Systems and methods for sustained release of agents in bladder

Abstract

Embodiments include systems and methods for treating diseases of the bladder, kidney, and urinary tract. The pharmaceutical product may be administered through the urethra in compacted form. Within the bladder, the product may expand or conform to a larger size, which prevents access into the urethra within a desired residence period. After the treatment period, at least a portion of the product may be dissolved or degraded such that individual particles excrete with urine. Embodiments also include drug particle delivery devices and methods of intravesical administration. The delivery device may use a drug-loaded cannula cartridge filled with a rod-like product that is administered into the bladder of a patient by actuation of a pressure source or a piston. The distal end of the barrel may be connected to a bladder sheath or a soft tip for direct insertion into the urethra of the patient.

Description

Related applications

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

[0002] The present invention relates generally to medical devices, and more particularly to devices and methods for administering pharmacologically active agents into the bladder to treat or prevent disorders of the urinary system. background

[0003] A urinary tract infection (“UTI”) is an infection that affects part of the urinary tract. When a UTI affects the lower urinary tract, it is called a bladder infection (i.e., cystitis), and when it affects the upper urinary tract, it is called a kidney infection (i.e., pyelonephritis). Symptoms from a lower UTI include painful urination, urinary frequency, and a feeling of needing to urinate despite emptying the bladder. The most common cause of UTI is Escherichia coli, although other bacteria or fungi can also be a cause. Risk factors include female anatomy, sexual intercourse, diabetes, obesity, and family history. In uncomplicated cases, UTI is 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 prevalence of UTI risk increases with age. They are particularly common in older adults using catheters or living in nursing homes or other full-time care facilities. Other conditions common in older adults (such as Alzheimer's disease, Parkinson's disease, and diabetes) can lead to urinary retention or neurogenic bladder, which increases the risk of UTI. More than 10% of women over 65 years of age report having a UTI in the past year. This number increases to nearly 30% in women over 85 years of age. Men also tend to experience more UTIs as they age. According to recent studies, more than one-third of all infections in nursing home residents are UTIs. In many cases, chronic urinary tract infections may require continuous medication, leading to a gradual increase in antibiotic tolerance and eventually kidney problems.

[0005] If left untreated or untreated, infection from a UTI can spread. UTI can eventually lead to bladder infection. There is a risk that the infection can spread through the ureters to the kidneys, which can lead to more serious consequences, including kidney failure and sepsis (i.e., urosepsis). This often occurs in elderly patients. In many cases, elderly patients do not present with typical signs of infection until they become septic, at which point hospitalization is required.

[0006] Treatment of UTIs and their complications is also expensive because they often require hospitalization. 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 medications, which have common side effects associated with long-term use. Furthermore, prolonged use of antibiotics can lead to drug-resistant bacteria. In many cases, UTIs reduce quality of life, especially when kidney damage leads to kidney failure, requiring dialysis or a donor kidney transplant.

[0007] Conventionally, UTIs are treated with oral antibiotics. High doses of antibiotics are required to ensure an effective amount reaches the urinary tract. When treating UTIs with systemic drug delivery, the volume of distribution of the therapy equals the total amount of urine entering the bladder. Therefore, the therapy becomes ineffective with each emptying of the bladder and requires continuous resuscitation. In other cases, the drug target may be limited (i.e., the bladder wall), but it is practically unreachable without raising the drug concentration in the urine to the desired therapeutic concentration.

[0008] Intravesical therapy refers to treatment in which a therapeutic agent is placed directly into the bladder (e.g., via a catheter or similar device) rather than administered orally or injected intravenously. Intravesical therapy is an attractive option for treating UTIs because it allows for local delivery of the medicament while minimizing side effects. Intravesical administration of active pharmaceutical agents can also be beneficial for treating other bladder / urinary tract conditions such as interstitial cystitis, overactive bladder, and cancer.

