter is wider than the narrowed urethral opening in the second half of the voiding cycle and as voiding approaches completion. Third, at the end of the voiding cycle (when the urethral opening is narrowed and the buoyant particles are brought to the level of the urethral opening) the particles tend to aggregate within the bladder and thereby prevent outflow of the particles.

[0205] Many catheters, intravesical or otherwise, or cystoscopes can easily slip or fall out once they have been installed. They can also be inserted too deeply. For operations that involve prolonged intravesical manipulation, this risk of the device sliding in and out complicates the procedure. Complications can arise from many factors including, but not limited to, increased risk of laceration or irritation, by preventing hands-free operation for the clinician, or by increasing the risk of needing to re-install the device once it has been unintentionally removed which can cause increased adverse effects to the tissue, or by changing the depth it has been inserted at all. Methods of Use

[0206] In embodiments, the particles within the pharmaceutical formulation include (a) a pharmacologically active agent and (b) a controlled release carrier. By gradual reduction in mass and / or other means, the particles release the active agent into thePATENT WM1-006WO bladder during an extended drug delivery time period. The components of the particles are described further herein.

[0207] As can be appreciated, the selection of pharmacologically active agent is dependent on the indication. Active agents that are administrable via intravesicular administration of a particle formulation of the invention are generally, although not necessarily, selected from the following categories: anti-infective agents, including anti- bacterial, anti-fungal, and anti-viral agents; chemotherapeutic agents; anti-inflammatory agents; anesthetic agents; analgesic agents; diuretic agents; coagulants and anti- coagulants; biologics; agents for treatment of incontinence, including overactive bladder (including antimuscarinic agents, ^3-adrenergic receptor agonists, anesthetic agents, and analgesic agents); renin-angiotensin-aldosterone system (RAAS) inhibitors; agents for modulating an immune response, agents for treating kidney stones; agents for gene therapy and contrast agents for diagnostics and monitoring.

[0208] As described above, drug formulations are most conveniently administered to a patient in a compacted form. Within the bladder, the capsules can expand or conform to a larger size which resists passage into the urethra over a desired residence period. In aspects, the particles have a combined volume of about 10 to 50 mm3. In aspects, the particles have a combined volume of about 1 mm3, about 2 mm3, about 3 mm3, about 5 mm3, about 7 mm3, about 10 mm3, about 12 mm3, about 15 mm3, about 20 mm3, about 25 mm3, about 30 mm3, about 35 mm3, about 40 mm3, about 45 mm3, about 50 mm3, about 60 mm3, about 70 mm3, about 80 mm3, about 90 mm3, about 100 mm3or larger. In aspects, the particles have a hollow core.

[0209] In additional aspects, the drug particles described herein are a grouping of cylinder-shaped (i.e., barrel-shaped or cylindrical) or substantially cylinder-shaped particles coupled or connected to another by a tether. In aspects, the particles have a combined volume of no more than 1 mm3, no more than 2 mm3, no more than 3 mm3, no more than 5 mm3, no more than 7 mm3, no more than 10 mm3, no more than 12 mm3, no more than 15 mm3, no more than 20 mm3, no more than 25 mm3, no more thanPATENT WM1-006WO 30 mm3, no more than 35 mm3, no more than 40 mm3, no more than 45 mm3, no more than 50 mm3, no more than 60 mm3, no more than 70 mm3, no more than 80 mm3, no more than 90 mm3, or no more than 100 mm3.

[0210] In further aspects, the particles have a combined surface area of about 2 mm2, about 3 mm2, about 5 mm2, about 7 mm2, about 10 mm2, about 12 mm2, about 15 mm2, about 20 mm2, about 25 mm2, about 30 mm2, about 35 mm2, about 40 mm2, about 45 mm2, about 50 mm2, about 60 mm2, about 70 mm2, about 80 mm2, about 90 mm2, about 100 mm2or larger.

[0211] In yet further aspects, the drug products are connected by a bioabsorbable tether or hinge, the bioabsorbable tether and hinge designed to maintain its integrity (i.e., not dissolve) until after one voiding cycle, two voiding cycles, three voiding cycles, four voiding cycles, five voiding cycles, six voiding cycles, seven voiding cycles, eight voiding cycles, nine voiding cycles, 10 voiding cycles, 11 voiding cycles, 12 voiding cycles, 13 voiding cycles, 14 voiding cycles, 15 voiding cycles, 16 voiding cycles, 17 voiding cycles, 18 voiding cycles, 19 voiding cycles, 20 voiding cycles, 25 voiding cycles, 30 voiding cycles, 35 voiding cycles, 40 voiding cycles, 45 voiding cycles, 50 voiding cycles, 55 voiding cycles, 60 voiding cycles, 65 voiding cycles, 70 voiding cycles, 75 voiding cycles, 80 voiding cycles, 90 voiding cycles, 100 voiding cycles, 110 voiding cycles, 125 voiding cycles, 150 voiding cycles, 175 voiding cycles, 200 voiding cycles, 225 voiding cycles, 250 voiding cycles, 275 voiding cycles, 300 voiding cycles, 325 voiding cycles, 350 voiding cycles, 375 voiding cycles, 400 voiding cycles, 450 voiding cycles, 500 voiding cycles, 600 voiding cycles, 700 voiding cycles, 800 voiding cycles, 900 voiding cycles, 1000 voiding cycles or more.

[0212] The bioabsorbable tether or hinge can be of a set or varying durometer. The durometer of the bioabsorbable tether or hinge can be of a Shore A durometer of about 1A, about 2A, about 3A, about 4A, about 5A, about 6A, about 7A, about 8A, about 9A, about 10A, about 11A, about 12A, about 13A, about 14A, about 15A, about 16A, about 17A, about 18A, about 19A, about 20A, about 21A, about 22A, about 23A, about 24A,PATENT WM1-006WO about 25A, about 26A, about 27A, about 28A, about 29A, about 30A, about 35A, about 40A, about 45A, about 50A, about 55A, about 60A, about 65A, about 70A, about 75A, about 80A, about 85A, about 90A, about 95A, about 96A, about 97A, about 98A, about 99A or about 100A.

[0213] The bioabsorbable tether or hinge can be of a set or varying durometer. The durometer of the bioabsorbable tether or hinge can be of a Shore A durometer of at least 1A, at least 2A, at least 3A, at least 4A, at least 5A, at least 6A, at least 7A, at least 8A, at least 9A, at least 10A, at least 11A, at least 12A, at least 13A, at least 14A, at least 15A, at least 16A, at least 17A, at least 18A, at least 19A, at least 20A, at least 21A, at least 22A, at least 23A, at least 24A, at least 25A, at least 26A, at least 27A, at least 28A, at least 29A, at least 30A, at least 35A, at least 40A, at least 45A, at least 50A, at least 55A, at least 60A, at least 65A, at least 70A, at least 75A, at least 80A, at least 85A, at least 90A, at least 95A, at least 96A, at least 97A, at least 98A, at least 99A or at least 100A.

[0214] The bioabsorbable tether or hinge can be of a set or varying durometer. The durometer of the bioabsorbable tether or hinge can be of a Shore A durometer of no more than 1A, no more than 2A, no more than 3A, no more than 4A, no more than 5A, no more than 6A, no more than 7A, no more than 8A, no more than 9A, no more than 10A, no more than 11A, no more than 12A, no more than 13A, no more than 14A, no more than 15A, no more than 16A, no more than 17A, no more than 18A, no more than 19A, no more than 20A, no more than 21A, no more than 22A, no more than 23A, no more than 24A, no more than 25A, no more than 26A, no more than 27A, no more than 28A, no more than 29A, no more than 30A, no more than 35A, no more than 40A, no more than 45A, no more than 50A, no more than 55A, no more than 60A, no more than 65A, no more than 70A, no more than 75A, no more than 80A, no more than 85A, no more than 90A, no more than 95A, no more than 96A, no more than 97A, no more than 98A, no more than 99A or no more than 100A.

