System and method for sustained release of medication in the bladder

Abstract

Embodiments include systems and methods for treating diseases of the bladder, kidneys, and urinary tract. The drug product may be administered in a compact form through the urethra. In the bladder, the product may expand to a larger size that resists passage through the urethra or conform to that size for a desired period of residence. After the treatment period, at least a portion of the product is soluble or biodegradable, so that the individual particles are excreted in the urine. Embodiments also include drug particle delivery devices and intravesical administration methods. The delivery device may use a straw-shaped cartridge filled with a rod-shaped product that is administered into the patient's bladder by the action of a pressure source or piston. The distal end of the barrel may be connected to a bladder sheath or a soft tip for direct insertion into the patient's urethra.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 524,229 filed on 30 June 2023 and U.S. Provisional Patent Application No. 63 / 541,493 filed on 29 September 2023. The contents of these applications are incorporated herein by reference.

[0002] The present invention relates generally to medical devices, and more specifically to devices and methods for administering pharmacologically active drugs intravesically to treat or prevent disorders of the urinary tract. [Background technology]

[0003] A urinary tract infection (UTI) is an infection that affects the urethra. 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 of a lower urinary tract infection include pain during urination, frequent urination, and the urge to urinate even when the bladder is empty. The most common cause of UTIs is Escherichia coli, but other bacteria or fungi can also cause them. Risk factors include female anatomy, sexual activity, diabetes, obesity, and family history. In asymptomatic 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 of recurrent infections.

[0004] The risk of developing a urinary tract infection (UTI) increases with age. UTIs are particularly common in older adults using catheters or those residing in nursing homes or other long-term care facilities. Other diseases 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 65 have reported having had a UTI in the past year. This number rises to nearly 30 percent in women over 85. Men also tend to experience more UTIs with age. Recent studies indicate that more than one-third of all infections in nursing home residents are UTIs. In many cases, chronic urinary tract infections may require ongoing medication, which can gradually increase antibiotic resistance and ultimately lead to kidney damage.

[0005] If not treated promptly or appropriately, infections caused by UTIs can spread. UTIs can eventually lead to bladder infections. This carries the risk of the infection spreading to the kidneys via the ureters, which can lead to more serious consequences, including renal failure and sepsis (i.e., urinary tract sepsis). This occurs frequently in elderly patients. In many cases, elderly patients do not present the typical signs of infection until sepsis develops, at which point hospitalization is required.

[0006] UTIs and the complications they cause often require hospitalization, making treatment costly. In many cases, UTIs are only treated after the infection has developed and become symptomatic. Current treatments aimed at preventing UTI formation require continuous prophylactic oral medication, which has side effects common to long-term medication. Furthermore, long-term use of antibiotics can lead to drug-resistant bacteria. In many cases, UTIs reduce quality of life, especially if kidney damage leads to renal failure requiring dialysis or donor kidney transplantation.

[0007] Traditionally, UTIs are treated with oral antibiotics. High doses of antibiotics are required to ensure an effective amount reaches the urinary tract. When systemic delivery of drugs is used to treat UTIs, the volume of distribution of the therapeutic agent is equal to the total volume of urine entering the bladder. Therefore, the therapeutic agent is excreted each time the bladder is emptied, requiring constant replenishment. In other cases, the target of the drug may be limited (i.e., the bladder wall), but it is practically impossible to reach the desired therapeutic concentration without increasing the drug concentration in the urine.

[0008] Intravesical therapy refers to a procedure in which therapeutic agents are delivered directly into the bladder (e.g., via a catheter or similar device) rather than being administered orally or intravenously. Intravesical therapy is an attractive option for treating UTIs because it allows for local delivery of medication while minimizing side effects. Intravesical administration of pharmaceutically active drugs may also be beneficial for treating other bladder / urinary tract diseases, such as interstitial cystitis, overactive bladder, and cancer.

[0009] Efforts to treat UTIs via intravesical therapy have been successful but limited. Antibiotics injected into the bladder are generally excreted before they can induce a significant therapeutic effect. Implantable devices require surgical procedures for implantation and removal. Recent improvements include implantable devices that gradually dissolve or decompose as the active ingredient is released. For example, International Publication No. 2022216287A1 describes controlled-release pharmaceutical formulations administered into a patient's bladder. The formulations contain particles that are buoyant in the urine and can remain in the patient's bladder during a course of antibiotic treatment. However, formulations are limited to small particles that can be administered through the urethra. Furthermore, the particles tend to be prematurely expelled during urination. Also, the particles are administered using conventional syringes, which can be problematic. [Overview of the project] [Problems that the invention aims to solve]

[0010] Conventional syringes are designed for injecting fluids and are prone to occlusion or blockage. Furthermore, syringes can cause and exacerbate patient discomfort. Even relatively large catheters can be ineffective in delivering solid drug products to the bladder. Therefore, there is an unaddressed need for a device that can reliably deliver solid drug products (e.g., spheres, rods, or other shapes) through the urethra without damaging the product or causing patient discomfort. There is also a need for small particles that can expand in the bladder so as not to be prematurely excreted in the urine.

[0011] The compositions and methods described herein can serve these purposes and may be particularly beneficial to patients at risk of UTIs, such as the elderly or those with disabilities. The systems and methods described herein may also be used to treat other diseases of the bladder / urethra / kidneys, such as cancer, overactive bladder, and cystitis. [Means for solving the problem]

[0012] The invention described and claimed herein has many attributes and embodiments, including, but not limited to, those specified, described, or referenced in this brief summary. The invention described and claimed herein is not limited to, or limited by, the characteristics or embodiments specified in this summary, and this summary is included for illustrative purposes only and not limiting.

[0013] Embodiments of the present invention include devices and methods for intravesical delivery of therapeutic agents into the bladder. Multiple floating (or semi-floating) drug products may be temporarily embedded inside the bladder and float in the fluid within the bladder. The drug products may release the therapeutic agent or drug in the bladder by direct absorption, passive or active dissolution, mechanical crushing, or other means.

[0014] In some embodiments, a drug product releases multiple active agents (e.g., to treat multiple diseases or to target drug-resistant bacteria). In some embodiments, drug products are homogeneous with respect to each other. In some embodiments, drug products are not homogeneous (e.g., drug products contain different excipients, have different physical properties, different active agents, and / or different sizes / shapes).

[0015] In various embodiments, the drug product is passively released from the bladder after a period of residence (i.e., no removal procedure is required).

[0016] In various embodiments, the drug product contains a soluble linker material, and the attachment and detachment of the rods are either (a) chemical adhesion or (b) decomposition. Chemical adhesion refers to the adhesive strength that weakens over time and releases the rods. For example, 2-octyl cyanoacrylate is a highly adhesive material that loses its strength over time in water. Decomposition requires the hydrolysis of ester bonds in the PLGA (poly(lactic-co-glycolic acid)) copolymer family. The rate of hydrolysis may vary depending on the molecular weight (MW) of the polymer chain, the lactic acid to glycolic acid ratio, and the ester or acid end caps, etc.

[0017] In various embodiments, the linker material swells and extrudes the rod. The linker material is swellable (due to either thermal deformation or water absorption) and extrudes the rod out of the socket. Poly(methyl methacrylate), poly(acrylic acid), carbopole, and hydroxypropyl methylcellulose are types of materials that swell up to 10 times their original size and extrude the rod. The rate of swelling can be controlled by the type of hydrophilic swelling polymer, its MW, salt, or acetic acid blend, a blend of hydrophilic swelling polymer and non-swellable hydrophobic material, and enteric coatings.

[0018] Accordingly, the embodiments include systems and methods for treating diseases such as urinary tract disorders. In some embodiments, the systems and methods include pharmaceutical formulations for intravesical administration of an active agent. The formulations may comprise particles, each having an excipient portion and an active agent. The formulations may be administered by transurethral delivery using drug delivery devices described herein.

[0019] In various embodiments, particles may adhere to each other (i.e., each package contains a first particle joined to a second particle by a tether). The particles may be administered into the target bladder in a stacked arrangement (i.e., having smaller diameters). The active drug may be released during the retention phase. The tether may then break down, thereby separating the individual particles from each other. The individual particles may be excreted during urination.

[0020] In various embodiments, two particles may adhere to or join with each other. The particles may be administered into the bladder of a target in a stacked configuration. The particles may then be transformed into a second configuration for retention. The active drug may be released during this retention phase. Subsequently, at least a portion of the particles (e.g., cylinder, cap, linker, or hinge) may decompose, thereby separating the individual particles from each other. The individual particles may be excreted during urination.

[0021] In various embodiments, the particles have a cross-sectional diameter of 4 mm or less for insertion, undergo a change in three-dimensional structure to have a cross-sectional diameter of 10 mm or more for retention after insertion into the bladder, and then decrease to a cross-sectional diameter of less than or equal to 4 mm for elimination.

[0022] In various embodiments, the particles may adhere to each other in a first three-dimensional structure that facilitates transurethral administration. After the particles enter the target bladder, they may expand into a second three-dimensional structure that is larger and resistant to excretion. During the retention phase, the active drug may be released from the particles into the bladder. Subsequently, the particles can gradually separate from each other, thereby being excreted during urination.

[0023] This specification also discloses insertable drug delivery devices, including catheter assemblies, and methods for enabling intravesical administration of pharmaceuticals, drug products, gels, devices, etc. Accordingly, embodiments include drug delivery devices for administering drug products into the bladder through the urethra. The device may comprise (a) an insertion tip, (b) a body, (c) a pressure source, and (d) a loading funnel. In some embodiments, the intravesical preparation passes from the loading funnel through the body and into the bladder from outside the insertion tip.

[0024] Embodiments also include methods for delivering a substance or formulation into a patient's bladder. The method may include (a) inserting the distal end of a lumen device into the patient's bladder through the patient's urethra, with the opposing proximal end of the lumen device remaining outside the patient; (b) securing the distal end of the lumen device; (c) driving a plurality of particles outside the lumen at the distal end of the lumen device, as well as inside the bladder and outside the lumen; (d) removing the lumen device from the patient's urethra; and (e) enabling the particles to release the drug from the drug delivery device into the patient's bladder. In some embodiments, the patient suffers from a disease of the bladder, urinary tract, and / or kidneys. The method may also include a step of treating the patient for the disease. In various embodiments, the diseases include urinary tract infections (UTIs), bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorders, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, or cystitis. The method may also include the step of adjusting the number of particles administered based on the desired dose of the active agent.

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

[0026] In some embodiments, the method includes a diagnostic imaging step. In some embodiments, the method includes observing a change in color in the excreted urine over at least a portion of the retention period (i.e., by adding a color indicator to the drug product). [Brief explanation of the drawing]

[0027] [Figure 1] This figure shows graphs representing the percentage of suspended particles for three types (beta, beta prime, and alpha) over a five-day course.

[0028] [Figure 2A] This figure shows cylindrical particles based on various embodiments.

[0029] [Figure 2B] This figure shows particles having a horseshoe shape based on various embodiments.

[0030] [Figure 2C] This is a diagram showing an image of a horseshoe-shaped particle.

[0031] [Figure 2D] This figure shows particles having a bowstring shape based on various embodiments.

[0032] [Figure 2E] This is a diagram showing an image of a particle with the shape of a bowstring.

[0033] [Figure 2F] This figure shows particles having an elbow shape according to various embodiments.

[0034] [Figure 2G] This figure shows an image of a particle with an elbow shape.

[0035] [Figure 3A]This figure shows the geometric shapes of particles that take on three three-dimensional configurations (i.e., a small shape for insertion, a large shape for retention, and a small shape for removal).

[0036] [Figure 3B] This diagram shows the components of a particle along with its geometric shape, including the angles between individual drug products.

[0037] [Figure 3C] This figure shows the particles in Figure 3B, which adopt the three-dimensional configurations for retention and removal.

[0038] [Figure 3D] This diagram shows the particles adopting the three-dimensional configuration of retention, and the three components (i.e., the linker, hinge, and cylindrical rod in which the API is embedded).

[0039] [Figure 3E] This diagram shows a flowchart representing particles in three stages: implantation, drug delivery, and disintegration for removal.

[0040] [Figure 3F] This figure shows different mechanisms for particle separation based on various embodiments.

[0041] [Figure 3G] This figure shows one embodiment in which a cylinder (or a portion thereof) swells and releases a rod upon exposure to a liquid.

[0042] [Figure 3H] This figure shows one embodiment in which the outer layer of the rod includes a layer that reduces water movement / absorption.

[0043] [Figure 3I] This figure shows the results of comparing different coatings (i.e., the percentage of rods that were retained over the long term).

[0044] [Figure 3J] This figure shows an approach to adjusting the residence time of a hinged rod, including steps using hinge melting, rod extrusion, hinge weakening, rod release, and hinge dismantling.

[0045] [Figure 4A] This figure shows a pair of particles joined by a tether, along with three stereochemical configurations: (a) stacked for administration, (b) tethered for retention in the bladder, and (c) separated for excretion in urine.

[0046] [Figure 4B] This figure shows a pair of particles joined by a connecting part, along with three stereochemical configurations: (a) stacked for administration, (b) linked for retention in the bladder, and (c) separated for excretion in urine.

[0047] [Figure 4C] This figure shows a pair of particles joined by a connecting part, along with three stereochemical configurations: (a) stacked for administration, (b) connected for retention in the bladder, and (c) broken down for excretion in urine.

[0048] [Figure 5A] This figure shows an image of particles joined together by a tether (for example, two cylinders).

[0049] [Figure 5B] This figure shows an image of particles joined together by a hinge connection.

[0050] [Figure 5C] This figure shows one embodiment in which a drug product includes a fibrous extension (e.g., a suture) that facilitates the retention of the drug product in the bladder.

[0051] [Figure 6]This figure shows three three-dimensional structural configurations of multiple particles: (a) stacked for administration, (b) joined together for retention in the bladder, and (c) separated for excretion in urine.

[0052] [Figure 7A] This figure shows one embodiment in which multiple drug products (i.e., cylinders) are joined together to form a circular three-dimensional arrangement having a large size for retention in the bladder.

[0053] [Figure 7B] This figure shows one embodiment in which multiple drug products (i.e., spheres) are joined together to form a circular three-dimensional arrangement having a large size for retention in the bladder.

[0054] [Figure 7C] This diagram shows the heterogeneous grouping of drug products.

[0055] [Figure 8] This figure shows a side view of a portable delivery device according to one embodiment of the present invention.

[0056] [Figure 9] This figure shows an overhead view of a depth-locking soft catheter.

[0057] [Figure 10] This figure shows a side view of a static sheath according to one embodiment of the present invention.

[0058] [Figure 11A] This figure shows a static sheath with an internal flexible sheath and an additional locking ring.

[0059] [Figure 11B] This figure shows an alternative design for a delivery device (i.e., "tampon-like") of cotton or similar material inserted into the urethra.

[0060] [Figure 12] This figure shows a catheter having a grapple member extending from its distal end.

[0061] [Figure 13A] This figure shows a first-person view of the chamber of a portable delivery device according to one embodiment of the present invention.

[0062] [Figure 13B] This is a top-down view of the chamber of a portable delivery device.

[0063] [Figure 13C] This figure shows a side view of the chamber of a portable delivery device.

[0064] [Figure 14] This figure shows the delivery of particles into the bladder through the lumen of the device of the present invention.

[0065] [Figure 15] This is a diagram showing a trocar inserted into a patient's bladder.

[0066] [Figure 16A] This is a diagram showing a magazine pre-loaded with particles.

[0067] [Figure 16B] This figure shows an obturator for use with a pre-loaded magazine.

[0068] [Figure 17] This figure shows an obturator pre-loaded with particles. [Modes for carrying out the invention]

[0069] List of reference numbers 5 Delivery devices 10. Main body of the delivery device 15 barrels 20 Insertion tip 25 Funnel area 27. Drug products (e.g., capsules or cylinders) 30 Pressure source 40 Trigger 50 Depth-locking soft catheter 55 Distal end (of a depth-locking soft catheter) 60 Proximal end (of a depth-locking soft catheter) 65 Fender Washer (Spinning Possible) 70 Convex locking nuts 75 Concave locking nut 80 Multi-Lumen Static Sheath 85 Internal tubular member 90 External tubular member 95 Distal end (multi-lumen static sheath) 100 External lock ring 105 Soft Grapple Member 110 Drug product delivery chamber 112 Trocar 115 Screw-type pistons and plungers 120 Loading pins 125 Pin for deloading 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 Catch 175 Tether 180 Fibrous extension 185 Cap 190 Connections 195 Bridge definition

[0070] In this specification, “one embodiment / aspect” or “one embodiment / aspect” means that a particular characteristic, structure, or feature described in relation to an embodiment / aspect is included in at least one embodiment / aspect of this disclosure. The use of the idiomatic phrases “in one embodiment / aspect” or “in another embodiment / aspect” in various places in this specification does not necessarily mean that all of them refer to the same embodiment / aspect, nor that separate or alternative embodiments / aspects are mutually exclusive with other embodiments / aspects. Furthermore, various characteristics are described that may be shown by some embodiments / aspects but not by other embodiments / aspects. Similarly, various requirements are described that may be required for some embodiments / aspects but not for other embodiments / aspects. Embodiments and aspects may be used interchangeably in particular cases.

[0071] The terms used herein generally have their common meanings in the art within the context of this disclosure and in the specific context in which each term is used. Specific terms used to describe this disclosure are discussed below or elsewhere in this specification to provide additional guidance to practitioners regarding the description of this disclosure. It will be understood that the same thing may be referred to in more than one way.

[0072] Accordingly, alternative languages ​​and synonyms may be used for any one or more terms discussed herein. Furthermore, there is no particular importance placed on whether or not a term is detailed or discussed herein. Synonyms for specific terms are provided. The listing of one or more synonyms does not preclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any terms discussed herein, is for illustrative purposes only and is not intended to further limit the scope and meaning of this disclosure or any exemplified terms. Similarly, this disclosure is not limited to the various embodiments presented herein.