[0009] Efforts to treat UTIs via intravesical therapy have had limited success. Antibiotics injected into the bladder are typically excreted before they can induce a significant therapeutic effect. Implantable devices require surgical intervention for implantation and removal. Recent improvements include implantable devices that gradually dissolve or degrade as the active agent is released. For example, WO2022216287A1 describes a controlled-release drug formulation administered to a patient's bladder. This formulation comprises particles that float in urine and can remain in the patient's bladder throughout the course of antibiotic treatment. However, this formulation is limited to small particles that can be administered via the urethra. Furthermore, the particles are prone to premature excretion during urination. The use of conventional syringes to administer the particles can also be problematic.

[0010] Conventional syringes are designed for injecting fluids and can easily become clogged or blocked. Furthermore, they can cause and exacerbate patient discomfort. Even relatively large catheters can be ineffective in delivering solid drug products into the bladder. Therefore, there is an unmet need for devices that reliably deliver solid drug products (e.g., balls, 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 within the bladder so that they are not prematurely excreted in the urine.

[0011] The compositions and methods described herein fulfill these objectives and can particularly benefit patients at risk of UTIs, such as elderly patients or patients with limited capacity. The systems and methods described herein can also be used to treat other bladder / urethra / kidney disorders, such as cancer, overactive bladder, and cystitis. Invention Overview

[0012] The inventions described and claimed herein have numerous attributes and embodiments, including, but not limited to, those set forth, described, or mentioned in this brief overview. The inventions described and claimed herein are not limited to, or not restricted by, the features or embodiments identified in this overview, which are included for illustrative purposes only and not for limitation.

[0013] Embodiments of the present invention include means and methods for delivering a therapeutic agent into the bladder. More than one floating (or semi-floating) pharmaceutical product may be temporarily implanted inside the bladder and float within the fluid inside the bladder. The pharmaceutical product may release the therapeutic agent or drug into the bladder through direct absorption, passive or active dissolution, mechanical fracturing, or other means.

[0014] In one aspect, the pharmaceutical product releases multiple active agents (e.g., to treat multiple diseases or target drug-resistant bacteria). In another aspect, the pharmaceutical products are homogeneous to each other. In yet another aspect, the pharmaceutical products are not homogeneous (e.g., they contain different excipients, have different physical properties, different active agents, and / or different sizes / shapes).

[0015] In this case, the drug product is passively released from the bladder after the retention period (i.e., no removal surgery is required).

[0016] In this context, pharmaceutical products include linker materials that dissolve and separate from the rod through (a) chemical adhesion or (b) degradation. Chemical adhesion refers to the weakening of adhesion strength over time to release the rod. For example, 2-octyl cyanoacrylate is a highly adhesive material that loses its strength over time in moisture. Degradation may require the hydrolysis of ester bonds in the PLGA (poly(lactic acid-co-glycolic acid) copolymer family). The hydrolysis rate can vary based on factors such as the molecular weight (MW) of the polymer chain, the ratio of lactic acid to glycolic acid, and whether it is ester-terminated or acid-terminated.

[0017] In this process, the connector material swells and ejects the rod. The connector material can swell (due to heat deformation or water absorption) and force the rod out of the socket. Poly(methyl methacrylate), poly(acrylic acid), carbomer, and hydroxypropyl methylcellulose are types of materials that swell to 10x size and eject the rod. The swelling rate can be controlled by the type of hydrophilic swellable polymer, their molecular weight (MW), salt or acetic acid blends, blends of hydrophilic swellable polymers with non-swellable hydrophobic materials, and enteric coating.

[0018] Therefore, implementation methods include systems and methods for treating diseases such as urinary system disorders. In one aspect, the system and method include a pharmaceutical formulation for intravesical administration of an active agent. The formulation may include particles, each particle having an excipient portion and an active agent. The formulation may be administered via transurethral delivery using a drug delivery device as described herein.

[0019] In this embodiment, the particles can attach to each other (i.e., each package includes a first particle attached to a second particle via a tether). The particles can be administered to the subject's bladder in a stacked arrangement (i.e., having a small diameter). The active agent can be released during the retention phase. Thereafter, the tether can degrade, causing the individual particles to separate from each other. The individual particles can be excreted during urination.