[0215] In aspects, administration of the drug products and devices of the presentPATENT WM1-006WO invention can improve urinary continence in a subject or patient by e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or at least 99.5%.

[0216] In aspects, administration of the drug products and devices of the invention can reduce signs / symptoms of a disease of the bladder / urinary tract / kidney by e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98%, about 99% or about 100%.

[0217] In aspects, administration of the drug products and devices of the present invention can reduce signs / symptoms of a disease of the bladder / urinary tract / kidney by e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or at least 99.5%.

[0218] In aspects, intravesical administration of a drug product using devices / methods of the invention can reduce reported patient discomfort (as compared to using a conventional catheter) by e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or at least 99.5%.

[0219] In aspects, administration of the drug products and devices of the invention decreases the time needed for intravesical administration of a drug product (e.g., including prep time) by e.g., about 5%, about 10%, about 15%, about 20%, about 25%,PATENT WM1-006WO about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98% or about 99%, compared to conventional methods (e.g., hand loading a catheter). In aspects, the devices and methods allow intravesical administration with fewer trained staff (i.e., administration by a single health care professional / technician).

[0220] In embodiments, the devices / methods described herein can deliver drug particles wherein the mean diameter of the particles or drug delivery product is about 50 nanometers, about 100 nanometers, about 200 nanometers, about 350 nanometers, about 500 nanometers, about 1,000 nanometers, about 2,000 nanometers, about 3,000 nanometers, about 5,000 nanometers, about 10,000 nanometers, about 10 micrometers, about 20 micrometers, about 30 micrometers, about 50 micrometers, about 100 micrometers, about 150 micrometers, about 250 micrometers, about 500 micrometers, about 750 micrometers, about 1,000 micrometers, about 1,500 micrometers, about 2,000 micrometers, about 3,000 micrometers, about 5,000 micrometers, about 10,000 micrometers, about 1 millimeter, about 1.25 millimeters, about 1.35 millimeters, about 1.45 millimeters, about 1.5 millimeters, about 1.65 millimeters, about 1.75 millimeters, about 1.85 millimeters, about 2 millimeters, about 2.15 millimeters, about 2.25 millimeters, about 2.5 millimeters, or about 3 millimeters or greater.

[0221] In aspects, the controlled release particles described herein are cylinder- shaped (i.e., barrel-shaped or cylindrical) or substantially cylinder-shaped. In aspects, they have a volume of about 10 to 50 mm3. In aspects, the particles have a volume of about 1 mm3, about 2 mm3, about 3 mm3, about 5 mm3, about 7 mm3, about 10 mm3, about 12 mm3, about 15 mm3, about 20 mm3, about 25 mm3, about 30 mm3, about 35 mm3, about 40 mm3, about 45 mm3, about 50 mm3, about 60 mm3, about 70 mm3, about 80 mm3, about 90 mm3, about 100 mm3or larger. In aspects, the particles have a hollow core.PATENT WM1-006WO

[0222] In aspects, the drug particles described herein are cylinder-shaped (i.e., barrel-shaped or cylindrical) or substantially cylinder-shaped. In aspects, the particles have a volume of no more than 1 mm3, no more than 2 mm3, no more than 3 mm3, no more than 5 mm3, no more than 7 mm3, no more than 10 mm3, no more than 12 mm3, no more than 15 mm3, no more than 20 mm3, no more than 25 mm3, no more than 30 mm3, no more than 35 mm3, no more than 40 mm3, no more than 45 mm3, no more than 50 mm3, no more than 60 mm3, no more than 70 mm3, no more than 80 mm3, no more than 90 mm3, or no more than 100 mm3.

[0223] In aspects, the particles have a surface area of about 2 mm2, about 3 mm2, about 5 mm2, about 7 mm2, about 10 mm2, about 12 mm2, about 15 mm2, about 20 mm2, about 25 mm2, about 30 mm2, about 35 mm2, about 40 mm2, about 45 mm2, about 50 mm2, about 60 mm2, about 70 mm2, about 80 mm2, about 90 mm2, about 100 mm2or larger. EXAMPLES

[0224] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of components of the formulation and / or methods and uses thereof. EXAMPLE 1 Comparison of Different Polymorphs

[0225] Polymorphs occur when a polymer solidifies in different chemically identical lattice structures that therefore have different tertiary and quaternary structure. Adjusting crystallinity of product or manufacturing different polymorphs enables tuning drug release, buoyancy, density, material properties such as hardness, stability,PATENT WM1-006WO packing, and appearance. In this example alpha ( ^), beta prime (β’) and beta (β) crystalline structures were produced and their buoyancies were compared over time.

[0226] Alpha ( ^) particles are cured at 4°C. They appear shiny / glossy because the lattice is highly ordered, and carbon chains are laid parallel so there is a smooth surface in the quaternary structure. To create alpha, the system’s energy must be lowered to reduce the movement along the monomers degrees of freedom and lower the intramolecular hindrance.

[0227] Beta prime (β’) particles are hard cured at 51°C. They are more randomly packed and “chalky” because the monomers have bent glycerol carbon chains. If beta is more randomly packed, then energy must be stored between the polymer units during the polymerization process. Similarly, Beta (β) are molten cured at 51°C. They appear chalky (i.e., not shiny).

[0228] Characteristics of each type of crystalline structure are compared in FIG.1. The β-rods maintained their buoyancy over the course of four days. Almost no β-rods sunk to the bottom of the flask. In contrast ^ -rods and β-rods lost their buoyancy after about three days. EXAMPLE 2 Comparison of Absorbable Sutures

[0229] In aspects, drug products are joined with an absorbable suture (e.g., a suture joining bowstring or a suture joining hinge). After the absorbable suture is sufficiently dissolved, individual drug products separate from one another and are excreted during urination.

[0230] Accordingly, the length of the retention period will depend on the material used for the sutures. Applicants compared different materials as summarized below. Monocryl has a low tissue reactivity, maintains high tensile strength, and has a half-lifePATENT WM1-006WO of 7 to 14 days. Catgut suture is made of twisted strands of purified collagen taken from the small intestine of domesticated ruminants or beef tendon. It is naturally degraded by the body's own proteolytic enzymes. Full tensile strength remains for at least 7 days, and absorption is complete by 90 days. Vicryl suture is rehydrolyzed into glycolic acid and lactic acid in the body in about 7 – 10 days. It retains about 50% of its breaking strength at 5 days and almost none at 14 days, and eventually the whole suture disappears. PDS (polydioxanone) sutures are more stable. They retain about 70% of their initial strength for two weeks, 50% for four weeks, 25% for six weeks. They are absorbed through simple hydrolysis and completely get absorbed within 180-210 days.