[0073] Without any intention to further limit the scope of this disclosure, examples of equipment, apparatus, methods, and their associated results based on embodiments of this disclosure are presented below. Titles or subtitles may be used in multiple examples for the convenience of the reader, but these should not be considered to limit the scope of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. In case of any conflict, including definitions, this document shall prevail.

[0074] The term "overactive bladder" or "OAB" refers to a group of urinary symptoms (not a disease). The most common symptom is a sudden, uncontrolled need or urge to urinate. Some people experience urinary leakage when they feel this urge. Another symptom is a frequent need to urinate during the day and at night. OAB can be described as a constant urge to urinate urgently. Urinary leakage is called "incontinence."

[0075] The term "stress urinary incontinence" or "SUI (stress urinary incontinence)" refers to a different common bladder problem. Individuals with SUI experience urine leakage while sneezing, laughing, or performing other physical activities.

[0076] The terms "interstitial cystitis," "IC (interstitial cystitis)," or "bladder pain syndrome" refer to a chronic or long-lasting condition that causes painful urinary symptoms. Symptoms of IC can vary from person to person. For example, some people experience mild discomfort, pressure, or tenderness in the pelvic area. Others may have severe bladder pain, or suffer from urinary urgency, i.e., a sudden need to urinate, or frequent urination, i.e., a need to urinate more often. Healthcare professionals diagnose IC by ruling out other conditions with similar symptoms.

[0077] The term "immunomodulator" or "immunomodulator" refers to drugs that can support immune function by modifying the immune system's response to a threat in a beneficial way. Immunotherapies designed to induce or amplify the immune response are classified as activating immunotherapies, while those designed to reduce or suppress the immune response are classified as suppressive immunotherapies.

[0078] The term "chronic inflammatory disease" refers to a disease that causes the body to overreact, and in some cases, attack the body itself. For example, in multiple sclerosis, the body's immune system attacks nerve coatings. Chronic inflammation is not a specific disease, but rather a mechanistic process. Numerous diseases are associated with chronic inflammation, including cardiovascular disease (CVD), diabetes, malignant tumors, autoimmune diseases, chronic liver disease, and kidney disease.

[0079] The term "catheter" refers to a flexible tube that can be inserted into a body cavity, conduit, blood vessel, brain, skin, or adipose tissue of a patient or subject through several entry points. Catheters perform several functions, including draining body fluids, enabling the administration of substances and materials to a patient or subject, and allowing surgical instruments to access the patient or subject.

[0080] The term "Foley catheter" refers to a flexible tube that a clinician inserts into the bladder via the urethra to drain urine.

[0081] An "indwelling catheter" is a catheter that is generally held in place by an inflatable balloon attached to the outer body of the catheter.

[0082] A “bladder sheath” refers to a hollow tube that functions as a conduit for introducing surgical instruments, materials, and other media into the urinary tract of an object or patient. As used herein, the sheath refers to the intermediate section of the device located between the distal balloon tip and the proximal lock ring assembly. The primary lumen's main length is within the intermediate sheath section, but the primary lumen is open from end to end to deliver the product through the entire device. The sheath should have low friction both externally and within the primary lumen so that it can be installed with minimal discomfort to the patient and so that the product can slide easily through the sheath. The material may be, for example, silicone-coated fiber, spring, or strut (for combining strength and flexibility in thin materials), PTFE coating for low friction, or metal for strength in thin materials.

[0083] The terms “active agent,” “active ingredient,” “active pharmaceutical ingredient,” or “API (active pharmaceutical ingredient)” refer to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect on the target to which it is administered. In other words, “active agent” or “active ingredient” refers to a component (singular or plural) of a composition to which all or part of the effects of the composition are attributed. An active agent may be a primary active agent, in other words, a component (plural) of a composition to which all or part of the effects of the composition are attributed. An active agent may be a secondary agent, in other words, a component (plural) of a composition to which additional parts and / or other effects of the composition are attributed.

[0084] The term “drug product” means any substance, device, particle, or product suitable for delivery to a subject or patient for the treatment of a disease, condition, illness, or disorder, and may further include excipients, adjuvants, carriers, placebos, powders, foams, gels, liquids, capsules, coatings, timed release mechanisms, delayed release mechanisms, robotic drug delivery, computer-programmed drug products, products driven or induced 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” means a material that is not biologically or otherwise undesirable; that is, a material that can be incorporated into the pharmaceutical compositions presented herein and does not cause any undesirable substantial biological effects or interact in a harmful manner with any other components of the composition. When the term “pharmaceutically acceptable” is used to refer to a solid or semi-solid carrier, liquid medium, or other excipient, that is, to refer to any inactive ingredient herein, it is implied that the carrier or excipient meets the required standards for toxicological and manufacturing testing, and / or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration and designated as “Generally Regarded as Safe” (GRAS).

[0086] The term "controlled-release" or "CR (controlled-release)" refers to a drug delivery method, carrier, or other platform that releases the active ingredient at a predetermined rate to maintain a constant drug level in the patient's body for a predetermined period. This allows the drug level to remain at an effective level for a given time. Unlike sustained-release (SR) forms, CR drug delivery methods allow for precise control of the drug dose in the body over a given time, not just its release. Administration of a formulation or fraction containing a controlled-release active drug does not result in the immediate release of all active drugs. The term is used interchangeably with "non-immediate release," as defined in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, PA: Mack Publishing Company, 1995). Generally, the term “controlled-release” as used herein includes sustained-release, modified-release, pulsed-release, and delayed-release formulations, as well as formulations combining two or more types of release profiles, such as immediate release of a bolus dose followed by pulsed release or subsequent sustained release. “Sustained-release” (synonymous with “sustained-release”) refers to a formulation that provides a gradual release of the active drug over a long period, preferably resulting in a substantially constant level of the drug in the volume of distribution (e.g., urine, bladder, total body water), which is not essential and is commonly referred to as “zero-order” release. “Controlled-release” also includes “delayed-release,” which refers to a formulation that provides a measurable time delay after administration to the patient before the active drug is released from the formulation into the patient’s body. However, as used herein, controlled-release formulations generally refer to sustained-release formulations.

[0087] The terms “particle” or “microparticle” refer to the carrier or controlled-release carrier described herein, which is formulated to contain a pharmacologically active drug. Particles may be substantially spherical, cylindrical, or rod-shaped, or have any other shape. Particle size is presented as the average particle diameter in a population of particles. The particle size distribution in a population of particles is relatively narrow (i.e., a given average particle size is associated with a fairly low standard deviation, generally less than 30%), for example, less than 20% or less than 15%. Particles in a formulation may or may not be substantially identical in shape and size. The terms “particle” and “microparticle” may be used interchangeably with the term “drug product,” which is also a form of drug product, and the term drug product is used as a comprehensive term encompassing both particles and microparticles.

[0088] The terms “grouping of intravesical delivery particles,” “grouping of solid drug products,” “grouping of drug product capsules,” “grouping of drug product carpules,” “grouping of delivery particles,” “grouping of coupled drug products,” “grouping of connected drug products,” “grouping of drug products,” “grouping of hinged drug products,” or “grouping of particles” are interchangeable and refer to the connection of separate drug particles or drug products or structures via a tether or other equivalent connecting structure.

[0089] The term "intravesical administration" or "intravesical therapy" refers to a procedure in which a therapeutic agent is introduced directly into the bladder (i.e., via a catheter) rather than being administered orally or intravenously. Similarly, intravesical drugs are administered directly into the bladder via a urethral catheter.

[0090] The term “enteric coating” refers to a polymer barrier applied to oral pharmaceuticals to prevent their dissolution or breakdown in the gastric environment. As used herein, cylindrical pellets made from a swellable material may be coated with a slow-degrading adhesive material. These pellets may be placed in a socket that joins the cylinders. In this design, the adhesive coating helps to keep the cylinders intact while the drug payload is delivered. Subsequently, as the coating degrades / dissolves over time, water becomes diffusible through access to the swellable material, causing the material to swell (e.g., to 10 times its original size), which pushes the rod out. In various embodiments, the rate of swelling is controlled by modifying the silicone hinge to change the rate at which water diffuses into the socket. This includes, for example, 1) changing the length and thickness of the hinge, 2) slits on the sides, 3) holes of various diameters on the hinge cap, and / or combinations thereof.

[0091] The term "mucosal adhesion" refers to the adhesion between two materials, one of which is a mucosal surface. Mucosal adhesive drug delivery systems extend the residence time of the dosage form at the application or absorption site. Mucosal adhesive drug delivery systems interact with the mucus layer and mucin molecules covering the mucosal epithelial surface, increasing the residence time of the dosage form at the absorption site.

[0092] In this specification, the term “spherical” means a precisely spherical particle, or more generally, a particle or object having a rounded surface that may or may not be substantially spherical.

[0093] The terms “average diameter,” “average longest dimension,” and “particle size” are used interchangeably herein. Where used herein, particle size is expressed by the average diameter for spherical particles and by the average longest dimension for non-spherical particles. The term “average diameter” technically corresponds to substantially spherical particles; however, as stated above, it should be noted that other particle shapes can also be incorporated into particulate formulations, provided that the particles have at least one dimension (i.e., at least one average dimension in the overall population of particles) within the range of 2.0 mm to approximately 12.0 mm, e.g., approximately 2.5 mm to approximately 6.5 mm, e.g., approximately 2.5 mm to approximately 6.0 mm, approximately 2.5 mm to approximately 5.5 mm, approximately 2.5 mm to 5.0 mm, etc. Elongated particles, e.g., cylindrical or rod-shaped particles, may have a length of, for example, approximately 9.0 mm and be thin enough to pass through a urethral catheter and urethral opening.

[0094] The terms “effective dose” and “therapeutic dose” for an active drug, combination of active drugs, or pharmaceutical preparation refer to a quantity or concentration that is non-toxic but sufficient to produce the desired result. The exact amount required varies from subject to subject, depending on factors such as the subject's age, weight, and overall health, the specific condition being treated, the severity of the condition, the given active drug, and the clinician's judgment.

[0095] The term "urinary tract" is conventionally used to refer to the lower and upper urinary tracts, and therefore includes the bladder, urethra, kidneys, and ureters.

[0096] The term "disorder" refers to a clinically relevant physiological condition, and therefore includes symptomatic or asymptomatic conditions, regardless of etiology. Thus, a disorder includes adverse conditions resulting from disease or injury. The disorder addressed by this invention is a disorder of the urinary tract.

[0097] "Drug delivery period" refers to the period during which a pharmacologically active drug is released from a formulation or fraction thereof, generally an extended period.

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

[0099] The term "pharmaceutically acceptable carrier," as used herein, refers to any solvent, dispersion medium, coating, isotonic agent, and absorption retarder, etc., that is suitable for pharmacopoeia administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also include other active compounds that provide supplemental, additional, or enhanced therapeutic function.

[0100] The term "pharmaceutically acceptable composition" as used herein means a composition comprising at least one of the compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers.

[0101] The term "to treat" or "treatment" means one or more of the following: (1) inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of a disease, condition, or disorder (i.e., stopping the further manifestation of the pathology and / or symptomatology); and (2) improving a disease; for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of a disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology), such as reducing the severity of the disease.

[0102] The term "specific gravity" refers to the ratio of the density of a material to the density of water at 4°C. Therefore, it is a unitless relative quantity. Urine specific gravity refers to the electrolytes and osmolality of urine. The normal range for urine specific gravity is 1.005 to 1.030. In the context of clinicopathology, specific gravity is a commonly used urine analysis parameter in the assessment of renal function and can be useful in the diagnosis of various kidney diseases.

[0103] The term "hygroscopic material" refers to a substance that absorbs water and expands. Many industrial polymers are hygroscopic, including nylon, ABS, polycarbonate, cellulose, carboxymethylcellulose, and poly(methyl methacrylate) (PMMA, plexiglas, Perspex).

[0104] The term "amikacin" refers to an antibiotic drug used to treat several bacterial infections. These include joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections (UTIs). It is also used to treat multidrug-resistant tuberculosis. It is commonly administered intravenously using an IV or intramuscular injection.

[0105] The term "excipient" refers to a pharmacologically inactive component that is intentionally added to a drug product for various functional purposes, such as increasing the volume or size of the dosage form, causing solid dosage forms to break down, binding particulate matter, lubrication during processing, masking taste, or altering drug release.

[0106] The term "zero-order" refers to a drug delivery system that releases drugs at a constant rate (i.e., the release rate is independent of the concentration or amount of drug remaining in the delivery system). When a constant amount of drug is released per unit time, but the rate is independent of the drug concentration, the drug release kinetics is said to be zero-order kinetics. Zero-order drug delivery systems (DDS) can overcome the problems faced by immediate-release and primary systems by releasing drugs at a constant rate, thereby maintaining drug concentrations within the therapeutic window over a long period.

[0107] The term "primary" refers to the drug release rate, which 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 a long period after a single dose has been administered.

[0108] The terms "therapeutic index," "TI (therapeutic index)," or "therapeutic ratio" refer to a quantitative measure of the relative safety of a drug. This is a comparison of the amount of therapeutic agent that produces a therapeutic effect to the amount that produces toxicity. The therapeutic window, or safety window, refers to the range of doses optimized between efficacy and toxicity to achieve the greatest therapeutic benefit without causing unacceptable side effects or toxicity. The TI is the dose that produces the desired pharmacological effect (e.g., the effective dose in 50% of the subject, or ED). 50 (E.g., toxic dose in 50% of subjects)) is the dose of a drug that causes adverse effects at an incidence / severity that does not match the targeted indication. 50 It is calculated from the ratio of (toxic dose in 50% of subjects).

[0109] With respect to “proximal,” for example, the “proximal portion” or “proximal end portion” of a catheter disclosed herein includes the portion of the catheter that is intended to be near the clinician when the catheter is used in a patient. Similarly, for example, the “proximal length” of a catheter includes the length of the catheter that is intended to be near the clinician when the catheter is used in a patient. For example, the “proximal end” of a catheter includes the end of the catheter that is intended to be near the clinician when the catheter is used in a patient. The proximal portion, proximal end portion, or proximal length of a catheter may include the proximal end of the catheter. However, the proximal portion, proximal end portion, or proximal length of a catheter does not necessarily include the proximal end of the catheter. That is, unless otherwise suggested by the context, the proximal portion, proximal end portion, or proximal length of a catheter is not the terminal portion or terminal length of the catheter.

[0110] With respect to “distal,” for example, the “distal portion” or “distal end portion” of a catheter disclosed herein includes the portion of the catheter that is intended to be near or within the patient when the catheter is used in a patient. Similarly, for example, the “distal length” of a catheter includes the length of the catheter that is intended to be near or within the patient when the catheter is used in a patient. For example, the “distal end” of a catheter includes the end of the catheter that is intended to be near or within the patient when the catheter is used in a patient. The distal portion, distal end portion, or distal length of a catheter may include the distal end of the catheter. However, the distal portion, distal end portion, or distal length of a catheter does not necessarily include the distal end of the catheter. That is, unless otherwise suggested by the context, the distal portion, distal end portion, or distal length of a catheter is not the terminal portion or terminal length of the catheter.

[0111] The term "pain" refers to a feeling of distress, often caused by a severe or damaging stimulus. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with or relating to actual or potential tissue damage." The terms "pain" and "discomfort" can be used interchangeably. Visual analogue scales (VAS) and numeric rating scales (NRS) are the most commonly used to assess the current intensity of acute pain.

[0112] The term "trocar" refers to a medical or veterinary device used in minimally invasive surgery, typically consisting of a trocar (which may be metal or plastic with a pointed or tapered tip), a cannula (a hollow tube that is essentially rigid), and often a seal. Some trocars also include a valve mechanism to allow for air insufflation. Trocars are designed to be placed through the chest and abdominal walls during thoracoscopic and laparoscopic surgery, and each trocar functions as a portal, and thus more commonly in colloquial term "port," for the subsequent insertion of other endoscopic instruments, such as grippers, scissors, staplers, electrocautery devices, suction tips, etc. Trocars also allow for the passive drainage of excess gas or fluid from organs within the body.

[0113] The term "obturator" or "obturator rod" refers to a thin, rigid (sometimes curved) rod that passes through a hollow passage or lumen to assist in the insertion of medical devices and other medical instruments into a patient or object.

[0114] The term "substantially" indicates a possible deviation from the enumerated chemical or physical properties, allowing for a difference of up to approximately 20%, or up to approximately 10%, or up to approximately 5% between the actual chemical or physical properties and those enumerated. The term "substantially homogeneous" refers to a material, for example, in the form of a mixture of two or more components, that is substantially homogeneous throughout, where any two individual regions within the material differ by up to approximately 20%, or up to approximately 10%, or up to approximately 5% in terms of the chemical or physical properties 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, etc. Similarly, the terms "approximately" or "about" are intended to imply a possible variation of up to approximately 20% in any given context. Generally, these terms imply a possible variation of up to approximately 10%, or up to approximately 5%.

[0115] Other technical terms used herein have their usual meanings in the art in which they are used, as exemplified by various technical dictionaries. Specific numerical values ​​and stereochemical configurations discussed in these non-limiting embodiments are modifiable and are cited only to illustrate at least one embodiment, and are not intended to limit their scope. Detailed explanation

[0116] Both the general description above and the detailed description below are illustrative and descriptive, and should be understood as intended to provide further explanation of the subject art described in the claims. Additional characteristics and advantages of the subject art are described below, and may be partially evident from the description or learned through practice of the subject art. The advantages of the subject art are realized and achieved by the descriptions and structures specifically noted in the claims herein.

[0117] The embodiments include a drug delivery device that can be implanted in the bladder for the duration of drug release. A successfully implanted bladder implant must be reliably retained in the bladder to effectively deliver its active pharmaceutical ingredient (API) throughout the intended period. To prevent unintentional dislodgement during normal urination, the implant may be designed to have a particularly large cross-sectional area or shape that makes it impossible to pass through the urethra.