[0020] In this embodiment, two particles can be attached or joined together. The particles can be administered to a subject's bladder in a stacked arrangement. Subsequently, the particles can be converted into a second configuration for retention. The active agent can be released during this retention phase. Thereafter, at least a portion of the particles can degrade (e.g., cylinder, cap, connector, or hinge), causing the individual particles to separate from each other. The individual particles can be excreted during urination.

[0021] In this process, the particles have a cross-sectional diameter of less than or equal to 4 mm for insertion, undergo a conformational change after insertion into the bladder to a cross-sectional diameter of 10 mm or greater for retention, and then decrease to a cross-sectional diameter of less than or equal to 4 mm for elimination.

[0022] In this process, the particles can adhere to each other in a first conformation that facilitates transurethral administration. After the particles enter the subject's bladder, they can swell to a second conformation, which is larger and more resistant to excretion. During the retention phase, the active agent can be released from the particles into the bladder. Thereafter, the particles can gradually separate from each other, allowing them to be excreted during urination.

[0023] This document also discloses insertable drug delivery devices (including catheter assemblies) and methods for allowing intravesical administration of medications, pharmaceutical products, gels, devices, etc. Therefore, embodiments include a drug delivery device for administering a pharmaceutical product through the urethra into the bladder. The device may include (a) an insertion tip, (b) a body, (c) a pressure source, and (d) a loading funnel. In one aspect, the intravesical preparation passes from the loading funnel through the body and exits the insertion tip into the bladder.

[0024] The implementation also includes a method for delivering a substance or formulation to a patient's bladder. The method may include the steps of: (a) inserting a distal end of a lumen device through the patient's urethra into the patient's bladder, wherein a relative proximal end of the lumen device remains outside the patient; (b) securing the distal end of the lumen device; (c) driving more than one particle out of the lumen in the distal end of the lumen device and into the bladder and out of the lumen; (d) removing the lumen device from the patient's urethra; and (e) allowing the particles to release the drug from the drug delivery device into the patient's bladder. In this aspect, the patient suffers from a disease of the bladder, urinary tract, and / or kidney. The method may also include treating the patient's disease. In this aspect, the disease is a urinary tract infection (UTI), bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, underactive bladder, urinary retention, diabetes, heart failure, kidney failure, or cystitis. The method may also include the step of adjusting the number of particles administered based on a desired dose of the active agent.

[0025] Other implementation methods include methods for treating or preventing urinary tract infections (UTIs) by administering the formulations and pharmaceutical products described herein. In this aspect, the methods are used for patients at risk of UTIs and / or with a history of UTIs.

[0026] In one aspect, the method includes a diagnostic imaging step. In another aspect, the method includes a step of observing color changes in excreted urine (i.e., via adding a color indicator to a pharmaceutical product) during at least a portion of a retention phase. Brief description of the attached diagram

[0027] Figure 1 It is a graph showing the percentage of three types (beta, beta prime, and alpha) of floating particles over a five-day process.

[0028] Figure 2A Cylindrical particles according to the implementation scheme are depicted.

[0029] Figure 2B Horseshoe-shaped particles according to the implementation scheme are depicted.

[0030] Figure 2C It is an image of horseshoe-shaped particles.

[0031] Figure 2D The bowstring-shaped particles according to the implementation scheme are depicted.

[0032] Figure 2E It is an image of bowstring-shaped particles.

[0033] Figure 2F Elbow-shaped particles according to the implementation scheme are depicted.

[0034] Figure 2G It is an image of elbow-shaped particles.

[0035] Figure 3A The geometry of particles in three configurations (i.e., small particles for insertion, large particles for retention, and small particles for elimination) is depicted.

[0036] Figure 3B The composition of the particles and their geometry, including the angles between individual drug products, are described.

[0037] Figure 3C Depicting the configurations of retention and elimination Figure 3B granules.