[0231] Table 1 shows characteristics of different materials and their stabilities within the bladder. material absorption 50% strength Fails in AUM Monocryl hydrolysis 7 days Cat gut proteolytic 7 – 28 days Vicryl hydrolysis 21 days 8 – 11 days PDS (<4-0) Slow hydrolysis ~4 weeks PDS Slow hydrolysis ~7 weeks 30+ days (BRID) EXAMPLE 3 Intravesical Administration of Controlled Release Particles (Conventional Catheter)

[0232] In this example, a female patient visits a healthcare provider to be administered intravesical controlled release particles. The use of intravesical particles allows drug delivery at a specified controlled rate and at a target site for greater efficacy and safety. As depicted in FIG.7, the particles can be inserted using a catheter / straw with a blunt end for entry. The catheter / straw can also include a valve for directional control.PATENT WM1-006WO Procedure Preparation 1. A sterile table is set up (e.g., to the right-side of the patient table base). 2. Four sterile straws are emptied onto the table (two straws hold 5 grams of therapy). 3. Two 5-gram packets are emptied onto the table. 4. The rods are placed into the straws “one by one.” 5. The four filled straws are laid on the table for administering the drug product to the patient. 6. A device is opened to advance the rods out of the straw into the cysto sheath: a. 6 Fr stent pusher can be used. b. 7 Fr vascular sheath can be used. c. 5 Fr vascular catheter with floppy tip can be used. Administration Procedure 1. The patient is placed supine with legs in stirrups. 2. The introitus is sterilized and the area draped in a sterile fashion. 3. The urethra is treated with viscous lidocaine. The sheath is coated on the outside with viscous lidocaine as lubricant. 4. A cysto sheath is inserted into the bladder: a. a 19.5 Fr sheath can be used. b. 22 Fr sheath can be used. c. a 17.5 Fr sheath can be used. 5. A bridge is attached, the cystoscope inserted, and saline used to fill the bladder. 6. The bladder is filled and surveyed for injury or disease. 7. The scope is removed and the sheath remains. 8. The sheath is angled from about a 45-degree position to the floor to about a 0- degree position to the floor (this prevents rods present within the bladder from floating out of the sheath). 9. The assistant prepares to insert the rods:PATENT WM1-006WO a. Assistant pinches the distal end of the straw so that the rods do not fall out. b. Assistant inserts the “pusher” into the proximal end of the straw. Now the rods are jailed between the distal pinch and the proximally-placed pusher 10. Assistant inserts distal end of straw into cysto funnel and engages straw to narrow chute: i. Straw is advanced maximally into cysto chute and then the rods are pushed through the straw into the bladder OR ii. Pusher is used to advance rods out of straw into the sheath. b. Assistant withdraws the straw, leaving the pusher advanced into the cysto chute to prevent reflux of rods. 11. Urologist clears sheath of rods: a. The urologist places obturator into the cysto funnel abutting the pusher. b. As the assistant withdraws the pusher, the obturator controls any pellets from exiting and then the obturator is advanced through the sheath to expel all rods into the bladder. c. This completes insertion of the first straw’s worth of rods. d. The sheath is angled to 0 degrees and the obturator is removed. 12. Repeat a. The procedure (steps 8-10) is repeated for the remaining straws. 13. Confirmation a. The Urologist removes the obturator, reattaches the bridge with scope, and then surveys the bladder to confirm presence of rods and absence of injury. b. If there is retained air in bladder, the urologist evacuates the air. 14. End of Procedure a. Urologist removes the scope, sheath, and bridge. b. The drapes are removed and the patient is helped off the table. EXAMPLE 4PATENT WM1-006WO Intravesical Administration of Controlled Release Particles (Delivery Device)

[0233] In this example, a female patient is administered intravesical controlled release particles using the devices of the present invention. The procedure summarized below for two different amounts of product. 1. Urethral Custody x 4, Delivery of Product x1 = 10 gram a. A 10-inch sheath (straw) is loaded with 2.5 gram of product measuring 200 mm (approx.8 inches). b. The sheath has an introducing tip that is blunt and acts as a one-way valve (e.g., a flip open valve, a duck-bill valve, a Heimlich valve, etc.). c. The sheath is inserted through the urethra into the bladder. d. Urine returns through the sheath to demonstrate entry. e. The sheath has a one-way valve on the external end to prevent reflux of product form the sheath during transit or during procedure. f. An obturator (pushing mechanism) is used to advance past the external valve and deliver the loaded product antegrade into the bladder. i. The force from the obturator is transmitted along the column of product and forces the introducer tip open. ii. This force cannot exceed the brittleness of the drug product. g. The obturator is advanced to its full length to dock with the posterior portion of the sheath. h. The sheath and the obturator are removed together. i. The process is repeated to deliver the target product amount in 2.5 gram increments. j. The sheath has a stiffness that resists kinking up to forces seen in packaging, transit, and user handling. k. The sheath may have a distal bump or ramp which directs the product off the axis of advancement as it exits the sheath. l. The sheath may have a dilation (e.g., 4 – 6 centimeters) from the introducer end to limit advancing of the sheath into the bladder.PATENT WM1-006WO m. In aspects, the sheath can hold the product and undergo concurrent ebeam sterilization (or other) without compromising sterility of product. 2. Urethral Custody x1, Delivery of Product x4 = 10 gram a. The distal tip of a gun-like device is inserted into the urethra. b. Several “magazines” of drug product are loaded and docked to the device in such a manner that they can be delivered sequentially through the urethra: i. In one embodiment, they are horizontal (i.e., matching axis of delivery) and brought in line with the main channel of the device one at a time. Once in line, the drug product is expelled from the magazine, through the main channel, and into the bladder. The spent magazine is then replaced with a full magazine and the process repeated. ii. In one embodiment, the magazine is a straw-like sheath. iii. In one embodiment, the magazine is expelled by means of a mechanical slide (operated by hand, by robotic piston, or other means). iv. In one embodiment, the magazine is expelled by the force of a gas or a liquid. 3. Urethral Custody x1, Delivery of Product x1 = 10gm a. French horn filled with product that can be delivered with a mechanical slide.

[0234] In aspects, the device includes an indicator of sheath orientation with color, texture or feature to alert an operator through external clue that the orientation of the sheath is internal to the patient. In aspects, an internal anchoring mechanism prevents retrograde movement of delivery mechanism during procedure (e.g., flaps or a balloon).

[0235] The provider can use the below procedure to insert a catheter into the urethra of the patient. The catheter is operatively attached to a handheld delivery device which includes a funnel for feeding cylindrically shaped and buoyant drug products into thePATENT WM1-006WO barrel of the body of the handheld delivery device. The provider actuates a trigger attached to an underside of the housing of the handheld delivery device and delivers time-released drug product into the patient’s bladder through her urethra. EXAMPLE 5 Treatment of Chronic UTI

[0236] In this example, a female patient visits a healthcare provider with signs / symptoms of a UTI. The provider notes that the patient has had three UTI’s within a six-month period. Previously, she has been prescribed oral anitibiotics (i.e., amoxicillin or nitrofurantoin). Although prophylacitc oral antibiotics are an option, the patient wishes to avoid them. Further, the healthcare provider acknowledges the risk of antibiotic resistance.

[0237] The provider presents the option of using intravesical controlled release particles. Conventional drug delivery systems (e.g., tablets, capsules, etc.) can suffer from poor bioavailability and fluctuations in plasma drug levels. The use of intravesical particles allows drug delivery at a specified controlled rate and at a target site for greater efficacy and safety.

[0238] Trocars are used during laparoscopic procedures and other minimally invasive surgery to make small, puncture-like incisions in outer tissue layers. These incisions allow surgeons to insert cannulas through which surgical instruments can be introduced. In this example, the provider inserts a trocar 112 into the urethra of the patient as depicted in FIG.15. The trocar can include a distal (internal) flange that opens to retain the trocar in place. It can also include a one-way valve to prevent release of fluid from the bladder during the procedure. As depicted, the trocar can be about 8 cm in length (based on a urethra length of about 6 cm).