[0118] It is important that drug delivery devices remain in the bladder only for the duration that they are therapeutically beneficial. Conventional approaches involve physically removing the device after the retention period. Active removal may require reactive disintegration. Implants may be designed to disintegrate into smaller pieces when a specific trigger occurs in response to certain stimuli, such as temperature, pH, salt, and enzymes. Alternatively, procedure-based removal may be performed by a medical professional. For example, the device may be physically retrieved or disintegrated via a cystoscopy procedure. The applicant hereby describes a third approach requiring passive removal. The implant and / or some of its components are designed to gradually decompose or dissolve, eventually passing through naturally with the urinary flow after its therapeutic window has expired.

[0119] Embodiments of the present invention include devices, systems, and methods for administering solid drug products to treat diseases related to the urinary tract. When administered to the bladder, “intravesical particles” or “drug products” can deliver the drug locally to the bladder / urethra. This avoids the need for oral and systemic administration. Low doses of antibiotics are effective, with fewer side effects. An improved therapeutic window is also possible through controlled release of the drug. Formulations containing particles with an active agent can be administered to a subject via the intravesical route (i.e., through the urethra or via bladder injection) using the devices described herein.

[0120] Embodiments also include methods of treatment that involve administering a drug product into the bladder of a target. The method may include intravesical administration of particles using a drug delivery device described herein. The particles may then release a therapeutic agent (or multiple drugs) into the bladder over a desired course of treatment. The method is useful for treating diseases such as infections (e.g., UTIs), interstitial cystitis, overactive bladder syndrome, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorders, overactive bladder, underactive bladder, urine retention, diabetes, heart failure, renal failure, or cystitis.

[0121] The shapes and forms of the drug products of the present invention may include solid drug products (e.g., drug products having the shape of particles, spheres, rods, cartridges, cylinders, tampons, or straws, or drug products having patterned or irregular cross-sections), fluid drug products (e.g., foams, gels, or coatings), or powdered or lyophilized drug products contained in capsules, cartridges, pellets, tablets, or any suitable encapsulation body. The shapes or forms of drug products for use with the devices of the present invention may further include connection forms, connection shapes, coupling forms, and coupling shapes.

[0122] Examples of coupling and connection configurations, as well as coupling and connection shapes, are shown in the drawings and may include multiple drug products or structures connected (e.g., by tethers, sutures, or other connecting parts). The drug product may include one or more active agents (i.e., pharmaceutically active parts) applied as a coating on or along particles and / or within particles. In various embodiments, the drug product (or some parts thereof) decomposes or dissolves in the patient's bladder.

[0123] The drug products described herein may be administered directly into the bladder through the urethra (i.e., transurethral administration). In various embodiments, the drug product is retained in the bladder for an intended period (i.e., a retention period). During the retention period, one or more active agents may be released into the bladder and urinary tract. After the retention period, the product may be expelled from the bladder by urination (i.e., elimination stage). As can be understood, particle size and urethral diameter are relevant to each of these stages.

[0124] While there is some variation among humans, the urethra has a normal cross-sectional diameter of approximately 6 mm, with a maximum diameter of approximately 10 mm. The applicant has demonstrated that an object 4 mm (length) can pass through the urethra with minimal irritation. On the other hand, objects larger than 5 mm generally cause discomfort and / or complications when expelled. Therefore, the applicant proposes that the optimal cross-sectional diameter for an object introduced into the bladder through the urethra is 4 mm or less. In various embodiments, the object has a cylindrical shape with a diameter of approximately 4 mm (as shown in Figure 3A). The length of the object may be, for example, approximately 6 mm, approximately 8 mm, approximately 10 mm, approximately 12 mm, approximately 14 mm, approximately 16 mm, approximately 18 mm, approximately 20 mm, or more.

[0125] Figure 2A illustrates the structure of individual particles with a cylindrical shape, showing their length (L) and diameter (D). From human experiments, the applicant demonstrated that objects with a 4 mm cross-section (D) are not retained in the bladder. Rather, they are excreted in the urine, with a short (or negligible) retention period. Objects with a 5 mm cross-section may have a longer retention period in the bladder, but these are also rejected. Reviewing objects in the bladder that are not easily rejected reveals a cutoff of a 10 mm cross-sectional diameter for retention. Drug products of this size have a long retention period, but their administration is not easy and they must be surgically removed or significantly degraded in the bladder.

[0126] If there is a gradient in the flow velocity toward the bladder outlet (i.e., the urethra), it is worth considering that objects within the bladder may rotate due to the mechanics of urination to minimize their cross-sectional diameter. This means that, assuming an object with a cross-sectional diameter (D) of 4 mm, increasing its length (L) (e.g., to 10 mm, 20 mm, or 30 mm) will have minimal effect on its retention rate. For hydrodynamic reasons, during the urination phase, the urethra "perceives" it as a 4 mm object. Therefore, a drug product with a diameter of 4 mm and a length of 10 mm will have similar properties to a drug product with a longer length (e.g., 4 mm x 30 mm).

[0127] Accordingly, the embodiments include drug products of different shapes that resist premature expulsion from the bladder. Figure 2B represents particles having a “horseshoe” shape. Figure 2C represents particles having a “bowstring” shape according to multiple embodiments. An image is shown in Figure 2C. In other embodiments, multiple drug products are joined together. The drug products may be joined using absorbable sutures (e.g., sutures for joining bowstrings or sutures for joining hinges). In some embodiments, the absorbable sutures may dissolve, releasing the individual drug products from each other. Figure 2D represents bowstring particles. An image is shown in Figure 2E. By using a larger angle (i.e., about 90°), the relative size and retention of the drug products may increase. Figure 2F represents particles having an elbow shape. An image is shown in Figure 2G.

[0128] The applicant has further discovered that drug products can be joined using fibrous structures (e.g., sutures) that prevent premature excretion of the drug product. The fibrous structures are decomposable after a desired retention period, at which point the drug product is excreted in the urine. Accordingly, the embodiments include a drug release rod having three or more fibrous extensions (e.g., sutures) protruding from a main body, as shown in Figure 5C. In the embodiments, each drug product has three fibers that are at least 8 mm long and are at 120 degrees to each other. In the embodiments, folds (i.e., folds in the bladder wall) prevent the excretion of the drug product.

[0129] The fibrous structure may be collapsible so that the drug product can be easily inserted through the urethra and expand once it enters the patient's bladder. The expansion of the fibrous structure allows the drug product to remain in the bladder throughout the course of treatment. In various embodiments, the fibrous structure may be bioabsorbable and dissolve after a predetermined period of time or after a predetermined number of urination cycles. 3D structural changes in drug products

[0130] The applicant describes herein a drug product that is easily administered (i.e., through the urethra), retained in the bladder, and subsequently excreted when the bladder is empty. In various embodiments, the drug product undergoes one or more steric changes. Figure 3A represents a drug product that is relatively small for insertion, larger for retention, and again small for elimination. This allows the product to be administered when small and expand to be retained in the bladder for a desired period (i.e., retention period). In various embodiments, the particle has a cross-sectional diameter of 4 mm or less for insertion, undergoes a steric change to have a cross-sectional diameter of 10 mm or more after bladder insertion for retention, and then decreases to a cross-sectional diameter of less than or equal to 4 mm for elimination.

[0131] In some embodiments, a first steric transformation (i.e., from 4 mm to 10 mm) occurs after insertion and before the first urination event (i.e., first urination). In some embodiments, a second steric transformation (i.e., from 10 mm to 4 mm) occurs after a course of treatment or gradually during a course of treatment. This allows the drug product to remain within a larger steric structure for the duration of drug treatment (i.e., the duration of administration of the active agent). As can be understood, the drug product may include a material known to expand when exposed to a liquid (i.e., a hygroscopic material).

[0132] In some embodiments, the steric structure change (after insertion) occurs mechanically through bending or joining of the object, as shown in Figure 3A. In other embodiments, the steric structure change occurs chemically through expansion or swelling, or through the accumulation of similar objects that form aggregates (not shown).

[0133] The drug product may also include a “elbow” having a deformable shape, as shown in Figure 3B. The elbow can take the form of a linear or curved three-dimensional structure with angles ranging from 10 to 180 degrees, allowing the cross-sectional diameter of the administered drug product to vary at their positions. For example, two drug products may be joined by a polymer (e.g., silicone) hinge or elbow at an angle of 10 to 180 degrees relative to each other. During insertion, the drug products may be parallel (i.e., about 180 degrees relative to each other). After insertion, the hinge or elbow may return to a second angle (e.g., about 90 degrees) for the retention phase. After the drug release period, the elbow may dissolve so that it is expelled through the urethra.

[0134] Figure 3C shows cylindrical particles joined by a connecting portion. In various embodiments, each cylinder 27 is fixed to a cap 185. A bridge portion 195 is connected to the connecting portion 195. One or more of these components can be disassembled. In various embodiments, the bridge portion 195 disassembles or dissolves, as shown, to release the cylindrical particles from each other. Alternatively, one or both of the caps 185 may disassemble or dissolve to release the cylindrical particles from each other (not shown). In another embodiment, one or both of the cylindrical particles 27 disassemble or dissolve, causing them to release from each other (not shown). In another embodiment, one or both of the cylinders swell, causing them to release from their caps. Once released from each other, the cylindrical particles are more easily expelled during urination.

[0135] When separated from each other (e.g., after decomposition), individual drug products can be excreted from the bladder. The decomposable portion of a drug product can be selected based on a desired decomposition rate, for example, so that approximately 25% of the product is removed after one week, approximately 50% after two weeks, etc.

[0136] The drug product may have a preferred three-dimensional structure (i.e., angles) after insertion. The elements that hold its position may be fabricated whole or partially from a soluble polymer. As shown in Figure 3B, angles of about 75–90 degrees may provide the maximum area. The linker components may be made of various materials known in the art and may be selected based on, for example, solubility, buoyancy, stability, tear / tensile strength, moldability, elasticity, flexibility, and hardness.

[0137] Figure 3D shows a drug product adopting a retention configuration and its three components (i.e., a linker, a hinge, and a cylindrical rod in which the API is embedded). As shown, the free end of each cylinder is approximately 4 mm in diameter. The capped portion is approximately 5 mm in diameter. As described above, disintegration of one or more of the components (i.e., the linker, hinge, or cylindrical rod) may trigger the cylinders to separate from each other. In various embodiments, the linker is made of a soluble, biodegradable, or bioabsorbable material. The hinge includes a silicone connecting piece that connects to the rod and improves retention within the bladder. The rod is also embedded in a polymer matrix. In various embodiments, the hinge may further include a) a socket (where the rod is inserted), b) a cap (a flat, circular top of the socket), and c) a connector (a flexible link or joint that bridges the two caps).

[0138] In some embodiments, the drug product is passively excreted from the bladder into the urine. In some embodiments, the product dissolves / breaks down into smaller sizes or pieces so that it can be naturally excreted through the urethra during urination. Alternatively, the rod may be coated with a biodegradable surface coating such that when the coating dissolves, the rod no longer fits into the socket and falls out, thereby causing the disintegration described in the embodiments. Alternatively, the silicone material of the hinge may be replaced with a bioabsorbable elastomer that is as flexible and elastic as silicone and dissolves over time.

[0139] In various embodiments, the drug product disintegrates into separate parts so that it is excreted in the urine. The disintegration function may be specific to a single component of the implant and does not impede other functionalities. This approach allows different sections of the implant to perform their individual roles, enabling independent adjustment of each component while minimizing the impact on overall performance. For example, an implant may include a rod made from a base material optimized for API diffusion, a connector primarily composed of flexible, non-degradable silicone, and a third component designed to ensure that the connector between the rod and hinges breaks at a predetermined rate or time. This third component, the linker, may be important as it connects different parts of the implant and ultimately triggers its disintegration. When the implant pieces remain intact, their size or shape prevents them from being spontaneously pushed out during urination. Alternatively, the connector between the two hinges may be replaced from silicone with an erosive elastic material (which, after erosion, causes disintegration of the socket and rod, which can be discharged).

[0140] Figure 3E illustrates the three stages of a drug product (i.e., implantation, drug delivery, and dismantling for elimination). Figure 3F illustrates different mechanisms of particle separation based on various embodiments. In some embodiments, pores on the hinge allow water to enter. The cylinder gradually swells until it is released. In some embodiments, slits on the hinge increase the degrees of freedom of movement. The cylinder is released as the adhesive material loses its strength. In some embodiments, adhesive material in a butt joint connects the cylinders. The cylinder is released as the adhesive material dissolves. Drug products tethered / linked

[0141] In various embodiments, multiple drug products are joined together by a tether or similar structure. “Grouping” the drug products increases their effective size. Due to their larger size, the grouping is more resistant to being excreted from the bladder with urine. Figure 4A shows multiple drug products (e.g., two cylinders) joined together by a tether or otherwise connected (e.g., by a hinge).

[0142] In some embodiments, tethered drug products are stacked on top of each other for administration (i.e., insertion). The cylindrical product 27 can be easily administered through a syringe or other device. After the product has been administered (e.g., when exposed to urine), it may form a “tethered grouping.” This arrangement increases the size and prevents the drug product from being excreted with the urine. In some embodiments, the active agent is released from the drug product during this “retention phase.”

[0143] In various embodiments, the tether 175 gradually decomposes or dissolves. The tether dissipates until the drug product is released from each other. The drug product can then be excreted when the patient urinates. In this respect, a drug product tethered can follow three stages: (a) administration stage, (b) retention stage, and (c) urination stage. In various embodiments, the duration of the retention stage is controlled by the size and / or composition of the tether. For example, administration of a 10-day antibiotic treatment requires the use of a tether that takes at least 10 days to dissolve. A tether that dissolves more rapidly (i.e., has a shorter retention stage) may be used for shorter antibiotic treatments.

[0144] In some embodiments, the drug product tethered (at the administration stage) has a diameter smaller than the diameter of the urethra (i.e., approximately 5 mm or less). In some embodiments, the drug product tethered (at the retention stage) is larger than the ureteral orifice (i.e., approximately 10 mm or more). Furthermore, the diameter of individual drug products (at the urination stage) is smaller than the diameter of the ureteral orifice (i.e., approximately 5 mm or less).

[0145] In various embodiments, cylindrical products have different compositions and / or functions. For example, a first cylinder containing an active agent may be paired with a second cylinder providing buoyancy. In various embodiments, the first and second cylinders each contain different active agents.

[0146] In various embodiments, more than two particles are coupled or connected by a tether. For example, a drug product may contain particles having three cylindrical shapes, four cylindrical shapes, five cylindrical shapes, six cylindrical shapes, seven cylindrical shapes, eight cylindrical shapes, nine cylindrical shapes, ten cylindrical shapes, or more. The particles may be stacked or configured to be arranged in another compact position for transurethral administration.

[0147] In other embodiments, multiple drug products are joined together by a linkage. The linkage may be flexible and / or rigid. As shown in Figure 4B, the “linked” drug product has a larger effective size. The linkage may keep the cylinders parallel to each other for administration. After administration (i.e., when exposed to the fluid in the bladder), the linkage may create an angle between the particles. Due to this angle, the particles are more resistant to expulsion from the bladder. The linkage may disintegrate so that the particles separate from each other.

[0148] Similarly, Figure 4C represents multiple drug products joined together by a connecting portion. Here, the cylinder decomposes during the retention phase. Upon decomposition, the individual drug products can be separated for excretion from the bladder. As described above, the decomposable portion can be selected based on a desired decomposition rate, for example, so that approximately 25% of the product is removed after one week, approximately 50% after two weeks, and so on.

[0149] Figure 5A is an image of particles joined by a tether 175 (e.g., two cylinders 27). Similarly, Figure 5B is an image of particles joined by a hinge connection. Three-dimensional structural arrangement of linked drug products

[0150] Figure 6 shows an arrangement of six drug products. The drug products are stacked to facilitate administration (i.e., insertion). This arrangement facilitates intravesical administration using a syringe or similar device. After the products are administered (e.g., when exposed to urine), the products may form a "tethered grouping." The cylinders may form a zigzag arrangement, as shown. The increased area of ​​this structure prevents the drug products from being excreted with the urine. In some embodiments, the active drug is released from the drug products during this "retention phase." As described above, the tethered portions may gradually disintegrate or dissolve until the individual drug products are released from each other. In some embodiments, the drug products are held on a single axis (i.e., flat). Alternatively, the drug products may form a multi-axis arrangement. Furthermore, the rods may be connected in series at their ends, as shown. The angle of this connection may be free (as in the case of a string) or fixed (as in the case of a hinge). Alternatively, there may be a single connection (for example, two rods joined at a certain angle) or multiple connections in series.

[0151] In various embodiments, the tether dissolves or decomposes over periods of approximately 2 days, 5 days, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or longer. In various embodiments, the tether is stable and does not dissolve.

[0152] The embodiments include other shapes and spatial arrangements of the drug product. In some embodiments, the tether material is rigid (e.g., 100% or semi-flexible) so that the drug product returns to a preferred shape. Figure 7A represents a cylindrical drug product taking a circular shape. As can be understood, the circular shape has a larger diameter and higher retention. Similarly, Figure 7B represents a spherical drug product taking a circular shape. In other embodiments, the drug product may take shapes such as a tampon, rod, cartridge, cylinder, straw, pretzel, horseshoe, or a drug product with a patterned or irregular cross-section. The grouping can form various three-dimensional shapes, such as coils, hexagons, open loops, closed loops, etc.

[0153] As can be understood, the tethered portion of a drug product can determine its three-dimensional shape when it undergoes structural changes. Therefore, the material, the number of hinges, tear / tensile strength, moldability, elasticity, flexibility, and hardness can influence the three-dimensional configuration. The material may be, for example, monocryl, cat gut suture material, Vicryl, or PDS (polydioxanone suture). In various embodiments, the material is bioabsorbable or biodegradable.

[0154] In various embodiments, drug products are connected in an orientation such that all rods lie in the same plane. Alternatively, drug products may be oriented out of the plane, or arranged alternately with or without periodicity. In such arrangements, the connections may share both a common plane and a common direction with other connections. For example, rods connected in series via hinged connections that all share the same plane and direction may bend to form a coil as a whole. In another example, connected hinges may be regularly alternating between two orientations on the same plane with a periodicity of 2, forming a zigzag arrangement.