[0038] Figure 3D The particles in their preserved configuration and three components (i.e., the joint, the hinge, and the API-embedded cylindrical rod) are depicted.

[0039] Figure 3E It is a flowchart depicting particles in three stages (i.e., implantation, drug delivery, and disassembly forelimination).

[0040] Figure 3F Different mechanisms of particle separation according to the implementation scheme are described.

[0041] Figure 3G An embodiment in which a cylinder (or a portion thereof) swells upon exposure to a liquid to release a rod is described.

[0042] Figure 3H An embodiment in which the outer layer of the rod includes a layer that reduces water movement / water absorption is described.

[0043] Figure 3IThe results of different coatings are shown (i.e., the percentage of bars retained over time).

[0044] Figure 3J Methods for adjusting the retention time of hinged rods are described, including using dissolving the hinge, pushing out the rod, weakening the hinge, releasing the rod, and disassembling the hinge.

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

[0046] Figure 4B It depicts a pair of particles joined by a linkage and three configurations: (a) stacked for application, (b) joined for retention in the bladder, and (c) separated for excretion with urine.

[0047] Figure 4C A pair of particles joined by a connector is described, along with three configurations: (a) stacked for application, (b) joined for retention in the bladder, and (c) degraded for excretion with urine.

[0048] Figure 5A It is an image of particles (e.g., two cylinders) joined together by a tether.

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

[0050] Figure 5C An embodiment in which the pharmaceutical product includes a filamentous extension (e.g., a suture) that promotes the retention of the pharmaceutical product in the bladder is described.

[0051] Figure 6 Three conformational arrangements of more than one particle are described: (a) stacking for application, (b) joining for retention in the bladder, and (c) separating for excretion with urine.

[0052] Figure 7A An implementation scheme is described in which multiple pharmaceutical products (i.e., cylinders) are joined to form a circular configuration with a large size for retention in the bladder.

[0053] Figure 7B An implementation scheme is described in which multiple pharmaceutical products (i.e., spheres) are joined to form a circular configuration with a large size for retention in the bladder.

[0054] Figure 7C The heterogeneous grouping of pharmaceutical products was described.

[0055] Figure 8 A side view of a handheld delivery device according to an embodiment of the present invention is depicted.

[0056] Figure 9 An overhead view of the deep-locking flexible catheter is depicted.

[0057] Figure 10 A side view of a static sheath according to an embodiment of the present invention is depicted.

[0058] Figure 11A A static sheath with an internal flexible sheath and a locking ring is depicted.

[0059] Figure 11B An alternative design (i.e., "tampon-like") for a delivery device for cotton or similar material inserted into the urethra is described.

[0060] Figure 12 A conduit with a grapple member extending from the distal end is depicted.

[0061] Figure 13A A first-person view of the chamber of a handheld delivery device according to an embodiment of the present invention is depicted.

[0062] Figure 13B A top-down view of the chamber of a handheld delivery device is depicted.

[0063] Figure 13C A side view of the chamber of a handheld delivery device is depicted.

[0064] Figure 14 The intravesical delivery of particles through the lumen of the device of the present invention is described.

[0065] Figure 15 The cannula inserted into the patient's bladder is depicted.

[0066] Figure 16A The text describes a magazine pre-loaded with granules.

[0067] Figure 16B An obturator is described for use with a pre-loaded granule hopper.

[0068] Figure 17 A sluice gate preloaded with particles is depicted. List of reference numerals in the attached figures