[0239] The provider uses the trocar as an entry point for the particles. FIG.16A depicts a magazine loaded with particles; FIG.17 further depicts an obturator. ThePATENT WM1-006WO magazine can include a one-way valve. The magazine can also include a marking or fairing to indicate length. For example, a fairing (i.e., external plastic / rubber structure) 160 can be embedded / attached 6 centimeters from the distal tip. This can indicate that safe insertion point into the trocar and prevent over-insertion and damage to the bladder. An obturator is also depicted. In aspects, the obturator matches the length of the magazine. It can also include a marking or fairing 165 to prevent over-insertion and damage to the bladder. In this example, the provider follows the steps described below. a) insert trocar 112 through urethra of patient; b) secure and open trocar; c) pass magazine through trocar to mark 160; d) insert obturator into magazine to mark 165 to expel particles; e) remove obturator and magazine; f) repeat steps (c) – (e) until full dose is administered (e.g., four magazines); g) remove trocar 112 from patient.

[0240] In summary, the provider inserts a magazine into the trocar carefully to avoid contact with the distal end of the bladder. Next, the obturator is used to expel particles from the magazine into the bladder. This step is repeated for a total of four magazines. Next, the trocar is removed from the patient’s urethra. The provider evaluates the patient for discomfort throughout the process.

[0241] The patient reports alleviation of symptoms within six hours of the procedure. The patient has no discomfort nor any feeling of the presence of the particles. The patient is evaluated one week later and has no signs / symptoms of infection. Further, the provider notes that there is no detectable circulating amikacin though it is present in the bladder at an effective concentration. Thereafter, the patient is advised to maintain routine visits to her healthcare provider and to report any signs / symptoms of possible UTI. EXAMPLE 6PATENT WM1-006WO Administration of Intravesical Particles using a Pre-loaded Obturator

[0242] A female patient who resides in a convalescent home experiences recurring urinary tract infections due to her inability to completely void her bladder. After an assessment of the patient’s condition, a physician recommends treatment with anti- infective drug product capsules. The anti-infective drug product capsules are buoyant and float in the urine within a patient’s bladder so that the drug product can release its active agent in a time-release fashion without being voided from the patient prematurely.

[0243] In this example, the obturator comes pre-loaded with particles (FIG.17). The provider inserts the obturator into the trocar and carefully avoids contact with the distal end of the bladder. Next, a handle or lever is used to expel the particles from the obturator into the bladder. The obturator is removed. These steps are repeated for a total of four obturators. Next, the trocar is removed from the patient’s urethra. FIG.17 depicts variations in the design of the obturator. In aspects, the obturator includes thumb catches 170. The thumb catches can be arranged in pairs at positions 0° and 180° or 90° and 270° from one another.

[0244] In embodiments, the devices and methods herein allow intravesical administration as a one-person procedure. In aspects, drug products can be administered without visualization by the health care provider (i.e., as a blind procedure).

[0245] In embodiments, the devices and methods described herein can transmit pieces of drug product (e.g., 160 pieces of 4x5 mm, 80 pieces of 4x10 mm, or 40 pieces of 5x15 mm to achieve 10 grams of delivered dose, etc.) through the female or male urethra into the bladder.

[0246] In embodiments, the devices and methods described herein prevent lateral movement, antegrade movement and / or retrograde catheter movement to improvePATENT WM1-006WO comfort or decrease pain during an intravesical administration procedure.

[0247] In embodiments, the devices and methods described herein have tactile feedback. This can alert the healthcare provider to adjust / terminate procedure if there is a blockage. EXAMPLE 7 Administration of Intravesical Particles using a device with an Intravesical Sheath

[0248] In this example, a female patient reports multiple and recurring urinary tract infections to her healthcare provider. After an assessment of the patient’s condition, the provider recommends treatment with anti-infective drug product capsule groupings. The anti-infective drug product capsule groupings are buoyant and float in the urine within the bladder so that the drug product is released over a period of time (e.g., five days).

[0249] The provider inserts an intravesical sheath 80 into the patient’s urethra and secures the sheath into place with the lobed distal end 95. Once the intravesical sheath is locked in place, a delivery chamber 110 is connected to the sheath (e.g., by securing to a threaded portion). The provider inserts the anti-infective drug product grouping through the interior lumen of the intravesical sheath by twisting a proximal handle of a threaded piston operatively connected to the proximal end of the intravesical sheath (FIG.4A). The action of the piston pushes the anti-infective drug product grouping past the inflatable depth-locking member 55 of the intravesical sheath and into the bladder of the patient. The practitioner repeats this step so that a total of four magazines are used. The intravesical sheath is removed from the patient, and the provider schedules the patient for a follow-up appointment.

[0250] The provider follows up with the patient two weeks after the procedure. The patient reports no discomfort and the provider finds no evidence of urinary tract infection.PATENT WM1-006WO EXAMPLE 8 Administration of “Tethered” Intravesical Particles

[0251] A female patient who resides in a convalescent home, experiences recurring urinary tract infections (UTIs) due to her inability to completely void her bladder. After an assessment of her condition, a physician recommends treatment with intravesical administrated antibiotics. The physician recommends a course of amikacin administered via tethered drug products (i.e., particles or cylinders).

[0252] As shown in FIG.4A, the tethered drug products are stacked and administered in the form of a cylinder (i.e., the administration phase) through the urethra. Upon exposure to urine in the bladder, the cylinders separate but stay attached to one another by a tether (i.e., the retaining phase). Due to their combined size, the tethered cylinders are resistant to being voided during urination.

[0253] The tether gradually dissolves during a period when an active agent is released from the particles (e.g., an amikacin). In this example, the tether maintains intact for about ten days as the amikacin is released into the bladder. The concentration of amikacin in the bladder remains relatively constant during this period.

[0254] The patient is periodically evaluated during the course of treatment. Approximately 48 hours after administration, she has no signs / symptoms of UTI and more than 90% of the particles remain in her bladder (via ultrasound). After ten days, most of the particles have separated from each other and are voided during urination. After two weeks, cylinders are absent from the bladder. EXAMPLE 9 Administration of “Confirmational Changing” Intravesical Particles

[0255] A female patient who visits a healthcare professional and complains of recurring urinary tract infections (UTIs). The healthcare provider notes that the patient had recently been treated with broad spectrum antibiotics (oral) for UTI. After anPATENT WM1-006WO assessment of her condition, a physician recommends treatment with intravesical administrated antibiotics. The use of intravesical particles allows drug delivery at a specified controlled rate and at a target site (i.e., the urinary tract) for greater efficacy and safety. Specifically, the provider recommends a course of amikacin administered via confirmational changing drug products (i.e., connected cylinders).

[0256] As shown in FIG.3A, the drug products are stacked and administered in the shape of a cylinder (i.e., administration phase) through the urethra. Upon exposure to urine in the bladder, the cylinders separate but stay attached to one another by a link or tether (i.e., retaining phase) at or near a capped region. Due to their combined size, the particles are resistant to being voided during urination.

[0257] The linker portion gradually dissolves as the amikacin is released from the cylinders into the bladder. In this example, the link portion stays intact for about ten days. The concentration of amikacin in the bladder remains relatively constant during this period.

[0258] The patient is periodically evaluated during the course of treatment. Approximately 48 hours after administration, she has no signs / symptoms of UTI and more than 90% of the cylinders remain in her bladder (as observed by ultrasound). After ten days, most of the cylinders have separated from each other and are voided during urination. After two weeks, cylinders are absent from the bladder. EXAMPLE 10 Administration Intravesical Particles with Bioresorbable Polymer Linkers

[0259] As in the above example, a female patient who visits a healthcare professional and complains of recurring urinary tract infections (UTIs). The physician recommends treatment with intravesical administrated antibiotics. Specifically, the provider recommends a course of amikacin administered via confirmational changing drug products (i.e., connected cylinders).PATENT WM1-006WO

[0260] As described above, the drug products are stacked and administered in the shape of a cylinder (i.e., administration phase) through the urethra. Upon exposure to urine in the bladder, the cylinders remain attached to one another by a link or tether (i.e., retaining phase).