[0155] The connecting portion can be incorporated into the cylinder, attached to the cylinder, or hold the cylinder. The connecting portion may be present between multiple cylinders or more. The connecting portion may take the form of two caps joined by a bridge, as shown in Figure 3B. The cap 185, the bridge 190, and the connection between the cap and the bridge 195 may be made from materials that vary in substance, behavior, dimensions, polarity, rigidity, angle, and number.

[0156] Figure 7C illustrates heterogeneous grouping of drug products. Particles may have homogeneous or heterogeneous functions. For example, rods can vary in buoyancy, length, material, drug payload, drug release kinetics, drug load, degradation rate and kinetics, surface and bulk erosion, aggregation (to each other), adhesion (to tissue), etc. In this example, cylinders are connected to spheres. Active drugs may be contained within the cylinders. The spheres, on the other hand, may provide buoyancy. For example, the spheres may be composed of a material that expands for buoyancy and decomposes in urine. Bladder regulation

[0157] In other embodiments, the entry point from the bladder into the urethra is adjusted during the retention phase. Embodiments include (not shown) changing the cross-sectional diameter threshold to allow retention in the bladder after therapeutic insertion. Embodiments include placement of a filter on the bladder neck, injection of an expander around the bladder neck to be aligned parallel to the urethral wall, or use of an intraurethral flow limiter to reduce flow velocity and thus retain the object in the bladder. Intravesical drug delivery devices

[0158] In one embodiment, the device of the present invention is a portable administration device comprising a loading funnel for receiving a solid drug product (e.g., drug products having the shape of particles, spheres, tampons, rods, cartridges, cylinders, straws, patterned or irregular cross-sections, etc.). Figure 8 shows a delivery device 5 according to various embodiments. The delivery device may comprise a body 10 with components. In various embodiments, the body comprises a substantially linear barrel 15 and an insertion tip 20. The insertion tip is passed into the urethra of the target and secured in place. The drug product can then pass from the funnel region 25 into the barrel 15. A pressure source 30 (e.g., compressed water or air) can drive the drug product through the device into the bladder. In various embodiments, a user (e.g., a healthcare professional) uses a trigger 40 to control the delivery (e.g., rate) of the drug product. For example, the user can vary the pressure applied to the trigger to adjust the pressure entering the device (and the resulting drug product discharge rate).

[0159] As can be understood, the size / diameter of the delivery device is important. Using a smaller insertion tip will result in less pain and discomfort experienced by the patient during device insertion and use. Therefore, in various embodiments, the barrel of the device has a length of approximately 1 centimeter (cm) to approximately 15 centimeters or more. The insertion tip may have an outer diameter ("OD (outer diameter)" or maximum cross-sectional dimension) of approximately 9 millimeters (mm) or less. In addition to the inner diameter ("ID (inner diameter)") of the barrel, the size / flexibility of the drug product and the amount of pressure applied may affect the delivery rate of the drug product.

[0160] Accordingly, the ID of the lumens of the barrel 15 and the insertion tip 20 can be determined based on the intended size of the drug product to be delivered. In some embodiments, the ID is approximately 0.3 mm to approximately 2 mm. In some embodiments, the lumen is elastomerous so that it may be flexible / elastically deformable. In some embodiments, the insertion tip 20 is tapered at the distal end for insertion through the urethra. In some embodiments, the insertion tip is for single use and may be discarded after use.

[0161] The body 10 may be any suitable biocompatible material for connecting / housing the components. In one embodiment, the drug capsule body 10 is constructed from plastic or silicone. The loading funnel may have a funnel shape, but other forms are also conceivable. The funnel can deliver drug products, pharmaceuticals, or any suitable substance or structure known in the art and within the scope of the device practitioner. In other embodiments, the funnel is a high-volume 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 units, or more of drug products. In further embodiments, the funnel is a high-speed delivery device capable of simultaneously, rapidly, and continuously delivering multiple units of drug products.

[0162] The loading funnel 25 may further include grooves, ridges, obstacles, pegs, springs, switches, latches, manifolds, valves, or labyrinthine structures to slow or alter the pace of drug product / pharmaceutical / excipient delivery. In some embodiments, the loading funnel is an integral component of the portable delivery device body. In some embodiments, the loading funnel is a modular component configured to be detachably attached to the portable delivery device body. Multiple funnels may be provided for delivering multiple drug products, excipients, pharmaceuticals, or combinations thereof, or for delivering drug products, excipients, or pharmaceuticals at a faster or more optimal delivery pace. The loading funnel is operably attachable to any device envisioned in the present invention.

[0163] A loading funnel can supply a drug product into a hollow passage within a barrel operably connected to a portable administration device, or a barrel integrally manufactured within the body of the portable administration device. As shown in Figure 8, a desired number of drug products can be placed / injected into the loading funnel 25. In various embodiments, the drug product in solution is supplied into the loading funnel. Alternatively, a magazine or loading tray (not shown) can be used to supply the drug product into the funnel. The barrel may be constructed in any known shape and may have any known inner and outer diameters. The barrel capacity may match the capacity of the loading funnel, or may include a capacity larger or smaller than the capacity of the loading funnel. The barrel may be smooth, semi-smooth, or partially smooth along its inner circumference, or may include ridges, notches, grooves, knurling, springs, or any known geometric projections to optimize the delivery of the drug product or any other suitable substance through its hollow passage. The barrel may be further tapered, truncated, or have a constant, non-constant, or irregular diameter along its entire length, substantially along its entire length, or along a portion or repeated stretch of its length. The barrel may also include a locking mechanism or a plurality of locking mechanisms to control, modify, and / or optimize the delivery rate of the drug product. In various embodiments, the funnel is shaped such that individual drug products are supplied into the lumen of the barrel (i.e., wider at the top and narrower towards the base).

[0164] In various embodiments, a "hopper mechanism" is operably mounted to the loading funnel. The hopper mechanism is constructed as a dispenser for drug particles. The hopper mechanism ensures that drug particles (e.g., rods) enter the barrel in the correct orientation and can avoid jamming. One design is a hopper having a conical shape with a narrow opening at the bottom leading to the barrel. The barrel may have a shape that is properly suited to the drug product. This allows the rods to be delivered into the barrel via the funnel in the correct orientation. Another design includes a series of small channels or tubes leading from the hopper to the barrel. The channels may be angled / curved to introduce the rods into the barrel in the correct orientation. In various embodiments, the device automatically stops dispensing after a predetermined dose (i.e., volume or number of particles) has been administered.

[0165] In various embodiments, the portable delivery device includes a trigger for activating the delivery of a drug product from the portable delivery device. The trigger may be spring-loaded using a tension spring, a compression spring, a leaf spring, or any spring suitable and known in the art. The trigger may be connected to a housing of the portable device body and may be enclosed by a hollow trigger housing. The trigger housing may be formed into any shape to accommodate the trigger of the portable delivery device. In one embodiment, the trigger housing is arc-shaped. In other embodiments, the trigger housing is substantially square. In yet another embodiment, the trigger housing is a thin, hollow projection that provides optimal clearance for activating the trigger. The trigger housing is designed to provide clearance for the practitioner's or user's fingers to access the trigger. The trigger may further include a gripping portion or gripping surface. The gripping portion or gripping surface may be made from any suitable material, such as elastomers, plastics, polymers, metals, alloys, or blends of alloys, or any of the materials described herein, or any suitable material known in the art. The grip portion of the trigger may include a modified geometric shape to assist in gripping. The modified geometric shape may take the form of a concave, convex, undulating, recessed, or projection. The grip portion of the trigger may further include a plurality of projections, undulating, or recessed areas to assist the user or practitioner in gripping the trigger. Such projections may take the form of a raised groove, notch, knurling, raised dot, orb, peg, or any other suitable gripping surface, or a geometric shape known in the art. Such undulating areas may take the form of a rounded apex, a pointed apex, a wavy pattern with plateaus, or any other suitable form to assist the user or practitioner in gripping the trigger.

[0166] The trigger may provide automated, semi-automatic, or any frequency known in the art for the delivery of drug products from a portable delivery device. One or more units of the drug product may be distributed with a single trigger action, or one drug product per trigger action, two drug products per trigger action, three drug products per trigger action, four drug products per trigger action, five drug products per trigger action, six drug products per trigger action, seven drug products per trigger action, eight drug products per trigger action, nine drug products per trigger action, ten drug products per trigger action, twelve drug products per trigger action, fifteen drug products per trigger action, or seventeen drug products per trigger action They may be distributed in the following proportions per trigger activation: 20 drug products per trigger activation, 25 drug products per trigger activation, 30 drug products per trigger activation, 40 drug products per trigger activation, 50 drug products per trigger activation, 65 drug products per trigger activation, 75 drug products per trigger activation, 100 drug products per trigger activation, 125 drug products per trigger activation, 150 drug products per trigger activation, 200 drug products per trigger activation, 500 drug products per trigger activation, 1000 drug products per trigger activation, or more.

[0167] In further embodiments, the drug product is approximately 1 drug product per trigger activation, approximately 2 drug products per trigger activation, approximately 3 drug products per trigger activation, approximately 4 drug products per trigger activation, approximately 5 drug products per trigger activation, approximately 6 drug products per trigger activation, approximately 7 drug products per trigger activation, approximately 8 drug products per trigger activation, approximately 9 drug products per trigger activation, approximately 10 drug products per trigger activation, approximately 12 drug products per trigger activation, approximately 15 drug products per trigger activation, approximately 17 drug products per trigger activation, approximately 20 drug products per trigger activation, approximately 25 drug products per trigger activation, and approximately 30 drug products per trigger activation. The drug products may be distributed in proportions or volumes of approximately 40 drug products per trigger action, approximately 50 drug products per trigger action, approximately 65 drug products per trigger action, approximately 75 drug products per trigger action, approximately 100 drug products per trigger action, approximately 125 drug products per trigger action, approximately 150 drug products per trigger action, approximately 200 drug products per trigger action, approximately 250 drug products per trigger action, approximately 300 drug products per trigger action, approximately 350 drug products per trigger action, approximately 400 drug products per trigger action, approximately 500 drug products per trigger action, approximately 1000 drug products per trigger action, or more.

[0168] In further multiple embodiments, the number of drug products per trigger operation may be 1 or less, 2 or less, 3 or less, 4 or less, 5 or less, 6 or less, 7 or less, 8 or less, 9 or less, 10 or less, 12 or less, 15 or less, 17 or less, 20 or less, or 25 or less. The drug products may be distributed in proportions or volumes such as 30 or fewer drug products per trigger activation, 40 or fewer drug products per trigger activation, 50 or fewer drug products per trigger activation, 65 or fewer drug products per trigger activation, 75 or fewer drug products per trigger activation, 100 or fewer drug products per trigger activation, 125 or fewer drug products per trigger activation, 150 or fewer drug products per trigger activation, 200 or fewer drug products per trigger activation, 250 or fewer drug products per trigger activation, 300 or fewer drug products per trigger activation, 350 or fewer drug products per trigger activation, 400 or fewer drug products per trigger activation, or 500 or fewer drug products per trigger activation.

[0169] In further embodiments, multiple drug products (i.e., different drug products) may be administered with each trigger action. These drug products may be administered simultaneously, sequentially, alternately, or in a patterned manner.

[0170] The portable administration device may further include a hose or conduit connected to its proximal end for delivering compressed air or pressurized fluid from a pressure source and for pushing a solid drug product from the outlet port of the funnel through a hollow barrel passage toward its distal end and outward through its distal end opening. The hose or conduit may be constructed from any suitable material or any combination of materials within the scope of the art of the art. The hose or conduit may be elastomeric, polymeric, rubber, or metallic, and may consist 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 located along its longitudinal direction. The pressurized fluid or compressed air supplied through the hose or conduit further acts to push the solid drug product distally beyond the outlet of the hollow barrel passage and through a protective insertion tip fixed to the distal end of the portable administration device, thereby delivering the solid drug product into the treatment area of ​​the patient or subject, for example, the urethra, bladder, or kidney. The hose or conduit may be connected to a source of compressed air or fluid, or to a disposable device containing compressed air or fluid. The hose or conduit may be further adapted to connect to any suitable port for delivering compressed air or fluid, including wall-mounted ports for delivering compressed air or fluid.

[0171] A pressure relief valve 35 may be present on the portable delivery device. The pressure relief valve 35 may be located above the coupling portion of the conduit to the portable device, below the coupling portion of the conduit to the portable device, attached to the funnel of the portable device, or in any other suitable location preferred by the user or practitioner of the device, as well as in any location known in the art. The pressure relief valve 35 acts to release the accumulated pressure within the portable device during operation and throughout the drug product delivery process. The release of pressure may occur through a single outlet, a single port, a single vent, or a manifold of ports, outlets, or vents.

[0172] Suitable forms and shapes of drug products for delivery through the device of the present invention include drug products having the shape of a rod, or straw-shaped cartridges filled with other drug and pharmaceutical products that fit into a straw-shaped cartridge, the straw-shaped cartridge fitting into the hollow barrel passage of the present invention. Other forms and shapes include, for example, spheres, cubes, pyramids, polyhedra, rails, cylinders, truncated cylinders, irregular cylinders, spheres with flat faces, teardrops, spikes, pretzel shapes, horseshoe shapes, and any other suitable shapes or forms known in the art. Combined forms, combined shapes, coupled forms, and coupled shapes are also conceivable.Examples of combined and coupled forms, as well as combined and coupled shapes, include: two or more cylindrical drug products or structures connected by tethers; two or more drug products having the shape of rods connected by tethers; two or more spherical drug products connected by tethers; two or more cubic drug products connected by tethers; two or more ellipsoidal drug products connected by tethers; two or more prism-shaped (prism-like) drug products connected by tethers; two or more pyramidal drug products connected by tethers; two or more cylindrical drug products or structures connected by hinges; two or more rod-shaped drug products connected by hinges; and two or more spherical drug products connected by hinges. Examples include drug products in the shape of two or more cubes connected by hinges, two or more ellipsoidal drug products connected by hinges, two or more prism-shaped (prism-like) drug products connected by hinges, two or more pyramidal drug products connected by hinges, two or more cylindrical drug products or structures connected by sutures, two or more rod-shaped drug products connected by sutures, two or more spherical drug products connected by sutures, two or more cube-shaped drug products connected by sutures, two or more ellipsoidal drug products connected by sutures, two or more prism-shaped (prism-like) drug products connected by sutures, and two or more pyramidal drug products connected by sutures. The forms and shapes described herein are further intended for storing active drugs and excipients, or any permutations or combinations thereof. Furthermore, the combined and coupled forms of the drug products may be connected via a bioabsorbable polymer or other suitable bioabsorbable material (e.g., sutures) that dissolves at a predetermined rate or after a predetermined number of urination cycles.

[0173] In some embodiments, the entry point for the device barrel (i.e., the insertion tip 20) is made from a flexible material (e.g., silicone) that is more comfortable for the patient. Such materials can allow for greater flexibility in the device design and can be molded into different shapes to suit different patients. The pressure for delivery can be determined to efficiently deliver the drug product while avoiding patient discomfort.

[0174] The insertion tip 20 fixed to the distal end of the barrel may be a bladder sheath, a lubricating tip, a Luer lock or taper provided for connection to a drug delivery device, or any known insertion device, or a coupling device known in the art. The gentle insertion tip may also be rigid, disposable, soluble, bioabsorbable, single-use, etc. The gentle insertion tip may be in the form of a catheter, cannula, or needle, and may be fixed to the distal end of the barrel of the device of the present invention or any other component. The insertion tip may be made from a single material, multiple materials, or a mixture of materials. In further embodiments, the insertion tip may be composed of different materials along its length, and may be composed of materials with a repeating pattern or materials with an irregular pattern along its length. The insertion tip may be further configured to be attached to an adapter or additional tip for versatility and functionality. The insertion tip may be a modular component that can be detachably attached to the distal end of the barrel of the device of the present invention or any other component. The insertion tip may be integrated with the device of the present invention, or it may be fixed or joined to the distal tip of the barrel or any component of the device of the present invention. Depth-locking soft catheter

[0175] In various embodiments, the insertion tip 20 includes an anchoring mechanism. Anchoring mechanisms have been used with conventional catheters. An example of such a device is the Foley catheter. Conventional Foley catheters often have a balloon that prevents the internal tip from slipping out once it has been inserted to the appropriate depth. However, such catheters are not designed to deliver any products, and therefore their lumen (i.e., channel) is narrow, and because they are made from a certain grade of silicone, they have relatively high frictional resistance.

[0176] In one embodiment, the delivery device includes a depth-locking soft catheter 50 having an anchoring mechanism to reduce / prevent tip movement after insertion into the urethra. Figure 9 shows the catheter 50 having a distal end 55 including an anchoring mechanism (e.g., a balloon) and a proximal end 60 including a locking mechanism (e.g., a screw and nut). In some embodiments, the screw portion extends longer than the length required by the lock ring assembly so that the assembly can be variably tightened at different depths along the longer screw portion. In some embodiments, the lock ring assembly is made of one relatively wide fender washer 65 that contacts the patient's skin and two lock nuts (70, 75) that tighten against each other at precisely the desired depth outside the fender washer. The lock nuts may have a large surface area (one convex, the other concave) so that they can be tightened against each other by friction, which helps prevent detachment. In some embodiments, the lock nuts are large enough to be easily separated by hand, but their width is narrower than that of the fender washer. The most proximal piece of the device may be a connector (e.g., screw lock or Luer slip lock), which allows other devices to be attached while the bladder sheath is stationary between parts of the procedure. The inner diameter (ID) of the catheter lumen may be, for example, approximately 1 mm to 9 mm in width, or smaller / larger, depending on the size of the particles being administered. In various embodiments, the length of the catheter is determined by the patient's sex (i.e., male or female).

[0177] As shown, the catheter may include a balloon or other structure protruding from the distal end 55. The balloon may be inflated or expanded with any suitable medium, for example, a fluid, air, gas, or any mixture of those described herein. The catheter may be a modular component that can be detachably attached to any component of the device of the present invention. Alternatively, the catheter may be an integral component that forms a unital device and is operably associated with the components of the device.