[0069] 5. Delivery device 10. Main body of the delivery device 15. Barrel 20 Insert tip 25 Funnel Region 27. Pharmaceutical products (e.g., capsules or cylinders) 30 Pressure Sources 40 triggers 50 Depth Locking Flexible Catheter 55 (Distal end of the depth-locking flexible catheter) 60 (proximal end of deep-locking soft catheter) 65 Mudguard Washer (Rotable) 70 Convex Locking Nut 75 Concave Locking Nut 80 Multi-lumen static sheath 85 Internal tubular components 90. External tubular components 95 (distal of multi-lumen static sheath) 100 outer locking ring 105 Soft hook component 110 Drug Product Delivery Chamber 112 cannula 115 Threaded pistons and plungers 120 Loading pin 125 Unloading pin 130 Loaded Straw Bay 135 Empty Explosive Tube Compartment 140 screw piston 145 Material Box Spring 155 Check Valve 160 Container Fairing 165 Blocker Fairing 170 Thumb Catches 175 tethering device 180 filamentous extensions 185 cap 190 Connector 195 Bridge definition In this specification, references to "an embodiment / aspect" or "an embodiment / aspect" mean that a particular feature, structure, or characteristic described in connection with that embodiment / aspect is included in at least one embodiment / aspect of this disclosure. The use of the phrase "in one embodiment / in one aspect" or "in another embodiment / in another aspect" throughout this specification does not necessarily refer to the same embodiment / aspect, nor to a separate or alternative embodiment / aspect that is mutually exclusive with other embodiments / aspects. Furthermore, various features that can be exhibited by some embodiments / aspects but not by others are described. Similarly, various requirements are described, which may be requirements of some embodiments / aspects but not of others. Embodiments and aspects may be used interchangeably in certain circumstances.

[0070] The terms used in this specification generally have their ordinary meanings in the art, in the context of this disclosure, and in the specific context in which each term is used. Certain terms used to describe this disclosure are discussed below or elsewhere in this specification to provide practitioners with additional guidance regarding the description of this disclosure. It should be understood that the same thing can be stated in more than one way.

[0071] Therefore, alternative languages ​​and synonyms may be used for any one or more terms discussed herein. There is no particular significance in whether a term is set forth or discussed herein. Synonyms for certain terms are provided. The description 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 illustrative only and is not intended to further limit the scope and meaning of this disclosure or any exemplary terms. Similarly, this disclosure is not limited to the various embodiments given in this specification.

[0072] This disclosure is not intended to further limit its scope. Examples of instruments, apparatus, methods, and related results according to embodiments of this disclosure are given below. It should be noted that headings or subheadings may be used in the embodiments for the convenience of the reader, but this should in no way limit the scope of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the definition herein shall prevail.

[0073] The term "overactive bladder" or "OAB" refers to a group of urinary symptoms (not a disease). The most common symptom is a sudden, uncontrollable urge or need to urinate. Some people will leak urine when they feel this urge. Another symptom is the need to urinate frequently during the day and night. OAB can be described as a persistent urge to urinate. Leakage is called "incontinence."

[0074] The term "stress urinary incontinence" or "SUI" refers to another common bladder problem. Subjects with SUI leak urine when sneezing, laughing, or engaging in other physical activities.

[0075] The terms "interstitial cystitis," "IC," or "bladder pain syndrome" refer to a chronic or long-term 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 experience severe bladder pain or struggle with urinary urgency, a sudden need to urinate, or urinary frequency, a need to urinate more frequently. Healthcare professionals diagnose IC by ruling out other conditions with similar symptoms.

[0076] The term "immunomodulator" or "immunomodulating agent" refers to a drug that can support immune function by beneficially altering the immune system's response to threats. Immunotherapy designed to elicit or enhance an immune response is classified as activating immunotherapy, while immunotherapy that reduces or suppresses it is classified as suppressive immunotherapy.

[0077] The term "chronic inflammatory disease" refers to a condition that causes the body to overreact and, in some cases, attack itself. For example, in multiple sclerosis, the body's immune system attacks the nerve lining. Chronic inflammation is not a specific disease, but rather a mechanistic process. Diseases associated with chronic inflammation are numerous and include CVD, diabetes, malignancies, autoimmune diseases, chronic liver and kidney diseases, among others.

[0078] The term "catheter" refers to a flexible tube that can be inserted into a patient's or subject's body cavity, duct, blood vessel, brain, skin, or adipose tissue through several points of entry. Catheters perform several functions, including allowing the drainage of bodily fluids, administering substances and materials to the patient or subject, and enabling surgical instruments to access the patient or subject.