[0261] As shown in FIG.3G, at least a portion of the cylinders includes a material that swells upon exposure to liquid. This occurs during the retention phase. Swelling causes the cylinders to be released from the caps. Thereafter, the individual cylinders and cap portion are readily excreted in the urine (i.e., the elimination phase).

[0262] In this example, the composition of the cylinders is modified to extend the duration of the retention phase. The cylinders and cap assembly can be modified or “tuned” to extend the retention phase. One approach relates to the use of an enteric coating. As shown in FIG.3H, the rods can be coated. The outer layer can reduce water movement / absorption. The coating gradually dissolves upon exposure to urine in the bladder.

[0263] FIG.3I shows the results of a comparison of different coatings (i.e., percent of rods retained over a 21-day period). Poly(acrylic acid) (“PAA”) cylinders with the following coatings were compared: ^ 10% DBVH ^ 10% LT460 ^ 20% LT460 ^ 60% LT460 ^ 7% DBHV ^ 10% LT435 In this study, PAA cylinders coated with 60% LT460 provided the most preferred retention period. In aspects, the cylinders are coated multiple times (i.e., multiple layers) to extend the retention period.

[0264] Alternatively, the cylinder can be made from combining materials. A swellable (i.e., hygroscopic) material can be combined with a hydrophobic material. Doing soPATENT WM1-006WO reduces the rate of swelling and extends the retention phase. As depicted in FIG.3J, other approaches include: “A Dissolving Hinge” – i.e., using a dissolving hinge portion. For example, the silicon material of the hinge can be replaced with a bioresorbable elastomer. “Push Out Rod” – Pores on hinge allow water diffusion and then material swells to push rod out. “Weaken Hinge” – Slits on hinge increase freedom of movement as adhesive material loses its strength “Release Rod” – Butt Joint (no socket overlap on rod) so when adhesive dissolves then rods release “Disassemble Hinge” – Use an erodible / dissolvable material for the hinge connector. EXAMPLE 11 Use of Buoyant Medical Devices

[0265] In embodiments, devices that are placed within fluid-filled organs, such as the bladder for drug delivery (or other therapeutic effects) are buoyant in the bodily fluid.

[0266] In this example, a device for intravesical drug delivery to minimize irritation of the sensory nerves of the bladder trigone in order to provide therapeutic treatment within the bladder. Such improvements decrease the pressure that the intravesical therapeutic device places on the trigone of the bladder as defined by the space defined by the urethral opening centrally and the bilateral ureteral orifices.

[0267] For example, US Patent No.11,135,161 teaches implantable devices for delivery of drugs to a patient where the device includes a first drug portion which has a first drug housing which contains a first drug formulation in a solid form; and a second drug portion which includes a second drug housing which contains a second drug formulation. Variations also include a device having a drug reservoir component which has an elastic tube having at least one lumen bounded by a porous sidewall having an open-cell structure, a closed-cell structure, or a combination thereof; and a drugPATENT WM1-006WO formulation contained within the at least one lumen, wherein the device is deformable between a low-profile deployment shape and a relatively expanded retention shape.

[0268] The implantable devices, including the ones discussed above can be modified to decreasing any pressure caused by delivery of the device to the trigone region. For example, the flotation or buoyancy of the delivery device can be modified by attaching the device to a buoyant object such that the combined density of the buoyant object and the drug delivery device is within 20% of the density of the urine in the bladder (assuming urine specific gravity of 1.005 to 1.03).

[0269] In additional variations, the buoyant object can include a central chamber (e.g., a balloon or other gas reservoir) where the buoyant object has a mass of low density material such as a lipid (e.g., glyceryl tristearate). In another variation, the intravesical drug delivery device includes in part or in whole a gas, liquid, or solid whose density is less than urine where a portion of the drug reservoir or retention reservoir is filled with a gas such as oxygen, nitrogen, carbon dioxide, carbon tetrafluoride, etc. EXAMPLE 12 Delivery of Drug Product into Bladder of Male Patient

[0270] In this example, drug products are delivered into the bladder of a male patient. The procedure is preferably outpatient and entails the use of a flexible device (single use). The maximum outer diameter of the device that crosses the urethra is 10mm with a preference for a device / conduit that is 7mm or smaller. The inner diameter of the device must be sufficient to transmit the drug product. As described herein, the drug product can have a diameter of about 5 mm. The thinner the wall of the conduit, the easier these goals are to achieve. A device made of polytetrafluoroethylene (PTFE) can be preferred as it has good stiffness for thickness and is used in vascular sheaths for this reason.

[0271] The conduit must be able to traverse the male urethra which undergoes a 0-60 degree bend below the prostate. The conduit must not kink as it makes this bend, soPATENT WM1-006WO the conduit needs to be deformable through a range of 0 to 15, 15 to 30, 30 to 45, or 45 to 60 degrees. To prevent kinking, the wall can be reinforced with coiled metal ribbon, plastic ribs, metal spring, etc.

[0272] When the product is inserted into the conduit, each product must be able to push the product in front of it. This means that the inner diameter of the conduit must be such that two drug products can only move forward in single file and cannot cam or ride up on each other. Perhaps you could have to products side by side, but they must not cam / jam with the paired products in front, etc. This causes jamming and product destruction. Friction within the conduit must be minimal in a wet setting, so hydrophobic coatings and PTFE are preferred materials.

[0273] Throughout the conduit, from entry to exit, the inner diameter must not have large step changes that would allow the drug product to become caught, chipped, etc. In existing vascular sheaths, there is a proximal dilated chamber to allow injection of fluid.

[0274] The method of clearing the conduit of drug product and delivering all drug product into the bladder is tricky. The leading edge of the “obturator” must not slip through a gap in either side of the drug product, thus causing camming and product destruction. Instead, the difference in diameter between the drug product and the ID of the conduit must be less than the cross-sectional area of the obturator’s leading face.

[0275] The obturator will have to advance past a bend in the conduit if it is in a male urethra. It is important that the obturator be deformable. This can be accomplished with compliant materials or with an obturator that has a distal “head on a neck”, the head providing the large face for advancing the drug product and the neck allowing deflection of the head off angle from the proximal portion of the advancing obturator.

[0276] Elements of product delivery can be summarized as follows: 1. Insertion of conduit a. Enter urethral meatusPATENT WM1-006WO b. Traverse urethra i. Spongy urethra ii. Membranous urethra iii. Prostatic urethra 2. Confirmation of bladder access a. Return of urine b. Pressure change 3. Custody of urethra to bladder maintained a. Balloon inflation b. Terminal anchoring flaps c. Transmural expansion, pressure, or friction 4. Preparation of bladder for receiving drug product a. Instillation of fluid i. Additional infusion port as part of sheath? 5. Placement of product into conduit a. Docking of magazine b. Manual loading c. Prefilled conduit d. Mechanical loading 6. Delivery of product through conduit into bladder a. Advancement of drug product delivers next b. Advancement of obturator to clear conduit i. Obturator design must negotiate bend 7. Repetition of steps 5 and 6 without reflux of product or bladder fluid a. Valve at proximal or distal end that allows one-way travel of drug product 8. Removal of conduit EXAMPLE 13 Treatment of Bladder Cancer

[0277] In this example, a 75-year-old male patient visits a healthcare provider and complains of blood in the urine, pain with urination, and low back pain. The provider conducts a visual inspection of the bladder via cystoscopy. Pathological examination confirms the presence of tumor cells.