[0178] The depth-locking soft catheter 50 may include any number of lumens. In one embodiment, the depth-locking soft catheter includes a single lumen for passing a drug product, pharmaceutical, excipient, adjuvant, carrier, 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, three, four, five, six, seven, or more lumens. The lumens may be coaxial, concentric, arranged, patterned, irregularly offset, discontinuous, or fully continuous, and may also have any length, circumference, diameter, gradient diameter, or variable diameter deemed suitable for the purposes of the present invention.

[0179] The depth-locking soft catheter may include internal and external components. In various embodiments, the external component is made of semi-rigid plastic with a screw / nut. The external component may include a spun washer 65, a clockwise convex nut (right-hand thread) 70, and a counterclockwise concave nut (left-hand thread) 75. The spun washer, clockwise convex nut, and counterclockwise concave nut are screw-coupled to the threaded proximal end 60 of the depth-locking soft catheter. The spun washer, clockwise convex nut, and counterclockwise concave nut may be coupled to the proximal end of the depth-locking soft catheter in any preferred manner known in the art or within the technical scope of the user or practitioner. The spun washer, clockwise convex nut, and counterclockwise concave nut may be replaced by equivalent fasteners and gaskets known in the art. Concentric multi-lumen static sheath

[0180] In another embodiment, the delivery device includes an insertion tip having a concentric multi-lumen static sheath 80 as shown in Figure 10. The concentric multi-lumen static sheath may include an outer tubular member 90 and an inner tubular member 85 configured to be concentrically and coaxially arranged.

[0181] In various embodiments, the internal tubular member 85 includes a flexible portion at its distal end. The flexible portion may expand or deform as it enters the urethra or bladder of a patient or subject, and may act as a locking member by maintaining the position of the external and internal tubular members. The flexible portion may form a “shoehorn” shape, or it may be open at the distal end 95 to fix the catheter in place. The flexible portion may be made of any suitable material known in the art. Examples of expandable and expandable materials include polymers, elastomers, plastics, latex, paraffin, malleable metals, malleable alloys, or any combination of those described herein. An expansion lumen, traction wire, pulling mechanism, or actuator (not shown) may be operably connected to the flexible portion to actuate the expansion or deformation of the flexible portion. The flexible portion may overlap with the outer tubular member and deform into a lobe or wing shape that locks the inner tubular member in place within the patient, and / or lock and secure the inner tubular member to the outer tubular member. The flexible portion may be coated or impregnated with a drug product and may act as a drug and pharmaceutical delivery component.

[0182] In various embodiments, the insertion tip includes an external locking ring 100 that is softly screw-type pressed down against the patient's skin to lock the sheath in place, as shown in Figure 11A. The locking ring allows for a versatile and adjustable sheath length, which can be set to a depth corresponding to the urethral length of a particular patient.

[0183] In an alternative design, the catheter has a “tampon-like” structure made from a flexible, sterile material, as shown in Figure 11B. The device may be supplied with a drug product 27 loaded inside. The internal drug product may be of any shape and convention described herein, including a bow-string alignment in which two drug products are connected by a bioabsorbable tether. The bow-string alignment allows the two drug products to enter at a 180-degree angle to each other, providing a minimum diameter for easy entry into the patient’s urethra. After entry, the bioabsorbable bow-string allows the drug products to take an angle of less than 180 degrees, ensuring that the drug products remain in the patient’s bladder for a predetermined amount of urination cycle. Finally, the bioabsorbable bow-string tether slowly dissolves, allowing each previously connected drug product to exit the patient’s bladder and urethra after a predetermined dissolution period. A push-button spring mechanism on the bottom of the device may cause the device to open outward once it is inserted into the urethra. This mechanism can comfortably hold the device in place during drug administration. It can also be used to deliver the drug product consistently and uniformly. The device may have a cord / wire that can be pulled to close the device after administration is complete, allowing for easy and comfortable removal. Unlike a cystoscope, the device provides comfort to the patient because it is made from a flexible and / or lubricating material (e.g., a blend of rayon and cotton with rayon, synthetic fibers, or similar). In various embodiments, the catheter is inserted using an applicator (not shown). Soft Grapple Member

[0184] In additional embodiments, the insertion tip includes one or more soft grapple members 105. Figure 12 shows soft grapple members that may be used as depth setting and locking mechanisms. The soft grapple members act to hold the bladder sheath in place while setting the administration depth of the drug product. Each soft grapple member may include a longitudinal body, which terminates with a bulbous end having a width greater than its width. The bulbous end may be processed 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, etc.

[0185] The soft grapple member 105 may begin within the wall of the tubular member of the delivery device, pass coaxially with or inside the delivery device, and project distally from the distal end of the delivery device of the present invention. The soft grapple member is generally flexible and configured to bend its bulbous end into an arc or arch shape to contact the inside of an opening or anatomical structure of the patient or subject, such as the inner wall of the urethra, bladder, or kidney. To set the depth, the soft grapple member is placed within the treatment area and pulled back via a connected traction member, traction wire, or actuator, which deforms the distal end of the grapple member into a curved or arch shape, allowing the bulbous end of the grapple member to contact the internal surface of an opening or anatomical structure of the patient or subject.

[0186] In various embodiments, a soft grapple member is part of a soft grapple member array. A soft grapple member array may include two or more soft grapple members connected to two or more traction members or traction means. A soft grapple member array may include soft grapple members arranged at equal intervals, or soft grapple members arranged at random intervals and categorized. The device of the present invention may include any number of soft grapple members or soft grapple member arrays. Soft grapple members may further be conceived as fibrous elements such as sutures, and may include arrays of sutures that help grasp the inside of a patient's bladder wall.

[0187] The soft grapple member may be made of any suitable material, such as elastomers, polymers, plastics, metals, metal alloys, or any or all of the materials described herein. The material structure of the soft grapple member may be uniform, patterned, or composed of distinguishable materials arranged alternately. The flexural modulus of the soft grapple member may vary along its length. For example, the soft grapple member may be made of a more rigid material at its base and a more flexible material at its distal tip. Any arrangement of flexural modulus or strength of flexural modulus that is well known in the art and / or within the technical scope of practitioners or users may be employed. Delivery device with ratchet mechanism

[0188] In further embodiments, the delivery device is a portable delivery device comprising a drug product loading bay, a receptacle bay, a drug product delivery chamber, and an operating mechanism comprising a piston, a plunger, and a screw-type coupling member. The drug product loading bay, receptacle bay, and drug product delivery chamber may be designed to fit any preferred dimensions and may be capable of handling different types of drug products. Figures 13A, 13B, and 13C show different views of the loading mechanism (i.e., a first-person perspective view, a top-down view, and a side view, respectively).

[0189] The drug product delivery chamber 110 can be dimensioned to any size and shape suitable for the intended use, as well as any size and shape known in the art. In some embodiments, the drug product delivery chamber 110 is sized and shaped to receive a screw-type piston and plunger 115 screw-connected to a screw-type throttling device within the drug product delivery chamber. In some embodiments, the screw-type throttling device receives the piston by screw connection and is located at the proximal end inside the drug product delivery chamber. In other embodiments, the screw-type throttling device is located in other parts of the drug product delivery chamber, for example, at the midpoint of the chamber, near the midpoint of the chamber, outside the proximal end of the chamber, at any location deemed appropriate by the user or practitioner, or at any location suitable for the purposes of the present invention and / or known in the art.

[0190] The drug product delivery chamber may also include a soft-pull trigger 40 connected to a swivel and a spring-loaded ratchet mechanism. The spring-loaded ratchet mechanism may be operably connected to a loading pin 120 and a deloading pin 125. When a practitioner pulls or activates the trigger 40, the trigger acts on both pins, releasing the drug product unit from the loading area (loaded straw bay) 130 into the receptacle bay (empty straw bay) 135. The trigger and pins then return to their original positions via the contraction of the spring, holding the next successive drug product units in place.

[0191] In various embodiments, the receptacle bay is located on the opposite side of the drug product loading bay and is operably connected to the drug product delivery chamber. The receptacle bay can receive cartridges, empty carpules, empty capsules, empty pellets, empty cartridges coupled or connected by tethers, empty carpules coupled or connected by tethers, empty capsules coupled or connected by tethers, empty pellets coupled or connected by tethers, empty structures coupled or connected by tethers, or equivalents thereof, by the action of a deloading pin operably connected to the trigger of the portable delivery device. When the trigger is activated, the deloading pin moves, allowing the empty drug product, after being ejected from the drug product delivery chamber, to enter the receptacle bay. The mode of connection between the deloading pin and the trigger of the portable delivery device can vary in design. The deloading pin and the trigger may be connected directly, via a spring, via a tension member, via a traction mechanism, via a pressing mechanism, or indirectly via any suitable means known in the art. The deloading pin may be electronically coupled to the trigger, and in a further embodiment, may not be physically connected, but instead may be tethered via near-field communication, wireless communication, RFID, Bluetooth, Wi-Fi, or any suitable equivalent, which allows the trigger to communicate with and act upon the deloading pin.

[0192] The magazine spring 145 of the drug product loading bay is capable of both contracting to receive the drug product unit and extending to eject the drug product unit into the drug product delivery chamber. The drug product delivery chamber is operably mounted to the drug product loading bay and receives the ejected drug product unit for delivery to a patient or subject by the action of the actuation mechanism. The actuation mechanism may be any form of actuator known in the art, including pistons, pistons coupled to plungers, screw pistons, screw pistons coupled to plungers, obturator rods, stylets, screw stylets, screw rods, pneumatic actuators, spring-loaded actuators, piezoelectric actuators, electronic actuators, and the like.

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

[0194] Drug product loading bays can be manufactured, designed, and technologically developed according to different capacities. In various 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 ten, up to twelve, up to fifteen, up to twenty, up to twenty, up to twenty-five, up to thirty, up to thirty, up to thirty, up to thirty, up to thirty, up to forty, up to forty-five, up to fifty, up to sixty, up to seventy, up to one hundred, up to one twenty-five, up to one fifteen, up to one hundred

[0195] In other embodiments, drug product units of 5 or fewer, 10 or fewer, 15 or fewer, 20 or fewer, 25 or fewer, 30 or fewer, 35 or fewer, 40 or fewer, 50 or fewer, 60 or fewer, 75 or fewer, 100 or fewer, 125 or fewer, 150 or fewer, 175 or fewer, 200 or fewer, 250 or fewer, 300 or fewer, 350 or fewer, 400 or fewer, 450 or fewer, or 500 or fewer can be loaded into the drug product delivery bay.

[0196] In other embodiments, approximately 2 drug product units, approximately 3 drug product units, approximately 4 drug product units, approximately 5, approximately 7, approximately 10, approximately 12, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 60, approximately 75, approximately 90, approximately 100, approximately 125, approximately 150, approximately 175, approximately 200, approximately 225, approximately 250, approximately 275, approximately 300, approximately 325, approximately 350, approximately 400, approximately 450, approximately 500, approximately 750, or approximately 1000 drug product units may be loaded into the drug product loading bay at any given time.

[0197] Receptacle bays can be manufactured, designed, and technologically developed to accommodate countless capacities. In various 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 ten, up to twelve, up to fifteen, up to twenty, up to twenty, up to twenty-five, up to thirty, up to thirty, up to thirty, up to thirty, up to forty, up to forty-five, up to fifty, up to sixty, up to seventy, up to one hundred, up to one twenty-five, up to one fifteen, up to one hundred

[0198] In other embodiments, drug product units of 5 or fewer, 10 or fewer, 15 or fewer, 20 or fewer, 25 or fewer, 30 or fewer, 35 or fewer, 40 or fewer, 50 or fewer, 60 or fewer, 75 or fewer, 100 or fewer, 125 or fewer, 150 or fewer, 175 or fewer, 200 or fewer, 250 or fewer, 300 or fewer, 350 or fewer, 400 or fewer, 450 or fewer, or 500 or fewer can be received in the receptacle bay.

[0199] In other embodiments, approximately 2 drug product units, approximately 3 drug product units, approximately 4 drug product units, approximately 5, approximately 7, approximately 10, approximately 12, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 60, approximately 75, approximately 90, approximately 100, approximately 125, approximately 150, approximately 175, approximately 200, approximately 225, approximately 250, approximately 275, approximately 300, approximately 325, approximately 350, approximately 400, approximately 450, approximately 500, approximately 750, or approximately 1000 drug product units may be received in the receptacle bay.

[0200] In a further embodiment, 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 ten, at least twelve, at least fifteen, at least seventeen, at least twenty, at least twenty-three, at least twenty-five, at least thirty, at least thirty-five, at least forty, at least forty-five, at least fifty, at least fifty-five, at least sixty, and a few At least 70, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000, or more drug product units may be accepted into the receptacle bay. Valve-type tubular delivery device

[0201] In further embodiments, the delivery device of the present invention may be equipped with valves at both the entry and exit ports of the delivery device body. The delivery device may terminate at a blunt distal end that is sealed by the valve when not in operation or use. An obturator rod, stylet, piston, or other insertion device may be employed to indirectly open the valve seal located at the distal end of the device by pressing the drug product against the inner surface of the distal valve and acting to open the valve as the drug product is pushed through. A proximal valve may also be present to seal the proximal opening of the delivery device of the present invention. The proximal valve may be opened by the action of the obturator rod, stylet, piston, or other insertion device when the obturator rod, stylet, piston, or other insertion device is inserted into the passage of the delivery device of the present invention.

[0202] In another embodiment, a tubular member is provided having an open proximal end and an open distal end, with a hollow passage extending between them containing multiple units of a drug product. A valve is fixed to the proximal end of the tubular member and seals the open proximal end. A second valve is fixed to the distal end of the tubular member and seals the open proximal end. An obturator rod, stylet, etc., is provided as a drug product advancement and ejection tool, which enters the proximal opening of the tubular member through the first valve, advances a waiting amount of drug product units or particles through the hollow passage, and ejects the drug product units to the outside of the open distal end of the tubular member through the second valve. In some embodiments, the valve may be opened or operated alternatively through a push-button spring mechanism attached to the distal end of the tubular member. In other embodiments, the push-button spring mechanism may be mounted along the length of the tubular member, on the underside of the tubular member, or at any location deemed appropriate by those skilled in the art. Drug products for use with a valve-type tubular delivery device may be of any shape and convention described herein, including a bow-string alignment in which two drug products are connected by a bioabsorbable tether. The bow-string alignment allows the two drug products to enter at a 180-degree angle to each other, providing a minimum diameter for easy entry into the patient's urethra. After entry, the bioabsorbable bow-string allows the drug products to take an angle of less than 180 degrees, ensuring that the drug products remain in the patient's bladder for a predetermined amount of urination cycle. Finally, the bow-string tether slowly dissolves, allowing each of the previously connected drug products to flow out of the patient's bladder and urethra after a predetermined dissolution period.

[0203] A marking member or marking indicia may be provided along the outer wall of a tubular member to specify the 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 the outer wall of the tubular member. The marking member may also be in the form of a phrase that indicates the proper placement of the tubular member in a subject or patient. Alternatively, the marking member may be in the form of a marking indicia, provided as a number, letter, symbol, color, word, arrow, coded indicator, or other known indicia to indicate the proper placement of the tubular member during use of the device.

[0204] In various embodiments, the type of particles or drug product used (e.g., size, shape, composition, and method of manufacture) may be selected based on the proposed treatment. For example, particles having a cylindrical shape with a length of 2 millimeters (containing an antibiotic active agent) may be optimal for treating female patients with UTIs. These relatively large particles (where 2 mm is the average longest dimension) can be retained in the bladder in three ways. Firstly, the majority of the particles in the formulation (i.e., more than 90%) are buoyant in the urine. This buoyancy keeps the particles away from the urethral opening in the first half of the urination cycle when the urethral opening is at its widest. Secondly, as the bladder empties and the urethral opening gradually narrows, the particle diameter becomes wider than the narrowed urethral opening in the second half of the urination cycle, as urination nears its end. Thirdly, at the end of the urination cycle (when the urethral opening narrows and the buoyant particles are carried to the level of the urethral opening), the particles tend to aggregate in the bladder, thereby preventing the particles from flowing out.

[0205] Many catheters (intravesical or otherwise) or cystoscopes, once in place, are prone to slipping out or becoming dislodged. They are also prone to being inserted too deeply. In surgeries involving prolonged intravesical manipulation, the risk of the device slipping out or becoming dislodged complicates the procedure. Complications can stem from a number of factors, including, but not limited to, an increased risk of laceration or irritation due to impaired hands-free operation for the clinician, the need to reposition the device if it is unintentionally removed (which may cause increased adverse effects on tissue), or altering the depth to which it was initially inserted. How to use

[0206] In various embodiments, particles within a pharmaceutical formulation include (a) a pharmacologically active agent and (b) a controlled-release carrier. By progressive decrease in mass and / or other means, the particles release the active agent into the bladder over an extended drug delivery period. The components of the particles are further described herein.

[0207] As can be understood, the selection of pharmacologically active agents depends on the indication. Active agents that can be administered via intravesical administration of the particle formulations of the present invention are generally selected from, but are not essential, the following categories: anti-infective agents including antibacterial, antifungal, and antiviral agents; chemotherapeutic agents; anti-inflammatory agents; anesthetic agents; analgesics; diuretics; coagulants and anticoagulants; biological agents; agents for treating incontinence, including overactive bladder (including antimuscarinic agents, β3-adrenergic receptor agonists, anesthetic agents, and analgesics); renin-angiotensin-aldosterone system (RAAS) inhibitors; agents for modulating immune responses; agents for treating kidney stones; agents for gene therapy; and contrast agents for diagnosis and monitoring.

[0208] As described above, the pharmaceutical formulation is most conveniently administered to the patient in a compressed form. In the bladder, the capsule can expand or conform to a size that resists passage into the urethra over the desired retention period. In various embodiments, the particles have a total volume of about 10 - 50 mm 3 and. In various embodiments, the particles are about 1 mm 3 , about 2 mm 3 , about 3 mm 3 , about 5 mm 3 , about 7 mm 3 , about 10 mm 3 , about 12 mm 3 , about 15 mm 3 , about 20 mm 3 , about 25 mm 3 , about 30 mm 3 , about 35 mm 3 , about 40 mm 3 , about 45 mm 3 , about 50 mm 3 , about 60 mm 3 , about 70 mm 3 , about 80 mm 3 , about 90 mm 3 , about 100 mm 3 , or more. In various embodiments, the particles have a hollow core.