[0079] The term "Foley catheter" refers to a flexible tube that a clinician inserts through the urethra and into the bladder to drain urine.

[0080] An "indwelling catheter" is a catheter that is typically kept in a fixed position by means of an inflatable balloon attached to the external body of the catheter.

[0081] A “vesical sheath” is a hollow tube used as a conduit to introduce surgical instruments, substances, and other media into the urinary system of a subject or patient. As used herein, the sheath refers to the middle section of the device between the distal balloon tip and the proximal locking ring assembly. The main length of the main lumen lies within the middle sheath section, but this lumen is open from one end to the other for delivery of products through the entire device. The sheath should have low friction externally and within the main lumen, allowing for insertion with minimal patient discomfort and enabling the product to glide easily through the sheath. Materials may be, for example, silicone-coated fibers, springs, or struts (for a combination of strength and flexibility in thin materials), PTFE-coated for low friction, or metal-coated for strength in thin materials.

[0082] The terms “active agent,” “active ingredient,” “active pharmaceutical ingredient,” or “API” refer to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect when administered to a subject. In other words, an “active agent” or “active ingredient” refers to one or more components of a composition attributable to all or part of the effects of that composition. An active agent may be a primary active agent, or in other words, a component of the composition attributable to all or part of the effects of that composition. An active agent may be a secondary agent, or in other words, a component of the composition attributable to an additional portion of the composition and / or attributable to other effects of the composition.

[0083] The term "pharmaceutical product" means any substance, device, particle, or product suitable for delivery to a subject or patient for the treatment of a disease, condition, malady, or disorder, and may also include excipients, excipients, carriers, placebos, powders, foams, gels, liquids, capsules, coatings, timed release mechanisms, delayed release mechanisms, robotic pharmaceuticals, computer-programmed pharmaceutical products, products driven or guided by artificial intelligence or machine learning, launchers, or any substance, device, or product known in the art suitable for delivery to a patient or subject.

[0084] The term "pharmaceuticalally acceptable" means a material that is not biologically or otherwise undesirable, meaning that the material can be incorporated into a pharmaceutical composition as provided herein and will not cause any materially undesirable biological effects or interact with any other component of the composition in a harmful manner. When the term "pharmaceuticalally acceptable" is used to refer to a solid or semi-solid carrier, liquid medium, or other excipient, i.e., any inactive ingredient herein, it means that the carrier or excipient meets the requirements of toxicological and manufacturing testing, and / or is included in the inactive ingredient guidance established by the U.S. Food and Drug Administration and is designated as "Generally Regarded as Safe" ("GRAS").

[0085] The term “controlled release” or “CR” refers to a drug, carrier, or other platform that releases the active ingredient at a specific rate to maintain a constant drug level in a patient’s body over a specific period of time. This allows the drug level to remain at an effective level for a period of time. Unlike sustained-release (SR) forms, CR drugs precisely control the amount of drug in your body at a given time, not just its release. Administration of a formulation containing a controlled-release active agent or a fraction thereof does not result in the immediate release of 100% of the active agent. This 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). In general, the term “controlled release,” as used herein, includes sustained-release, modified-release, pulsatile-release, and delayed-release formulations, as well as formulations combining two or more types of release profiles, such as an immediate release of a bolus dose followed by pulsatile or sustained release. "Sustained release" (synonymous with "extended release") refers to a formulation that provides a gradual release of the active agent over an extended period of time, and preferably, though not necessarily, produces a substantially constant dose level in a volume of distribution (e.g., urine, bladder, total body water, etc.), often referred to as "zero-order" release. "Controlled release" also includes "delayed release," indicating a formulation that, upon administration to a patient, provides a measurable time delay before the active agent is released from the formulation into the patient's body. However, the controlled-release dosage forms discussed herein are typically sustained-release dosage types.