[0278] The provider presents the option of using intravesical controlled release particles. Conventional drug delivery systems (e.g., tablets, capsules, etc.) can suffer from poor bioavailability and fluctuations in plasma drug levels. The use of intravesical particles allows drug delivery at a specified controlled rate and at a target site for greater efficacy and safety.PATENT WM1-006WO

[0279] The patient receives intravesical chemotherapy. Specifically, he receives a single instillation of chemotherapy into the bladder. Cylindrical particles as described herein include mitomycin C (MMC) as an active agent. The particles are administered in a stacked arrangement (i.e., two cylinders joined by a dissolvable linkage). After insertion, the particles undergo a confirmational change an increase in size (i.e., from 4 mm to 10 mm). The particles remain in the bladder as the MMC is released into the bladder and nearby tissue.

[0280] After about five days, the particles undergo a second confirmational change (i.e., from 10 mm to 4 mm) after the course of treatment. The particles (and components) are expelled in the patient’s urine. The provider conducts a second visual inspection of the bladder via cystoscopy. The number and size of the tumors has decreased substantially (i.e., by about 85%). The provider suggests immunotherapy and regular monitoring of the patient’s bladder. EXAMPLE 14 Use of Drug Product with Filamentous Extensions

[0281] An 88-year-old female patient experiences recurring urinary tract infections (UTIs) due to her inability to completely void her bladder. After an assessment of her condition, a physician recommends treatment with intravesical administrated antibiotics. The physician recommends a course of amikacin administered via drug products with extending filamentous structures (i.e., sutures) and administers the drug products into the patient’s urethra via a handheld delivery device.

[0282] As shown in FIG.5B, the drug products are cylinders joined with filamentous extensions. Prior to administration, the filamentous extensions are collapsed onto the circumference of the cylindrical drug products, offering ease of use for loading the handheld delivery device and administering the medicament through the urethra of the patient and into the bladder.PATENT WM1-006WO

[0283] The physician administers the drug products to the patient via the handheld delivery device and follows-up with the patient after one week. During the follow-up appointment, the physician notes that the drug product remains within the bladder eluting medicament and that the patient’s UTI symptoms have abated. At a subsequent appointment (three weeks after administration), the physician conducts an ultrasound of the bladder. The filamentous extensions have dissolved and more than 90% of the drug product has been expelled in the urine.

[0284] The above non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of the disclosed subject matter. These examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the pharmaceutical compositions, or methods and uses for treating a disease or infection. * * *

[0285] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0286] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosedPATENT WM1-006WO herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0287] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term "about." As used herein, the term "about" means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0288] The terms "a," "an," "the" and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed inPATENT WM1-006WO any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0289] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0290] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and / or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

PATENT WM1-006WO CLAIMS What is claimed is:

1. A method of treating and / or preventing an ailment in a subject, the method comprising: a) providing a plurality of linked particles, each linked particle comprised of a first particle joined to a second particle, b) delivering the plurality of linked particles into the urinary bladder of the subject, c) allowing degradation of the at least a portion of the linked particles over a retention phase to form individual particles, d) allowing excretion of the individual particles during urination, wherein each of the plurality of linked particles is comprised of an excipient portion and an active agent, and wherein the active agent is released into the urinary bladder during at least a portion of the retention phase.

2. The method of claim 1, wherein the ailment is a urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis.

3. The method of claim 1, further comprising a step of diagnostic imaging.

4. The method of claim 1, further comprising a step of observing a color change in excreted urine over at least a portion of the period of the retention phase.

5. The method of claim 1, wherein each of the plurality of linked particles is substantially cylindrically shaped.

6. The method of claim 1, wherein each of the plurality of linked particles is buoyant in urine.PATENT WM1-006WO 7. The method of claim 1, wherein each of the plurality of linked particles has a hollow core.

8. The method of claim 1, wherein each of the plurality of linked particles has a solid core.

9. The method of claim 1, wherein the excipient portion is comprised of a degradable material.

10. The method of claim 1, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

11. The method of claim 1, wherein the active agent is one or more of an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulating agent an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

12. The method of claim 11, wherein the anti-infective agent is an antibacterial agent.

13. The method of claim 11, wherein the anti-infective agent is an anti-fungal agent.

14. The method of claim 11, wherein the anti-infective agent is an antiviral agent.

15. The method of claim 11, wherein the anti-infective agent comprises elemental silver, silver ions, a silver salt, or a silver coordination compound.

16. The method of claim 11, wherein the anti-infective agent comprises silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate,PATENT WM1-006WO silver tetrafluoroborate, silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate, silver sulfadiazine (fosfomycin), or a degradation product of fosfomycin generated in situ.

17. The method of claim 1, wherein the step of delivering the plurality of linked particles into the urinary bladder of the subject comprises intraurethral delivery.

18. The method of claim 1, wherein a syringe is used in the step of delivering the plurality of linked particles into the urinary bladder of the subject.

19. The method of claim 1, wherein the retention phase is more than one month.

20. The method of claim 1, wherein each of the plurality of linked particles has a cross- sectional diameter of about 4 mm of less for insertion, and a cross-sectional diameter of about 10 mm or more during retention, and a cross-sectional diameter of about 4 mm or less for excretion.

21. The method of claim 1, wherein each of the plurality of linked particles is comprised of a matrix and the pharmacologically active agent dispersed therein.

22. The method of claim 1, wherein each of the plurality of linked particles is comprised of a coating on a core that comprises the pharmacologically active agent dispersed therein.

23. The method of claim 1, wherein the plurality of linked particles are dispersed in a liquid vehicle for delivery into the urinary bladder of the subject.

24. The method of claim 22, wherein the liquid vehicle comprises at least one of a viscosity adjusting agent, a tonicity adjusting agent, a buffer and a dispersant.PATENT WM1-006WO 25. The method of claim 1, wherein the active agent is released into the bladder at a substantially steady state.

26. The method of claim 1, where the step of delivering the plurality of linked particles into the urinary bladder of the subject further comprises disrupting biofilm with the urethra or bladder.

27. The method of claim 1, where the plurality of linked particles is administered to the bladder of the patient in a stacked arrangement.

28. A method of treating and / or preventing an ailment in a subject, the method comprising: a) providing a plurality of particles arranged in a first confirmation, each particle comprised of an excipient portion and an active agent, b) delivering the plurality of particles into the urinary bladder of the subject, c) allowing the plurality of particles to transition to a second confirmation in the bladder, d) releasing an active agent from the plurality of particles into the bladder of the subject, and e) allowing the plurality of particles to separate from one another so that they are excreted during urination.

29. The method of claim 28, wherein the shape of each particle is a cylinder, a sphere, a tear drop, a horseshoe, a pretzel, a rod, a pyramid, a cube, a prism or a straw.

30. The method of claim 28, wherein the ailment is a urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure, chronic inflammatory disease or cystitis.

31. The method of claim 28, further comprising a step of diagnostic imaging.PATENT WM1-006WO 32. The method of claim 28, further comprising a step of observing a color change in urine when the plurality of particles are excreted.

33. The method of claim 28, wherein each of the plurality of particles is substantially cylindrically shaped.

34. The method of claim 28, wherein each of the plurality of particles is buoyant in urine.

35. The method of claim 28, wherein each of the plurality of particles has a hollow core.

36. The method of claim 28, wherein each of the plurality of particles has a solid core.

37. The method of claim 28, wherein the excipient portion is comprised of a degradable material.

38. The method of claim 28, wherein the active agent is a medicament for treating a disorder of the urinary system.

39. The method of claim 28, wherein the active agent is one or more of an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

40. The method of claim 39, wherein the anti-infective agent is an antibacterial agent.

41. The method of claim 39, wherein the anti-infective agent is an anti-fungal agent.

42. The method of claim 39, wherein the anti-infective agent is an antiviral agent.PATENT WM1-006WO 43. The method of claim 39, wherein the anti-infective agent comprises elemental silver, silver ions, a silver salt, or a silver coordination compound.