[0209] In additional embodiments, the pharmaceutical particles described herein are particles having a cylindrical shape (i.e., having a barrel shape or being cylindrical) that are coupled or connected to another particle by a tether, or groupings of particles having a substantially cylindrical shape. In various embodiments, the particles are 1 mm 3 or less, 2 mm 3 or less, 3 mm 3 or less, 5 mm 3 or less, 7 mm<s 3 or less, 10 mm 3 or less, 12 mm 3 or less, 15 mm 3 or less, 20 mm 3 or less, 25 mm 3 or less, 30 mm 3 or less, 35 mm 3 or less, 40 mm 3 or less, 45 mm 3Less than 50 mm 3 Less than 60 mm 3 Less than 70 mm 3 Less than 80 mm 3 Less than 90 mm 3 or 100 mm 3 and has a total volume of less than the above.

[0210] In a further aspect, the particles are about 2 mm 2 about 3 mm 2 about 5 mm 2 about 7 mm 2 about 10 mm 2 about 12 mm 2 about 15 mm 2 about 20 mm 2 about 25 mm 2 about 30 mm 2 about 35 mm 2 about 40 mm 2 about 45 mm 2 about 50 mm 2 about 60 mm 2 about 70 mm 2 about 80 mm 2 about 90 mm 2 about 100 mm 2 or have a total surface area of more than the above.

[0211] In a still further aspect, the pharmaceutical product is connected by a bioabsorbable tether or hinge, and the bioabsorbable tether and hinge are designed to maintain their integrity (i.e., not dissolve) until after one urinary cycle, two urinary cycles, three urinary cycles, four urinary cycles, five urinary cycles, six urinary cycles, seven urinary cycles, eight urinary cycles, nine urinary cycles, ten urinary cycles, eleven urinary cycles, twelve urinary cycles, thirteen urinary cycles, fourteen urinary cycles, fifteen urinary cycles, sixteen urinary cycles, seventeen urinary cycles, eighteen urinary cycles, nineteen urinary cycles, twenty urinary cycles, twenty-five urinary cycles, thirty urinary cycles, thirty-five urinary cycles, forty urinary cycles, forty-five urinary cycles, fifty urinary cycles, fifty-five urinary cycles, sixty urinary cycles, sixty-five urinary cycles, seventy urinary cycles, seventy-five urinary cycles, eighty urinary cycles, ninety urinary cycles, one hundred urinary cycles, one hundred and ten urinary cycles, one hundred and twenty-five urinary cycles, one hundred and fifty urinary cycles, one hundred and seventy-five urinary cycles, two hundred urinary cycles, two hundred and twenty-five urinary cycles, two hundred and fifty urinary cycles, two hundred and seventy-five urinary cycles, three hundred urinary cycles, three hundred and twenty-five urinary cycles, three hundred and fifty urinary cycles, three hundred and seventy-five urinary cycles, four hundred urinary cycles, four hundred and fifty urinary cycles, five hundred urinary cycles, six hundred urinary cycles, seven hundred urinary cycles, eight hundred urinary cycles, nine hundred urinary cycles, one thousand urinary cycles, or more urinary cycles.

[0212] Bioabsorbable tethers or hinges may have a predetermined or variable durometer. The durometer of a bioabsorbable tether or hinge is approximately 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, and 25A. This may correspond to a Shore A durometer of approximately 26A, 27A, 28A, 29A, 30A, 35A, 40A, 45A, 50A, 55A, 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 96A, 97A, 98A, 99A, or 100A.

[0213] Bioabsorbable tethers or hinges may have a predetermined or variable durometer. The durometer of a bioabsorbable tether or hinge may have 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, and at least It may also correspond to a Shore A durometer of 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] Bioabsorbable tethers or hinges may have a predetermined or variable durometer. The durometer of a bioabsorbable tether or hinge may be 1A or less, 2A or less, 3A or less, 4A or less, 5A or less, 6A or less, 7A or less, 8A or less, 9A or less, 10A or less, 11A or less, 12A or less, 13A or less, 14A or less, 15A or less, 16A or less, 17A or less, 18A or less, 19A or less, 20A or less, 21A or less, 22A or less, 23A or less, 24A or less, 25A or less. The following may correspond to a Shore A durometer of 26A or less, 27A or less, 28A or less, 29A or less, 30A or less, 35A or less, 40A or less, 45A or less, 50A or less, 55A or less, 60A or less, 65A or less, 70A or less, 75A or less, 80A or less, 85A or less, 90A or less, 95A or less, 96A or less, 97A or less, 98A or less, 99A or less, or 100A or less.

[0215] In various embodiments, administration of the drug products and devices of the present invention can improve urine suppression in subjects or patients by, for example, 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 various embodiments, administration of the drug products and devices of the present invention can reduce signs / symptoms of bladder / urinary tract / kidney disease by, for example, 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 various embodiments, administration of the drug products and devices of the present invention can reduce signs / symptoms of bladder / urinary tract / kidney disease by, for example, 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 various embodiments, intravesical administration of a drug product using the device / method of the present invention can reduce reported patient discomfort (compared to the use of conventional catheters) by, for example, 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 various embodiments, the administration of the drug product and device of the present invention reduces the time required for intravesical administration of the drug product (e.g., preparation time) by, for example, 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%, or about 99% compared to conventional methods (e.g., manual loading into a catheter). In various embodiments, the device and method enable intravesical administration by a smaller number of trained staff (i.e., administration by a healthcare professional / technician alone).

[0220] In various embodiments, the devices / methods described herein can deliver drug particles, where the average diameter of the particles or drug delivery product is approximately 50 nanometers, approximately 100 nanometers, approximately 200 nanometers, approximately 350 nanometers, approximately 500 nanometers, approximately 1,000 nanometers, approximately 2,000 nanometers, approximately 3,000 nanometers, approximately 5,000 nanometers, approximately 10,000 nanometers, approximately 10 micrometers, approximately 20 micrometers, approximately 30 micrometers, approximately 50 micrometers, approximately 100 micrometers, approximately 150 micrometers, approximately 250 micrometers, and approximately 5 These are approximately 00 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 more.

[0221] In various embodiments, the controlled-release particles described herein have a cylindrical shape (i.e., a barrel shape or is cylindrical) or are substantially cylindrical. In various embodiments, the controlled-release particles are approximately 10 to 50 mm in diameter. 3 It has a volume of approximately 1 mm. In various embodiments, the particles are approximately 1 mm in size. 3 Approximately 2mm 3 , about 3mm 3 , about 5mm 3 , about 7mm 3 , about 10mm 3 Approximately 12mm 3 , about 15mm 3 , about 20mm 3 , about 25mm 3 , about 30mm 3 , about 35mm 3 Approximately 40mm 3 , about 45mm 3 Approximately 50mm 3 , about 60mm3 、 about 70 mm 3 、 about 80 mm 3 、 about 90 mm 3 、 about 100 mm 3 、 or have a volume of more. In various embodiments, the particles have a hollow core.

[0222] In various embodiments, the drug particles described herein have a cylindrical shape (i.e., have a barrel shape or are cylindrical), or substantially have a cylindrical shape. In various embodiments, the particles are 1 mm 3 or less, 2 mm 3 or less, 3 mm 3 or less, 5 mm 3 or less, 7 mm 3 or less, 10 mm 3 or less, 12 mm 3 or less, 15 mm 3 or less, 20 mm 3 or less, 25 mm 3 or less, 30 mm 3 or less, 35 mm 3 or less, 40 mm 3 or less, 45 mm 3 or less, 50 mm 3 or less, 60 mm 3 or less, 70 mm 3 or less, 80 mm 3 or less, 90 mm 3 or less, or 100 mm 3 or less in volume.

[0223] In various embodiments, the particles are about 2 mm 2 、 about 3 mm 2 、 about 5 mm 2 、 about 7 mm 2 、 about 10 mm 2 、 about 12 mm 2 、 about 15 mm 2 、 about 20 mm 2 、 about 25 mm 2 、 about 30 mm 2 、 about 35 mm 2 、 about 40 mm 2 、 about 45 mm 2 、 about 50 mm 2 、 about 60 mm 2 、 about 70 mm 2, about 80mm 2 , about 90mm 2 Approximately 100mm 2 It has a surface area of ​​, or greater than that. [Examples]

[0224] The following non-limiting embodiments are provided solely for illustrative purposes to facilitate a more complete understanding of the representative embodiments assumed herein. These embodiments are intended to represent merely a subset of all possible contexts in which the components of the formulation may be combined. Therefore, these embodiments should not be construed as limiting any of the embodiments described herein, including those relating to the type and quantity of the components of the formulation, and / or the method and use thereof. Example 1 Comparison of different polymorphs

[0225] Polymorphs are formed when a polymer solidifies into lattice structures that are chemically identical but have different lattice structures, and therefore different tertiary and quaternary structures. By adjusting the crystallinity of the product or by producing different polymorphs, it is possible to adjust drug release, buoyancy, density, and material properties such as hardness, stability, packing, and appearance. In this example, alpha (α), beta-prime (β'), and beta (β) crystal structures were generated, and their buoyancy was compared over time.

[0226] Alpha (α) particles harden at 4°C. Because the lattice is highly regular and the carbon chains are arranged in parallel, a smooth surface exists in the quaternary structure, making alpha particles appear glossy. To create alpha particles, the system's energy must be kept low, reducing the motion along the monomer's degrees of freedom and minimizing intramolecular interference.

[0227] Beta-prime (β') particles harden rigidly at 51°C. Because the monomer has a bent glycerol carbon chain, these particles are more randomly packed and "chalk-like." If beta is more randomly packed, energy must be accumulated between polymer units during the polymerization process. Similarly, beta(β) melts and hardens at 51°C. Beta(β) appears chalk-like (i.e., matte).

[0228] Figure 1 compares the characteristics of each type of crystal structure. The β-rods maintained their buoyancy over a 4-day course. Almost all of the β-rods did not settle at the bottom of the flask. In contrast, the α-rods and β-rods lost their buoyancy after about 3 days. Example 2 Comparison of absorbable sutures

[0229] In various embodiments, the drug products are joined together with absorbable sutures (e.g., sutures used to join bowstrings or hinges). After the absorbable sutures have dissolved completely, the individual drug products separate from each other and are excreted during urination.

[0230] Therefore, the length of the residence period depends on the material used for the suture. The applicant compared different materials as summarized below. Monocryl has low tissue reactivity, maintains high tensile strength, and has a half-life of 7 to 14 days. Catgut suture is made from a twisted thread of purified collagen taken from the small intestine of domesticated ruminants or the tendons of cattle. The suture is naturally degraded by proteolytic enzymes possessed by the body. The full tensile strength persists for at least 7 days, and absorption is completed within 90 days. Vicryl suture is rehydrolyzed into glycolic acid and lactic acid within about 7 to 10 days in the body. It retains about 50% of its breaking strength on the 5th day, hardly retains it on the 14th day, and finally the entire suture disappears. PDS (polydioxanone) suture is more stable. PDS suture retains about 70% of its initial strength at 2 weeks, 50% at 4 weeks, and 25% at 6 weeks. PDS suture is absorbed through simple hydrolysis and will be completely absorbed within 180 to 210 days.

[0231] Table 1 shows the characteristics of different materials and their intravesical stability.

Table 1

[0232] In this example, a female patient visits a healthcare provider to receive intravesical administration of controlled-release particles. By using intravesical particles, it becomes possible to deliver the drug to the target site at a predetermined controlled rate, and higher efficacy and safety can be obtained. As shown in Figure 7, the particles can be inserted using a catheter / straw having a blunt end for entry. The catheter / straw may also be equipped with a valve for direction control. Preparation of the procedure 1. Set up a sterile table (e.g., on the right side of the patient table base). 2. Place 4 sterile straws on the table (two straws will hold 5 grams of medication). Take out two 3.5-gram packets and place them on the table. 4. Place the rods into the straw "one by one". 5. Place four pre-filled straws on the table to administer the drug product to the patient. 6. Open the device to push the rod out of the straw and insert it into the bladder sheath: a. A 6Fr stent pusher can be used. b. A 7Fr vascular sheath can be used. c. A 5Fr vascular catheter with a floppy-disk tip can be used. Administration Procedure 1. Place the patient in a supine position with their legs in stirrups. 2. Sterilize the vaginal opening and cover the area sterilely with a drape. 3. Treat the urethra with viscous lidocaine. Coat the outside of the sheath with viscous lidocaine as a lubricant. 4. Insert the bladder sheath into the bladder: a. A 19.5Fr sheath is available. b.22Fr sheaths are usable. A c.17.5Fr sheath is usable. 5. Attach the bridge, insert the cystoscopy, and fill the bladder with saline solution. 6. Fill the bladder and check for any injury or disease. 7. Remove the scope and leave the sheath in place. 8. Set the angle of the sheath from approximately 45 degrees to the floor to approximately 0 degrees to the floor (this prevents the rod inside the bladder from protruding outside the sheath). 9. The assistant prepares for rod insertion: a. The assistant holds the distal end of the straw to prevent the rod from falling out. b. The assistant inserts the “pusher” into the proximal end of the straw. Here, the rod is sandwiched between the distal pinch and the pusher positioned proximal. 10. The assistant inserts the distal end of the straw into the cysto funnel and fits the straw into the narrow chute: i. Advance the straw as far as it will go into the bladder chute, then push the rod into the bladder through the straw, or ii. Use the pusher to push the rod out of the straw into the sheath. b. The assistant removes the straw and holds the pusher forward inside the bladder chute to prevent the rod from flowing back out. 11. The urologist removes the rod from the sheath: a. The urologist positions the obturator within the bladder funnel so that it contacts the pusher. b. When the assistant removes the pusher, the obturator controls the pellets to prevent any from escaping, and then the obturator moves forward through the sheath to expel all the rods into the bladder. c. This completes the insertion of the rod for the first straw. d. Set the sheath angle to 0 degrees and remove the obturator. 12. Repeat a. Repeat the procedure (steps 8-10) for the remaining straws. 13. Confirmation a. The urologist removes the obturator, reattaches the bridge with the scope, and then examines the bladder to confirm that the rod is present and undamaged. b. If air is present in the bladder, a urologist will remove it. 14. End of procedure a. The urologist removes the scope, sheath, and bridge. b. Remove the drape and assist the patient to get down from the table. Example 4 Intravesical administration of controlled-release particles (delivery devices)

[0233] In this embodiment, female patients are administered controlled-release intravesical particles using the device of the present invention. The procedure for two different product dosages is summarized below. 1. Urethral insertion x 4, product delivery x 1 = 10 grams a. Load a 2.5-gram product, 200 mm (approximately 8 inches) in length, into a 10-inch sheath (straw). b. The sheath has a blunt end and an inlet tip that acts as a one-way valve (e.g., a flip-open valve, a duckbill valve, a Heimlich valve, etc.). c. Insert the sheath into the bladder through the urethra. d. If urine flows back through the sheath, entry is demonstrated. e. The sheath has a one-way valve at its outer end to prevent the product from flowing back out of the sheath during transport or handling. f. An obturator (push mechanism) is used to advance the loaded product through an external valve and deliver it into the bladder in an anterograde direction. i. The force applied from the obturator is transmitted along the product column, pushing open the tip of the introducer. ii. This force cannot overcome the vulnerabilities of the pharmaceutical product. To dock with the rear section of the sheath, advance the obturator to its full length. h. Remove both the sheath and the obturator. i. Repeat this process, increasing the target product quantity by 2.5 grams at a time while delivering the product. The j. sheath possesses rigidity to withstand kinking up to the maximum force encountered during packaging, transport, and user handling. k. The sheath may have distal bumps or ramps that orient the product so that it deviates from the forward axis as it exits the sheath. l. To restrict the sheath from advancing into the bladder, the sheath may have an expansion portion (e.g., 4-6 centimeters) from the introducer end. m. In various embodiments, the sheath can hold the product and can be subjected to simultaneous electron beam sterilization (or other) without compromising the sterility of the product. 2. Urethral insertion x 1, product delivery x 4 = 10 grams a. Insert the distal tip of a gun-type device into the urethra. b. Load several “magazines” of drug products into the device in a manner that allows them to be delivered continuously through the urethra, and then dock them with the device. i. In one embodiment, the magazine is placed horizontally (i.e., aligned with the delivery axis) and is aligned with the main channel of the device one at a time. Once aligned, the drug product is ejected from the magazine through the main channel into the bladder. The used magazine is then replaced with a fully filled magazine, and this process is repeated. ii. In one embodiment, the magazine is a straw-shaped sheath. iii. In one embodiment, the magazine is ejected by a mechanical slide (operated manually, by a robotic piston, or by other means). iv. In one embodiment, the magazine is ejected by the force of a gas or liquid. 3. Urethral insertion x 1, product delivery x 1 = 10gm a. A product that can be delivered using a mechanical slide, filled with French horns.

[0234] In some embodiments, the device includes a sheath orientation indicator having color, texture, or properties to warn the operator via an external cue that the sheath orientation is facing inward relative to the patient. In some embodiments, an internal anchoring mechanism prevents the delivery mechanism (e.g., flap or balloon) from moving backward during the procedure.

[0235] The provider can insert the catheter into the patient's urethra using the following procedure. The catheter is cylindrical in shape and is operably attached to a portable delivery device that has a funnel for supplying a floating drug product into the barrel of the portable delivery device body. The provider activates a trigger mounted on the underside of the housing of the portable delivery device to deliver the time-release drug product into the patient's bladder through the urethra. Example 5 Treatment of chronic UTIs

[0236] In this example, a female patient visits a healthcare provider with signs / symptoms of a UTI. The provider records that the patient has had three UTIs within a six-month period. To date, the female patient has been prescribed oral antibiotics (i.e., amoxicillin or nitrofurantoin). Prophylactic oral antibiotics are an option, but the patient wishes to avoid them. Furthermore, the healthcare provider is aware of the risk of antibiotic resistance.