[0086] The terms “particle” or “microparticle” refer to the carrier or controlled-release carrier described herein, which is formulated to contain a pharmacologically active agent. Particles may be substantially spherical, cylindrical, or rod-shaped, or have some other shape. Particle size is given as the average particle size within a group of particles. The particle size distribution within the group of particles is relatively narrow (i.e., the specified average particle size is associated with a fairly low standard of deviation, typically less than 30%, for example less than 20% or less than 15%). Particles within a formulation may or may not have substantially the same shape and size. The terms “particle” and “microparticle” are used interchangeably with the term “pharmaceutical product” and are also a form of pharmaceutical product in which the term pharmaceutical product is used as a comprehensive term encompassing both particles and microparticles.

[0087] The terms “intravesical delivery particle grouping,” “solid drug product grouping,” “drug product capsule grouping,” “drug product carpule grouping,” “delivery particle grouping,” “connecting drug product grouping,” “linking drug product grouping,” “drug product grouping,” “hinge drug product grouping,” or “particle grouping” are interchangeable and refer to individual drug particles or drug products or structures connected by a tether or other equivalent connecting structure.

[0088] The terms "intravesical administration" or "intravesical therapy" refer to treatment in which the therapeutic agent is placed directly into the bladder (i.e., via a catheter) rather than administered orally or injected intravenously. Similarly, intravesical medications are administered directly into the bladder via a urinary catheter.

[0089] The term "enteric coating" refers to a polymer barrier applied to orally administered drugs that prevents the drugs from dissolving or disintegrating in the gastric environment. As used herein, cylindrical pellets made of a swellable material can be coated with a slowly degrading binder material. This can be placed in a socket that holds the cylinder together. In this design, the binder coating helps hold the cylinders together during drug delivery. Subsequently, as the coating degrades / dissolves over time, water can diffuse through proximity to the swellable material, causing the material to swell (e.g., up to 10x size), which pushes the rod out. In this aspect, the swelling rate is adjusted by altering the rate of water diffusion in the socket via modifications to the silicone hinge. This includes, for example, 1) changing the length and thickness of the hinge, 2) slits on the sides, 3) holes of different diameters on the hinge cap, and / or combinations thereof.

[0090] The term "mucosal adhesion" refers to the adhesion between two materials, one of which is a mucosal surface. Mucosal adhesive drug delivery systems prolong the residence time of dosage forms 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.

[0091] The term “spherical” in this document refers to particles that are precisely spherical, or more generally, to particles or objects with a circular surface that may or may not be substantially spherical.

[0092] The terms “mean diameter,” “mean longest dimension,” and “particle size” are used interchangeably herein. As used herein, particle size is given by the mean diameter of spherical particles and the mean longest dimension of non-spherical particles. It should be noted that the term “mean diameter” technically corresponds to substantially spherical particles; however, other particle shapes may also be incorporated into granular formulations provided that the particles have at least one dimension (i.e., at least one mean dimension throughout the particle group) greater than 2.0 mm, for example, in the range of 2.0 mm to about 12.0 mm, for example, about 2.5 mm to about 6.5 mm, for example, about 2.5 mm to about 6.0 mm, about 2.5 mm to about 5.5 mm, about 2.5 mm to 5.0 mm, etc., as previously stated. Elongated particles, such as cylindrical or rod-shaped particles, may, for example, have a length of about 9.0 mm and are still narrow enough to pass through a catheter and urethral opening.

[0093] The terms "effective amount" and "therapeutic effective amount" for active agents, combinations of active agents, or pharmaceutical preparations refer to a non-toxic amount or concentration sufficient to produce the desired results. The exact amount required will vary from subject to subject, depending on factors such as the subject's age, weight and general condition, the specific condition being treated, the severity of the condition, the specific active agent, and the clinician's judgment.

[0094] The term "urinary system" is used in a conventional sense to refer to both the lower and upper urinary tracts, and therefore includes the bladder, urethra, kidneys, and ureters.

[0095] The term "disorder" refers to a clinically relevant physiological condition, and therefore includes symptomatic or asymptomatic conditions unrelated to any underlying cause. Thus, disorder includes adverse conditions resulting from disease or injury. The disorder involved in this invention is a disorder of the urinary system.