44. The method of claim 39, wherein the anti-infective agent comprises silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate, silver tetrafluoroborate, silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate, silver sulfadiazine (fosfomycin), or a degradation product of fosfomycin generated in situ.

45. The method of claim 28, wherein the step of step of delivering the plurality of linked particles into the urinary bladder of the subject comprises intraurethral delivery.

46. The method of claim 28, wherein a syringe is used in the step of delivering the plurality of linked particles into the urinary bladder of the subject.

47. The method of claim 28, wherein the plurality of particles remains in the second confirmation for more than one week or longer.

48. The method of claim 28, wherein each of the plurality of linked particles has a cross- sectional diameter of about 4 mm of less in the first confirmation, and a cross-sectional diameter of about 10 mm or more in the second confirmation, and a cross-sectional diameter of about 4 mm or less after separation.

49. The method of claim 28, wherein each particle of the plurality of particles is comprised of a matrix and the pharmacologically active agent dispersed therein.

50. The method of claim 28, wherein each of the plurality of particles is comprised of a coating on a core that comprises the pharmacologically active agent dispersed therein.PATENT WM1-006WO 51. The method of claim 28, wherein the plurality of particles is dispersed in a liquid vehicle for delivery into the urinary bladder of the subject.

52. The method of claim 51, wherein the liquid vehicle comprises at least one of a viscosity adjusting agent, a tonicity adjusting agent, a buffer and a dispersant.

53. The method of claim 28, wherein the active agent is released into the bladder over a period of about one month.

54. The method of claim 28, wherein the active agent is released into the bladder at a substantially steady state.

55. The method of claim 28, where the step of delivering the plurality of particles into the urinary bladder of the subject further comprises disrupting biofilm with the urethra or bladder.

56. The method of claim 28, where the first confirmation of the plurality of particles is a stacked arrangement.

57. The method of claim 28, where the first confirmation of the plurality of particles is a stacked arrangement with a diameter of about 4 mm or less.

58. The method of claim 28, where the second confirmation of the plurality of particles is a zigzag or circular arrangement.

59. The method of claim 28, where the second confirmation of the plurality of particles is a zigzag or circular arrangement with a diameter of about 10 mm or more.

60. An intravesical drug delivery system, the system comprised of a plurality of particles, each particle having an excipient portion and an active agent, wherein the particles are buoyant in urine.PATENT WM1-006WO 61. The intravesical drug delivery system of claim 60, wherein the particles are substantially cylindrically shaped.

62. The intravesical drug delivery system of claim 60, wherein the particles are buoyant in urine.

63. The intravesical drug delivery system of claim 60, wherein the particles have a hollow core.

64. The intravesical drug delivery system of claim 60, wherein the particles have a solid core. 65.The intravesical drug delivery system of claim 60, wherein the excipient portion is comprised of a degradable material.

66. The intravesical drug delivery system of claim 60, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

67. The intravesical drug delivery system of claim 60, wherein the active agent is one or more of an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

68. The intravesical drug delivery system of claim 67, wherein the anti-infective agent is an antibacterial agent.

69. The intravesical drug delivery system of claim 67, wherein the anti-infective agent is an anti-fungal agent.PATENT WM1-006WO 70. The intravesical drug delivery system of claim 67, wherein the anti-infective agent is an antiviral agent.

71. The intravesical drug delivery system of claim 67, wherein the anti-infective agent comprises elemental silver, silver ions, a silver salt, or a silver coordination compound.

72. The intravesical drug delivery system of claim 67, wherein the anti-infective agent comprises silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate, silver tetrafluoroborate, silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate, silver sulfadiazine (fosfomycin), or a degradation product of fosfomycin generated in situ.

73. An intravesical delivery system, the system comprised of: a) an insertion tip, b) a body, c) a pressure source, and d) a loading funnel, wherein an intravesical formulation passes from the loading funnel through the body and out of the insertion tip into a bladder of a subject.

74. The intravesical delivery system of claim 73, wherein the intravesical formulation is comprised of particles.

75. The intravesical delivery system of claim 74, wherein the particles are contained within two structures connected by a tether.

76. The intravesical delivery system of claim 74, wherein the particles are contained within two cylinder-shaped structures connected by a tether.PATENT WM1-006WO 77. The intravesical delivery system of claim 74, wherein the particles are contained within two rod-shaped structures connected by a tether.

78. The intravesical delivery system of claim 74, wherein each particle of the formulation has an excipient portion and an active agent.

79. The intravesical delivery system of claim 78, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

80. The intravesical delivery system of claim 78, wherein the active agent is one or more of an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

81. The intravesical delivery system of claim 73, wherein the insertion tip is comprised of an inflatable balloon.

82. The intravesical delivery system of claim 73, wherein the insertion tip is variable in length.

83. The intravesical delivery system of claim 73, wherein the insertion tip is comprised of a threaded lock ring set.

84. The intravesical delivery system of claim 83, wherein the threaded lock ring set is adjusted to a size of the subject’s urethra.

85. The intravesical delivery system of claim 73, wherein the insertion tip is comprised of an internal sheath.PATENT WM1-006WO 86. The intravesical delivery system of claim 73, wherein the insertion tip is comprised of a plurality of soft grapple members.

87. The intravesical delivery system of claim 83, wherein the threaded lock ring set is adjusted to a size of the subject’s urethra.

88. A method of delivering a substance or formulation into the bladder of a subject using the intravesical delivery system of claim 73.

89. A method of delivering a substance or formulation into the bladder of a subject, the method comprised of: a) inserting a tip region of a catheter through the urethra and into the bladder, b) securing the tip region, and c) using a pressure source to force the substance or formulation into the bladder from a loading funnel.

88. The method of claim 89, wherein the substance or formulation is comprised of particles.

89. The method of claim 88, wherein the particles are contained within two structures connected by a tether.

90. The intravesical delivery system of claim 88, wherein the particles are contained within two cylinder-shaped structures connected by a tether.

91. The intravesical delivery system of claim 88, wherein the particles are contained within two rod-shaped structures connected by a tether.

92. The method of claim 88, wherein each particle of the formulation has an excipient portion and an active agent.PATENT WM1-006WO 93. The method of claim 92, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

94. The method of claim 92, wherein the active agent is one or more of an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an agent for treating kidney stones, an immunomodulating agent, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

95. The method of claim 89, wherein an inflatable balloon is used in the step of securing the tip region.

96. The method of claim 89, further comprising a step of adjusting the length of the tip region of the catheter using a threaded lock ring set.

97. The method of claim 89, wherein an internal sheath is used in the step of securing the tip region.

98. The method of claim 89, wherein a plurality of soft grapple members is used in the step of securing the tip region.

99. A method for delivering an active agent into the bladder of a subject, the method comprising: a) inserting a distal end of a lumen device through a patient’s urethra and into the patient’s bladder, wherein an opposing proximal end of the lumen device remains outside of the patient; b) securing the distal end of the lumen device; b) driving a plurality of particles out of a lumen in the distal end of the lumen device and into the bladder and out of the lumen, c) removing the lumen device from the patient’s urethra; andPATENT WM1-006WO d) allowing the plurality of particles to degrade or dissolve thereby releasing an active agent into the patient’s bladder.