[0237] The provider offers the option of using controlled-release intravesical particles. Conventional drug delivery systems (e.g., tablets, capsules) may have problems such as insufficient bioavailability and variability in plasma drug levels. Using intravesical particles allows for drug delivery to the target site at a predetermined, controlled rate, resulting in higher efficacy and safety.

[0238] Trocars are used in laparoscopic procedures and other minimally invasive surgeries to make small, puncture-like incisions in the outer tissue layers. These incisions allow the surgeon to insert a cannula, through which surgical instruments can be introduced. In this embodiment, the provider inserts a trocar 112 into the patient's urethra, as shown in Figure 15. The trocar may include a distal (internal) flange that is open to hold the trocar in place. The trocar may also have a one-way valve to prevent fluid from leaking out of the bladder during the procedure. As shown, the trocar may be approximately 8 cm in length (based on a urethral length of approximately 6 cm).

[0239] The provider uses a trocar as the entry point for the particles. Figure 16A represents a magazine loaded with particles, and Figure 17 further represents an obturator. The magazine may be equipped with a one-way valve. The magazine may also include markings or a fairing to indicate the length. For example, a fairing (i.e., an external structure made of plastic / rubber) 160 may be embedded / attached at a position 6 centimeters from the distal tip. This can indicate a safe insertion point into the trocar and prevent overinsertion and damage to the bladder. The obturator is also shown. In various embodiments, the obturator is the same length as the magazine. The obturator may also include markings or a fairing 165 to prevent overinsertion and damage to the bladder. In this embodiment, the provider follows the steps below. a) Insert the trocar 112 through the patient's urethra; b) Secure the trocar and open it; c) Insert the magazine through the Trocar up to Mark 160; d) Insert the obturator into the magazine up to mark 165 to eject the particles; e) Remove the obturator and magazine; f) Repeat steps (c) to (e) until the entire dose has been administered (e.g., four magazines); g) Remove Trocar 112 from the patient.

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

[0241] The patient reports symptom relief within 6 hours of the procedure. The patient experiences no discomfort or presence of particles. The patient is evaluated one week later and shows no signs / symptoms of infection. Furthermore, the provider records that amikacin is present in the bladder at effective concentrations, but no detectable circulating amikacin is present. The patient is then advised to maintain regular visits to their healthcare provider and report any signs / symptoms that may be attributable to a UTI. Example 6 Administration of intravesical particles using a pre-loaded obturator.

[0242] A female patient residing in a nursing home is experiencing recurrent urinary tract infections due to complete bladder emptying. After evaluating the patient's condition, the physician recommends treatment with anti-infective drug capsules. The anti-infective drug capsules are buoyant and float in the urine within the patient's bladder, allowing the drug product to release its active ingredient over time without being prematurely excreted from the patient.

[0243] In this embodiment, the obturator is pre-loaded with particles (Figure 17). The provider inserts the obturator into the trocar, carefully avoiding contact with the distal end of the bladder. Next, the particles are ejected from the obturator into the bladder using a handle or lever. The obturator is removed. These steps are repeated for a total of four obturators. The trocar is then removed from the patient's urethra. Figure 17 shows variations in the obturator design. In various embodiments, the obturator includes a thumb catch 170. The thumb catches may be configured to be paired at positions of 0° and 180° or 90° and 270° relative to each other.

[0244] In various embodiments, the devices and methods described herein enable intravesical administration as a standalone procedure. In various embodiments, the drug product may be administered without visualization by the healthcare provider (i.e., as a blind procedure).

[0245] In various embodiments, the devices and methods described herein can deliver pieces of a drug product (for example, 160 pieces in the case of 4 x 5 mm, 80 pieces in the case of 4 x 10 mm, or 40 pieces in the case of 5 x 15 mm, etc., so that the delivered dose is 10 grams) into the bladder through the female or male urethra.

[0246] In various embodiments, the devices and methods described herein prevent lateral, forward, and / or reverse catheter movement, thereby improving comfort or reducing pain during intravesical administration procedures.

[0247] In some embodiments, the devices and methods described herein have tactile feedback, which can alert healthcare providers to adjust / terminate the procedure if an obstruction is present. Example 7 Administration of intravesical particles using a device with an intravesical sheath.

[0248] In this example, a female patient reports multiple and recurrent urinary tract infections to her healthcare provider. After assessing the patient's condition, the provider recommends treatment using a grouping of anti-infective drug capsules. The grouping of anti-infective drug capsules is buoyant and floats in the urine within the bladder, thereby releasing the drug product over a period of time (e.g., 5 days).

[0249] The provider inserts the intravesical sheath 80 into the patient's urethra and secures the sheath in place with its leaf-shaped distal end 95. Once the intravesical sheath is locked in place, the delivery chamber 110 is connected to the sheath (for example, by securing it to a screw-type portion). The provider inserts a grouping of the anti-infective drug product through the internal lumen of the intravesical sheath by twisting the proximal handle of a screw-type piston operably connected to the proximal end of the intravesical sheath (Figure 4A). The piston's action pushes the grouping of the anti-infective drug product through the inflatable depth-locking member 55 of the intravesical sheath into the patient's bladder. 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's follow-up visit.

[0250] The provider will follow up with the patient two weeks after the procedure. The patient will report no discomfort, and the provider will not find any evidence of a urinary tract infection. Example 8 Administration of bladder particles "tethered"

[0251] A female patient residing in a care facility is experiencing recurrent urinary tract infections (UTIs) due to complete bladder emptying. After assessing the patient's condition, the physician recommends treatment with intravesical antibiotics. The physician also recommends a course of amikacin administered via a tethered drug product (i.e., particles or a cylinder).

[0252] As shown in Figure 4A, the tethered drug products are stacked and administered through the urethra in the form of cylinders (i.e., administration phase). Even when exposed to urine in the bladder, the cylinders separate but remain attached to each other by the tethers (i.e., retention phase). Due to their combined size, the tethered cylinders resist being expelled during urination.

[0253] The tether gradually dissolves over a period of time during which the active drug (e.g., amikacin) is released from the particles. In this example, the tether remains intact for approximately 10 days as amikacin is released into the bladder. The concentration of amikacin in the bladder remains relatively constant during this period.

[0254] The patient is regularly evaluated throughout the course of treatment. Approximately 48 hours after administration, the patient shows no signs / symptoms of UTI, and more than 90% of the particles remain in the patient's bladder (via ultrasound). After 10 days, most of the particles separate from each other and are expelled during urination. After 2 weeks, the cylinder is gone from the bladder. Example 9 Administration of bladder particles that undergo "three-dimensional structural changes"

[0255] A female patient visits a healthcare professional complaining of recurrent urinary tract infections (UTIs). The healthcare provider records that the patient has recently been treated for a UTI with a broad-spectrum antibiotic (oral). After assessing the patient's condition, the physician recommends treatment with an antibiotic administered intravesically. Using intravesical particles allows for drug delivery to the target site (i.e., the urinary tract) at a controlled, predetermined rate, resulting in higher efficacy and safety. Specifically, the provider recommends a course of amikacin administered via a sterically altered drug product (i.e., a connected cylinder).

[0256] As shown in Figure 3A, the drug product is stacked and administered through the urethra in a cylindrical shape (i.e., administration phase). Even when exposed to urine in the bladder, the cylinders separate but remain attached to each other by linkage or tethers in or near the capped area (i.e., retention phase). Due to their combined size, the particles resist being expelled during urination.

[0257] As amikacin is released from the cylinder into the bladder, the linker portion gradually dissolves. In this example, the connecting portion remains intact for approximately 10 days. The concentration of amikacin in the bladder remains relatively constant during this period.

[0258] The patient is regularly evaluated throughout the course of treatment. Approximately 48 hours after administration, the patient shows no signs / symptoms of UTI, and more than 90% of the cylinder remains in the patient's bladder (as observed by ultrasound). After 10 days, most of the cylinder separates from each other and is expelled during urination. After 2 weeks, the cylinder is gone from the bladder. Example 10 Administration of intravesical particles containing bioabsorbable polymer linkers

[0259] Similar to the example described above, a female patient visits a healthcare professional complaining of recurrent urinary tract infections (UTIs). The physician recommends treatment with intravesical antibiotics. Specifically, the provider recommends a course of amikacin administered via a sterically altered drug product (i.e., a connected cylinder).

[0260] As described above, the drug products are stacked and administered through the urethra in a cylindrical shape (i.e., administration stage). Even when exposed to urine in the bladder, the cylinders remain attached to each other by coupling or tethering (i.e., retention stage).

[0261] As shown in Figure 3G, at least a portion of the cylinder contains a material that swells when exposed to liquid. This occurs during the retention phase. The swelling releases the cylinder from the cap. Subsequently, the individual cylinder and cap portions are readily excreted in the urine (i.e., the elimination phase).

[0262] In this embodiment, the composition of the cylinder is modified to extend the duration of the retention phase. The cylinder and cap assembly may be modified or "tuned" to extend the retention phase. One approach involves the use of an enteric coating. As shown in Figure 3H, the rod may be coated. The outer layer may reduce water movement / absorption. The coating gradually dissolves when exposed to urine in the bladder.

[0263] Figure 3I shows the results of comparing different coatings (i.e., the percentage of rods retained over 21 days). The following 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 test, PAA cylinders coated with 60% LT460 provided the most favorable residence period. In various embodiments, the cylinders are coated multiple times (i.e., multiple layers) to extend the residence period.

[0264] Alternatively, the cylinder can be made from a composite material. A swellable (i.e., hygroscopic) material can be combined with a hydrophobic material. Doing so reduces the swelling rate and extends the retention phase. Other approaches, as shown in Figure 3J, include: "Hinge dissolution"—that is, using dissolvable hinge components. For example, the silicone material of the hinge can be replaced with a bioabsorbable elastomer. "Rod extrusion" - The pores on the hinge allow water to diffuse, and then the material swells and extrudes the rod. "Hinge weakening" - As the adhesive material loses its strength, the slits on the hinge increase the degree of freedom of movement. "Rod release" - butt joint (no overlapping socket portion on the rod). This releases the rod as the adhesive dissolves. "Hinge Disassembly" - Use corrosive / dissolving materials for hinge connectors. Example 11 Use of floating medical devices

[0265] In various embodiments, the device, which is placed in a fluid-filled organ such as the bladder for drug delivery (or other therapeutic effect), is buoyant in body fluids.

[0266] In this embodiment, the intravesical drug delivery device minimizes stimulation of sensory nerves in the bladder trigone in order to deliver therapeutic treatment within the bladder. Such improvement reduces the pressure exerted by the intravesical treatment device on the bladder trigone, which is defined as the space defined by the central urethral opening and the bilateral ureteral orifices.

[0267] For example, U.S. Patent No. 11,135,161 teaches an implantable device for delivering a drug to a patient, comprising a first drug portion having a first drug housing for containing a first drug formulation in solid form, and a second drug portion including a second drug housing for containing a second drug formulation. Another variant comprises a device having a drug reservoir component having an elastic tube having at least one lumen bounded by porous sidewalls having an open-cell structure, a closed-cell structure, or a combination thereof, and a drug formulation contained within the at least one lumen, wherein the device is deformable between a low-profile deployed shape and a relatively expanded retaining shape.

[0268] Implantable devices can be modified to reduce any pressure caused by device delivery to the triangular region, including those discussed above. For example, the buoyancy or floating properties of a delivery device can be modified by attaching the device to a floating object such that the combined density of the floating object and the drug delivery device is within 20% of the density of urine in the bladder (assuming a urine specific gravity of 1.005 to 1.03).

[0269] In an additional variant, the floating object may include a central chamber (e.g., a balloon or other gas reservoir) where the floating object has the mass of a low-density material such as a lipid (e.g., glyceryl tristearate). In another variant, the intravesical drug delivery device partially or entirely contains a gas, liquid, or solid whose density is less than that of urine, where a portion of the drug reservoir or retention reservoir is filled with a gas, such as oxygen, nitrogen, carbon dioxide, or carbon tetrafluoroethylene. Example 12 Delivery of drug products to the bladder of male patients

[0270] In this embodiment, the drug product is delivered into the bladder of a male patient. The procedure is preferably outpatient and requires the use of a flexible device (single-use). The maximum outer diameter of the device passing through the urethra is 10 mm, and devices / conduits of 7 mm or less are preferred. The inner diameter of the device must be sufficient to transport the drug product. As described herein, the drug product may have a diameter of approximately 5 mm. The thinner the conduit wall, the easier it is to achieve this goal. Devices made of polytetrafluoroethylene (PTFE) are preferred because they have good rigidity with respect to thickness, and for this reason they are used in vascular sheaths.

[0271] The conduit must be able to pass through the male urethra, which bends at an angle of 0 to 60 degrees below the prostate. The conduit must not kink when making such bends, and therefore it must be deformable in the range of 0 to 15 degrees, 15 to 30 degrees, 30 to 45 degrees, or 45 to 60 degrees. To prevent kinking, the walls may be reinforced with coiled metal ribbons, plastic ribs, metal springs, etc.

[0272] When products are 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 a single line and cannot jam or ride up against each other. It may be possible to place products side by side, but they must not jam with the pair of products in front of them. This will cause jamming and product failure. Friction within the conduit must be minimized in a humid environment, and therefore hydrophobic coatings and PTFE are preferred materials.

[0273] Throughout the entire conduit, from inlet to outlet, the inner diameter must not have large step changes that would allow the drug product to get stuck or scraped away. Existing vascular sheaths have a proximal dilation chamber to allow fluid injection.

[0274] Removing the drug product from the conduit and delivering all of it into the bladder is not straightforward. The anterior edge of the "obturator" must not slip through any gap on either side of the drug product, thus causing jamming and product destruction. Instead, the difference in diameter between the drug product and the inner diameter (ID) of the conduit must be less than the cross-sectional area of ​​the anterior edge surface of the obturator.

[0275] When an obturator is located inside the male urethra, it must advance through bends within the conduit. It is important that the obturator is deformable. This can be achieved by a flexible material or by an obturator having a distal "head on a neck," where the head provides a broad surface for advancing the drug product, and the neck allows the head to deflect at an angle relative to the proximal portion of the advancing obturator.

[0276] The elements of product delivery can be summarized as follows: 1. Insertion of the conduit a. Entry into the urethral opening b. Urethral passage i. The corpus cavernosum of the urethra ii. Membranous part of the urethra iii. Urethral prostatic region 2. Check bladder access a. Urine return b. Pressure changes 3. Maintaining the indwelling from the urethra to the bladder. a. Inflating the balloon b. End mooring flap c. Wall expansion, pressure, or friction 4. Prepare the bladder to receive the drug product. a. Fluid injection i. Should we add an injection port as part of the sheath? 5. Placement of products within the conduit a. Docking the magazine b.Manual loading c. Pre-filled conduit d. Mechanical loading 6. Delivery of the product into the bladder via a conduit. a. By advancing drug products, deliver the next b. Clear the conduits by advancing the obturator. i. The design of the obturator must be adapted to the bending. 7. Repeat steps 5 and 6 without backflow of the product or bladder fluid. a. Valves located at the proximal or distal end allow for unidirectional movement of the drug product. 8. Removal of Conduits Example 13 Treatment for bladder cancer

[0277] In this example, a 75-year-old male patient visits a healthcare provider complaining of hematuria, pain during urination, and lower back pain. The provider performs a visual examination of the bladder using cystoscopy. Pathological examination confirms the presence of tumor cells.

[0278] The provider offers the option of using controlled-release intravesical particles. Conventional drug delivery systems (e.g., tablets, capsules) may have problems such as insufficient bioavailability and variability in plasma drug levels. By using intravesical particles, it is possible to deliver the drug to the target site at a predetermined, controlled rate, resulting in higher efficacy and safety.

[0279] The patient receives intravesical chemotherapy. Specifically, the patient receives a single intravesical infusion of chemotherapy. The cylindrical particles described herein contain mitomycin C (MMC) as the active agent. The particles are administered in a stacked configuration (i.e., two cylinders joined by a soluble connector). After insertion, the particles undergo a steric change and increase in size (i.e., from 4 mm to 10 mm). The particles remain in the bladder while MMC is released into the bladder and surrounding tissues.

[0280] Approximately 5 days later, after a course of treatment, the particles undergo a second steric change (i.e., from 10 mm to 4 mm). The particles (and components) are excreted in the patient's urine. The provider performs a second visual examination of the bladder by cystoscopy. The number and size of the tumors have substantially decreased (i.e., by approximately 85%). The provider suggests immunotherapy and regular monitoring of the patient's bladder. Example 14 Use of drug products having fibrous extensions

[0281] An 88-year-old female patient is experiencing recurrent urinary tract infections (UTIs) due to complete bladder emptying. After assessing the patient's condition, the physician recommends treatment with intravesical antibiotics. The physician also recommends a course of amikacin administered via a drug product with a long, fibrous structure (i.e., suture), with the drug product being delivered into the patient's urethra via a portable delivery device.

[0282] As shown in Figure 5B, the drug product is a cylinder joined by a fibrous extension. Before administration, the fibrous extension is collapsed around the circumference of the cylindrical drug product, facilitating the loading of a portable delivery device and the administration of the medicine into the bladder through the patient's urethra.

[0283] The physician administers the drug product to the patient via a portable delivery device and follows up with the patient one week later. At the follow-up visit, the physician records that the drug product remains in the bladder and is leaching out the medication, and that the patient's UTI symptoms have subsided. At a subsequent visit (three weeks after administration), the physician performs an ultrasound examination of the bladder. The fibrous extensions have dissolved, and more than 90% of the drug product has been excreted in the urine.

[0284] The above non-limiting embodiments are presented solely for illustrative purposes to facilitate a more complete understanding of the disclosed subject matter. These embodiments should not be construed as limiting any of the embodiments described herein, including embodiments relating to pharmaceutical compositions, methods, or uses for treating diseases or infections.