100. The method of claim 99, wherein the particles are contained within two structures connected by a tether.

101. The method of claim 99, wherein the particles are contained within two cylinder- shaped structures connected by a tether.

102. The method of claim 99, wherein the particles are contained within two rod-shaped structures connected by a tether.

103. The method of claim 99, wherein each particle of the plurality of particles has an excipient portion and an active agent.

104. The method of claim 103, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

105. The method of claim 103, wherein the active agent is one or more of an anti- infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

106. The method of claim 99, wherein an inflatable balloon is used in the step of securing the tip region.

107. The method of claim 99, further comprising a step of adjusting the length of the tip region of the catheter using a threaded lock ring set.PATENT WM1-006WO 108. The method of claim 99, wherein an internal sheath is used in the step of securing the tip region.

109. The method of claim 99, wherein a plurality of soft grapple members is used in the step of securing the tip region.

110. The method of claim 99, wherein the subject suffers from a disorder of the urinary system.

111. The method of claim 99, wherein the disorder of the urinary system is one or more of a urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis 112. The method of claim 99, further comprising a step of treating the subject for a disorder of the urinary system.

113. The method of claim 103, where the active agent is one or more of a urease inhibitor, a chelating agent, an antibacterial agent and an enzyme.

114. The method of claim 99, wherein the particles are substantially cylindrically shaped.

115. The method of claim 99, wherein the particles are buoyant in urine.

116. The method of claim 99, wherein the particles are comprised of an excipient portion that degrades in the bladder.

117. The method of claim 116, wherein the excipient portion degrades over a period of time that is more than one month.PATENT WM1-006WO 118. The method of claim of claim 103, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

119. The method of claim 103, wherein the active agent is one or more of an anti- infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

120. The method of claim 103, wherein the active agent is an antibacterial agent, anti- fungal agent or an antiviral agent.

121. The method of claim 103, wherein the active agent is comprised of elemental silver, silver ions, a silver salt, or a silver coordination compound.

122. The method of claim 99, wherein the subject is male.

123. The method of claim 99, wherein the subject is female.

124. The method of claim 103, wherein the particles are comprised of a coating on a core that comprises the active agent dispersed therein.

125. The method of claim 99, wherein the particles are dispersed in a liquid vehicle for delivery into the urinary bladder of the subject.

126. The method of claim 125, wherein the liquid vehicle comprises at least one of a viscosity adjusting agent, a tonicity adjusting agent, a buffer and a dispersant.

127. The method of claim 99, further comprising a step of determining a specific volume or number of particles to be administered based on a desired dose of the active agent.PATENT WM1-006WO 128. A system for intravesical administration of an active agent, the system comprised of: a) a plurality of particles arranged in a first confirmation, each particle comprised of an excipient portion and the active agent, b) wherein the plurality of particles is configured to expand to a second confirmation upon exposure to fluid, c) wherein the plurality of particles is configured to release an active agent from the plurality of particles upon exposure to fluid, and d) wherein the plurality of particles is configured to separate into individual particles after a retention period in fluid.

129. The system of claim 128, wherein each of the plurality of particles is substantially cylindrically shaped.

130. The system of claim 128, wherein each of the plurality of particles is buoyant in urine.

131. The system of claim 128, wherein each of the plurality of particles has a hollow core.

132. The system of claim 128, wherein each of the plurality of particles has a solid core.

133. The system of claim 128, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

134. The system of claim 128, wherein the active agent is one or more of an anti- infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, anPATENT WM1-006WO immunomodulator an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

135. The system of claim 134, wherein the anti-infective agent is an antibacterial agent.

136. The system of claim 134, wherein the anti-infective agent is an anti-fungal agent.

137. The system of claim 134, wherein the anti-infective agent is an antiviral agent.

138. The system of claim 134, wherein the anti-infective agent comprises elemental silver, silver ions, a silver salt, or a silver coordination compound.

139. The system of claim 134, wherein the anti-infective agent comprises silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate, silver tetrafluoroborate, silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate, silver sulfadiazine (fosfomycin), or a degradation product of fosfomycin generated in situ.

140. The system of claim 128, wherein the shape of each particle is a cylinder, a sphere, a tear drop, a horseshoe, a pretzel, a rod, a pyramid, a cube, a prism or a straw.

141. A method of treating an ailment, the method comprised of intravesical administration of the system of claim 128.

142. The method of claim 141, wherein the ailment is a urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis.PATENT WM1-006WO 143. A method of treating and / or preventing an ailment in a subject, the method comprising: a) providing a plurality of particles, each particle comprised of a first particle joined to a second particle by a linkage, b) delivering the plurality of particles into the urinary bladder of the subject, c) allowing degradation of the linkage and / or particles over a retention phase, d) allowing excretion of the linkage and particles during urination, wherein each of the plurality of particles is comprised of an excipient portion and an active agent, and wherein the active agent is released into the urinary bladder during at least a portion of the retention phase.

144. The method of claim 143, wherein the ailment is a urinary tract infection, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anticoagulant disease, overactive bladder, underactive bladder, retained urine, diabetes, heart failure, kidney failure or cystitis.

145. The method of claim 143, further comprising a step of diagnostic imaging.

146. The method of claim 143, further comprising a step of observing a color change in excreted urine over at least a portion of the period of the retention phase.

146. The method of claim 143, wherein each of the plurality of particles is substantially cylindrically shaped.

147. The method of claim 143, wherein each of the plurality of particles is buoyant in urine.

148. The method of claim 143, wherein each of the plurality of particles has a hollow core.

149. The method of claim 143, wherein each of the plurality of particles has a solid core.PATENT WM1-006WO 150. The method of claim 143, wherein the excipient portion is comprised of a degradable material.

151. The method of claim 143, wherein the active agent is a drug for the treatment of a disorder of the urinary system.

152. The method of claim 143, wherein the active agent is one or more of an anti- infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or an anti-coagulant, a chemotherapeutic agent, an agent for the treatment of incontinence, a renin-angiotensin-aldosterone system (RAAS) inhibitor, an immunomodulating agent an agent for treating kidney stones, an agent for gene therapy or a contrast agent for diagnostics and monitoring.

153. The method of claim 143, wherein the step of delivering the plurality of particles into the urinary bladder of the subject comprises intraurethral delivery.

154. The method of claim 143, wherein a syringe is used in the step of delivering the plurality of particles into the urinary bladder of the subject.

155. The method of claim 143, wherein the retention phase is more than one month.

156. The method of claim 143, wherein each of the plurality of particles is comprised of a matrix and the pharmacologically active agent dispersed therein.

157. The method of claim 143, wherein each of the plurality of particles is comprised of a coating on a core that comprises the pharmacologically active agent dispersed therein.

158. The method of claim 143, wherein the plurality of particles is dispersed in a liquid vehicle for delivery into the urinary bladder of the subject.PATENT WM1-006WO 159. The method of claim 158, wherein the liquid vehicle comprises at least one of a viscosity adjusting agent, a tonicity adjusting agent, a buffer and a dispersant.

160. The method of claim 143, wherein the active agent is released into the bladder over a period of about one month.

161. The method of claim 143, wherein the active agent is released into the bladder at a substantially steady state.

162. The method of claim 143, where the step of delivering the plurality of particles into the urinary bladder of the subject further comprises disrupting biofilm with the urethra or bladder.

163. The method of claim 143, where the plurality of particles is administered to the bladder of the patient in a stacked arrangement.

164. The method of claim 143, where the first of the plurality of particles provide for buoyancy and the second of the plurality of particles is provided for administering an active agent.

165. The method of claim 1, wherein one or more of the plurality of particles has a hollow core.

166. The method of claim 1, wherein one or more of the plurality of particles has a solid core.

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