[0285] Specific embodiments of the present invention, including the best mode known to the inventors for carrying out the invention, are described herein. Needless to say, variations relating to these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect that those skilled in the art will appropriately adopt such variations, and they intend that the invention may be practiced in ways other than those specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter described in the claims appended herein, as permitted by applicable law. Furthermore, unless otherwise suggested herein or unless clearly contradicted by the context, any combination of the above embodiments in all possible variations is encompassed by the invention.

[0286] Any grouping of alternative embodiments, elements, or steps of the present invention should not be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. For convenience and / or patentable reasons, it is anticipated that one or more members of a group may be included in or removed from a group. Where such inclusion or removal occurs, this specification shall be deemed to include the group as modified and thus satisfy the description of all Markush groups used in the appended claims.

[0287] Unless otherwise indicated, all numerical terms used herein and in the claims to represent features, items, quantities, parameters, characteristics, terms, etc., should be understood in all cases to be modified by the term “approximately.” Where used herein, “approximately” means that the feature, item, quantity, parameter, characteristic, or term thus modified encompasses a range of ±10 percent above and below the value of the described feature, item, quantity, parameter, characteristic, or term. Therefore, unless otherwise indicated, the numerical parameters described in the specification and the appended claims are variable approximations. At the very least, but not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical expression should be interpreted in light of the reported number of significant figures and by applying common rounding techniques. Although the numerical ranges and figures defining the broad scope of the invention are approximations, the numerical ranges and figures described in specific embodiments are reported as accurately as possible. However, both numerical ranges and figures inherently contain certain errors, which inevitably result from the standard deviation found in each of their test measurements. The enumeration of numerical ranges in this specification is intended solely as a simplified method for individually referring to each distinct numerical value that falls within that range. Unless otherwise indicated herein, each individual numerical value within a numerical range is incorporated herein as if it were individually enumerated.

[0288] In the context describing this invention (particularly in the context of the following claims), the terms “a,” “an,” “the,” and similar demonstrative pronouns shall be interpreted as encompassing both singular and plural unless otherwise suggested herein or unless clearly contradicted by the context. All methods described herein may be performed in any preferred order unless otherwise suggested herein or unless clearly contradicted by the context. Any and all examples or exemplary language presented herein (e.g., “such as”) are intended merely to better illustrate the invention and, unless otherwise claimed, do not limit the scope of the invention. No language in this specification should be interpreted as suggesting that any element not described in the claims is essential to the practice of the invention.

[0289] All patents, patent publications, and other public materials referenced and identified herein are incorporated herein individually and expressly by reference in their entirety, for the purpose of describing and disclosing, for example, compositions and methodologies described in such public materials that may be used in connection with the present invention. These public materials are presented solely for the purpose of disclosing them prior to the filing date of this application. In this regard, nothing should be construed as an acknowledgment that the inventors have no prior rights to such disclosures, either by prior invention or for any other reason. All statements regarding the dates of such documents or representations regarding their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of such documents.

[0290] In conclusion, while aspects of this specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily grasp that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is not in any way limited to the specific methodologies, protocols, and / or reagents described herein. Accordingly, various modifications or alterations to the disclosed subject matter, or alternative configurations thereof, may be made in accordance with the teachings herein without departing from the spirit of this specification. Finally, the terms used herein are used solely for the purpose of describing specific embodiments and are not intended to limit the scope of the invention as defined solely by the claims. Therefore, the invention is not precisely limited to what is shown and described.

Claims

1. A method for treating and / or preventing a disease in a subject, a) A step of providing a plurality of linked particles, wherein each linked particle consists of a first particle bonded to a second particle. b) The step of delivering the plurality of linked particles into the target bladder, c) A step of enabling the decomposition of at least a portion of the linked particles over the retention stage to form individual particles, d) A step that allows the excretion of the individual particles during urination. A method comprising, wherein each of the plurality of linked particles comprises an excipient portion and an active agent, and the active agent is released into the bladder during at least a portion of the retention stage.

2. The method according to claim 1, wherein the disease is a urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, or cystitis.

3. The method according to claim 1, further comprising the step of diagnostic imaging.

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

5. The method according to claim 1, wherein each of the plurality of connected particles has a substantially cylindrical shape.

6. The method according to claim 1, wherein each of the plurality of linked particles is buoyant in urine.

7. The method according to claim 1, wherein each of the plurality of linked particles has a hollow core.

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

9. The method according to claim 1, wherein the excipient portion is made of a biodegradable material.

10. The method according to claim 1, wherein the active agent is a drug for treating disorders of the urinary tract.

11. The method according to claim 1, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

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

13. The method according to claim 11, wherein the anti-infective agent is an antifungal agent.

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

15. The method according to claim 11, wherein the anti-infective agent comprises a silver element, a silver ion, a silver salt, or a silver coordination compound.

16. The method according to claim 11, 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 produced in situ.

17. The method according to claim 1, wherein the step of delivering the plurality of linked particles into the target bladder includes urethral delivery.

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

19. The method according to claim 1, wherein the retention period is more than one month.

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

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

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

23. The method according to claim 1, wherein the plurality of linked particles are dispersed in a liquid medium for delivery into the bladder of the target.

24. The method according to claim 22, wherein the liquid medium comprises at least one of a viscosity modifier, an isotonic agent, a buffer, and a dispersant.

25. The method according to claim 1, wherein the active agent is released into the bladder in a substantially steady state.

26. The method according to claim 1, wherein the step of delivering the plurality of linked particles into the target bladder further comprises disrupting a biofilm in the urethra or bladder.

27. The method according to claim 1, wherein the plurality of linked particles are administered to the patient's bladder in an stacked arrangement.

28. A method for treating and / or preventing a disease in a subject, a) A step of providing a plurality of particles arranged in a first three-dimensional structure, wherein each particle consists of an excipient portion and an active agent, b) The step of delivering the plurality of particles into the bladder of the target, c) A step that allows the plurality of particles to transition to a second three-dimensional structure within the bladder, d) The step of releasing an active drug into the target bladder from the plurality of particles, e) A step of enabling the plurality of particles to separate from each other so that they are excreted during urination. A method that includes this.

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

30. The method according to claim 28, wherein the disease is a urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disease, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, chronic inflammatory disease, or cystitis.

31. The method according to claim 28, further comprising the step of diagnostic imaging.

32. The method according to claim 28, further comprising the step of observing a change in the color of the urine when the plurality of particles are excreted.

33. The method according to claim 28, wherein each of the plurality of particles has a substantially cylindrical shape.

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

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

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

37. The method according to claim 28, wherein the excipient portion is made of a biodegradable material.

38. The method according to claim 28, wherein the active agent is a pharmaceutical product for treating disorders of the urinary tract.

39. The method according to claim 28, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

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

41. The method according to claim 39, wherein the anti-infective agent is an antifungal agent.

42. The method according to claim 39, wherein the anti-infective agent is an antiviral agent.

43. The method according to claim 39, wherein the anti-infective agent comprises a silver element, a silver ion, a silver salt, or a silver coordination compound.

44. The method according to 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 produced in situ.

45. The method according to claim 28, wherein the step of delivering a plurality of linked particles into the bladder of the target includes urethral delivery.

46. The method according to claim 28, wherein a syringe is used in the step of delivering a plurality of linked particles to the bladder of the target.

47. The method according to claim 28, wherein the plurality of particles remain in the second three-dimensional structure for one week or more.

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

49. The method according to claim 28, wherein each of the plurality of particles consists of a matrix and a pharmacologically active agent dispersed therein.

50. The method according to claim 28, wherein each of the plurality of particles comprises a coating on a core containing a pharmacologically active agent dispersed therein.

51. The method according to claim 28, wherein the plurality of particles are dispersed in a liquid medium for delivery into the bladder of the target.

52. The method according to claim 51, wherein the liquid medium comprises at least one of a viscosity modifier, an isotonic agent, a buffer, and a dispersant.

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

54. The method according to claim 28, wherein the active agent is released into the bladder in a substantially steady state.

55. The method according to claim 28, wherein the step of delivering the plurality of particles into the bladder of the target further comprises disrupting a biofilm in the urethra or bladder.

56. The method according to claim 28, wherein the first three-dimensional structure of the plurality of particles is a stacked arrangement.

57. The method according to claim 28, wherein the first three-dimensional structure of the plurality of particles is a stacked arrangement having a diameter of about 4 mm or less.

58. The method according to claim 28, wherein the second three-dimensional structure of the plurality of particles is arranged in a zigzag or circular pattern.

59. The method according to claim 28, wherein the second three-dimensional structure of the plurality of particles is a zigzag or circular arrangement having a diameter of about 10 mm or more.

60. An intravesical drug delivery system comprising multiple particles, wherein each particle has an excipient portion and an active drug, and the particles are buoyant in urine.

61. The intravesical drug delivery system according to claim 60, wherein the particles have a substantially cylindrical shape.

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

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

64. The intravesical drug delivery system according to claim 60, wherein the particles have a solid core.

65. The intravesical drug delivery system according to claim 60, wherein the excipient portion is made of a biodegradable material.

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

67. The intravesical drug delivery system according to claim 60, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

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

69. The intravesical drug delivery system according to claim 67, wherein the anti-infective agent is an antifungal agent.

70. The intravesical drug delivery system according to claim 67, wherein the anti-infective agent is an antiviral agent.

71. The intravesical drug delivery system according to claim 67, wherein the anti-infective agent comprises a silver element, a silver ion, a silver salt, or a silver coordination compound.

72. The intravesical drug delivery system according to 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 produced in situ.

73. a) Insertion tip, b) Main body, c) Pressure source, and d) Loading funnel A bladder delivery system comprising: An intravesical delivery system in which an intravesical preparation passes from the loading funnel through the main body and into the target bladder from outside the insertion tip.

74. The intravesical delivery system according to claim 73, wherein the intravesical preparation comprises particles.

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

76. The intravesical delivery system according to claim 74, wherein the particles are housed in a structure having the shape of two cylinders connected by a tether.

77. The intravesical delivery system according to claim 74, wherein the particles are housed within a structure having the shape of two rods connected by a tether.

78. The intravesical delivery system according to claim 74, wherein each particle of the formulation comprises an excipient portion and an active drug.

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

80. The intravesical delivery system according to claim 78, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

81. The intrabladder delivery system according to claim 73, wherein the insertion tip is an inflatable balloon.

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

83. The intravesical delivery system according to claim 73, wherein the insertion tip consists of a screw-type lock ring set.

84. The intravesical delivery system according to claim 83, wherein the screw-type lock ring set is adjusted to the size of the target urethra.

85. The intravesical delivery system according to claim 73, wherein the insertion tip portion consists of an internal sheath.

86. The intrabladder delivery system according to claim 73, wherein the insertion tip portion consists of a plurality of soft grapple members.

87. The intravesical delivery system according to claim 83, wherein the screw-type lock ring set is adjusted to the size of the target urethra.

88. A method for delivering a substance or preparation into a target bladder using the intravesical delivery system described in claim 73.

89. A method for delivering a substance or preparation into the target bladder, a) The step of inserting the tip region of the catheter into the bladder through the urethra, b) The step of fixing the tip region, c) A step of using a pressure source to push the substance or preparation from a loading funnel into the bladder. A method consisting of the following.

88. The method according to claim 89, wherein the substance or formulation consists of particles.

89. The method according to claim 88, wherein the particles are housed within two structures connected by a tether.

90. The intravesical delivery system according to claim 88, wherein the particles are housed in a structure having the shape of two cylinders connected by a tether.

91. The intravesical delivery system according to claim 88, wherein the particles are housed within a structure having the shape of two rods connected by a tether.

92. The method according to claim 88, wherein each particle of the formulation has an excipient portion and an active agent.

93. The method according to claim 92, wherein the active agent is a drug for treating disorders of the urinary tract.

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

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

96. The method according to claim 89, further comprising the step of adjusting the length of the tip region of the catheter using a screw-type locking ring set.

97. The method according to claim 89, wherein the internal sheath is used in the step of fixing the tip region.

98. The method according to claim 89, wherein a plurality of soft grapple members are used in the step of fixing the tip region.

99. A method for delivering an active drug into the target bladder, (a) The step of inserting the distal end of the lumen device into the patient's bladder through the patient's urethra, wherein the opposing proximal end of the lumen device remains outside the patient; (b) The step of fixing the distal end of the lumen device, (b) The steps of driving a plurality of particles to the outside of the lumen at the distal end of the lumen device, and to the inside of the bladder and to the outside of the lumen, (c) The step of removing the lumen device from the patient's urethra, (d) The step of enabling the plurality of particles to decompose or dissolve, thereby releasing the active drug into the patient's bladder. A method that includes this.

100. The method according to claim 99, wherein the particles are housed within two structures connected by a tether.

101. The method according to claim 99, wherein the particles are housed in a structure having the shape of two cylinders connected by a tether.

102. The method according to claim 99, wherein the particles are housed within a structure having the shape of two rods connected by a tether.

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

104. The method according to claim 103, wherein the active agent is a drug for treating disorders of the urinary tract.

105. The method according to claim 103, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

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

107. The method according to claim 99, further comprising the step of adjusting the length of the tip region of the catheter using a screw-type locking ring set.

108. The method according to claim 99, wherein the internal sheath is used in the step of fixing the tip region.

109. The method according to claim 99, wherein multiple soft grapple members are used in the step of fixing the tip region.

110. The method according to claim 99, wherein the subject is suffering from a urinary tract disorder.

111. The method according to claim 99, wherein the urinary tract disorder is one or more of the following: urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, or cystitis.

112. The method according to claim 99, further comprising the step of treating the subject with respect to a disorder of the urinary tract.

113. The method according to claim 103, wherein the active agent is one or more of urease inhibitors, chelating agents, antibacterial agents, and enzymes.

114. The method according to claim 99, wherein the particles have a substantially cylindrical shape.

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

116. The method according to claim 99, wherein the particles consist of an excipient portion that decomposes in the bladder.

117. The method according to claim 116, wherein the excipient portion decomposes over a period of more than one month.

118. The method according to claim 103, wherein the active agent is a drug for treating disorders of the urinary tract.

119. The method according to claim 103, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

120. The method according to claim 103, wherein the active agent is an antibacterial agent, an antifungal agent, or an antiviral agent.

121. The method according to claim 103, wherein the active agent comprises a silver element, a silver ion, a silver salt, or a silver coordination compound.

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

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

124. The method according to claim 103, wherein the particles consist of a coating on a core containing an active agent dispersed therein.

125. The method according to claim 99, wherein the particles are dispersed in a liquid medium for delivery into the bladder of the target.

126. The method according to claim 125, wherein the liquid medium comprises at least one of a viscosity modifier, an isotonic agent, a buffer, and a dispersant.

127. The method according to claim 99, further comprising the step of determining the specific volume or number of particles to be administered based on a desired dose of the active agent.

128. A system for intravesical administration of active drugs, a) Multiple particles are arranged in a first three-dimensional structure, and each particle consists of an excipient portion and the active agent. b) The plurality of particles are configured to expand into a second three-dimensional structure when exposed to a fluid. c) The plurality of particles are configured to release an active agent when exposed to a fluid, and d) The plurality of particles are configured to separate into individual particles in the fluid after a residence period. A system consisting of these elements.

129. The system according to claim 128, wherein each of the plurality of particles has a substantially cylindrical shape.

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

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

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

133. The system according to claim 128, wherein the active agent is a drug for treating disorders of the urinary tract.

134. The system according to claim 128, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

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

136. The system according to claim 134, wherein the anti-infective agent is an antifungal agent.

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

138. The system according to claim 134, wherein the anti-infective agent comprises a silver element, a silver ion, a silver salt, or a silver coordination compound.

139. The system according to 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 produced in situ.

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

141. A method for treating a disease, comprising intravesical administration of the system according to claim 128.

142. The method according to claim 141, wherein the disease is a urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disease, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, or cystitis.

143. A method for treating and / or preventing a disease in a subject, a) A step of providing a plurality of particles, wherein each particle consists of a first particle joined to a second particle by a connecting portion, b) The step of delivering the plurality of particles into the bladder of the target, c) A step that enables the decomposition of the connecting portion and / or particles over the retention stage, d) A step that allows the excretion of the connecting part and particles during urination. A method comprising a plurality of particles, each of which consists of an excipient portion and an active agent, wherein the active agent is released into the bladder during at least a portion of the retention stage.

144. The method according to claim 143, wherein the disease is a urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disease, overactive bladder, underactive bladder, urine retention, diabetes mellitus, heart failure, renal failure, or cystitis.

145. The method according to claim 143, further comprising the step of diagnostic imaging.

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

146. The method according to claim 143, wherein each of the plurality of particles has a substantially cylindrical shape.

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

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

149. The method according to claim 143, wherein each of the plurality of particles has a solid core.

150. The method according to claim 143, wherein the excipient portion is made of a biodegradable material.

151. The method according to claim 143, wherein the active agent is a drug for treating disorders of the urinary tract.

152. The method according to claim 143, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic agent, an analgesic agent, a diuretic, an anti-inflammatory agent, a coagulant or anticoagulant, a chemotherapeutic agent, an agent for treating 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 diagnosis and monitoring.

153. The method according to claim 143, wherein the step of delivering the plurality of particles into the bladder of the target includes urethral delivery.

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

155. The method according to claim 143, wherein the retention period is more than one month.

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

157. The method according to claim 143, wherein each of the plurality of particles comprises a coating on a core containing a pharmacologically active agent dispersed therein.

158. The method according to claim 143, wherein the plurality of particles are dispersed in a liquid medium for delivery into the bladder of the target.

159. The method according to claim 158, wherein the liquid medium comprises at least one of a viscosity modifier, an isotonic agent, a buffer, and a dispersant.

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

161. The method according to claim 143, wherein the active agent is released into the bladder in a substantially steady state.

162. The method according to claim 143, wherein the step of delivering the plurality of particles into the target bladder further comprises disrupting a biofilm in the urethra or bladder.

163. The method according to claim 143, wherein the plurality of particles are administered to the patient's bladder in an stacked arrangement.

164. The method according to claim 143, wherein the first plurality of particles provide buoyancy and the second plurality of particles are provided for administering an active agent.

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

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

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