[0096] "Drug delivery time" refers to the time period during which a pharmacologically active agent is released from the formulation or its fraction, and is usually an extended time period.

[0097] The terms "subject" or "patient" refer to any single animal, more preferably a mammal (including non-human animals such as, for example, dogs, cats, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human primates). Most preferably, the patient herein is a human.

[0098] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0099] As used herein, the term "pharmaceuticalally acceptable composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0100] The term “treating” or “treatment” means one or more of the following: (1) suppressing a disease; for example, suppressing a disease, condition or disorder in an individual who is experiencing or exhibiting a pathology or symptom of a disease, condition or disorder (i.e., preventing the further development of said pathology and / or symptom); (2) improving a disease; for example, improving a disease, condition or disorder in an individual who is experiencing or exhibiting a pathology or symptom of a disease, condition or disorder (i.e., reversing the pathology and / or symptom), such as reducing the severity of the disease.

[0101] The term "specific gravity" refers to the ratio of a material's density at 4°C to the density of water. Therefore, it is a unitless relative quantity. In urine, specific gravity refers to electrolyte levels and urine osmolarity. The normal range for urine specific gravity is 1.005 to 1.030. In the context of clinicopathology, specific gravity is a commonly used urinary analysis parameter for assessing kidney function and can aid in the diagnosis of various kidney diseases.

[0102] The term "hygroscopic material" refers to a substance that absorbs water and swells. Many engineered polymers are hygroscopic, including nylon, ABS, polycarbonate, cellulose, carboxymethyl cellulose, and poly(methyl methacrylate) (PMMA, plexiglas, perspex).

[0103] The term "amikacin" refers to an antibiotic used for a variety of 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 typically administered via intravenous injection or intramuscular injection.

[0104] The term "excipient" refers to a pharmacologically inert ingredient that is intentionally added to a pharmaceutical product for a variety of functional purposes, such as enhancing dosage form volume or size, disintegration of solid dosage forms, binding of microparticles, lubrication during processing, masking of taste, or alteration of drug release.

[0105] 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). Drug release kinetics are called zero-order kinetics when a constant amount of drug is eliminated per unit time, but the rate is independent of the drug concentration. Zero-order drug delivery systems (DDS) overcome the problems faced by immediate release and first-order systems by releasing drugs at a constant rate, thereby maintaining drug concentrations within the therapeutic window over extended periods.

[0106] The term "first-order" refers to the drug release rate that is proportional to the concentration gradient and varies with the amount of drug remaining in the dosage form. Similarly, "sustained release" refers to the slow release of the drug over an extended period of time following the administration of a single dose.

[0107] The terms "therapeutic index," "TI," or "therapeutic ratio" refer to a quantitative measure of the relative safety of a drug. It is a comparison of the amount of therapeutic agent that causes a therapeutic effect to the amount that causes toxicity. The therapeutic window, or safety window, refers to the optimized dose range between efficacy and toxicity, achieving maximum therapeutic benefit without causing unacceptable side effects or toxicity. TI is the rate / severity of adverse drug reactions that cause adverse reactions incompatible with the target indication (e.g., the toxic dose in 50% of subjects, TD). 50 ) and the dose that leads to the desired pharmacological effect (e.g., the effective dose for 50% of subjects, ED). 50 The ratio is calculated.

[0108] The terms "proximal," "proximal portion," or "proximal-end portion" for catheters, as disclosed herein, include a portion of the catheter intended to be close to the clinician when used with a patient. Similarly, for example, the term "proximal length" of a catheter includes the length of the catheter intended to be close to the clinician when used with a patient. For example, the term "proximal end" of a catheter includes the tip of the catheter intended to be close to the clinician when used with 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 need not include the proximal end of the catheter. That is, unless the context otherwise requires, the proximal portion, proximal-end portion, or proximal length of a catheter is not the distal portion or distal length of the catheter.

[0109] The terms "distal," "distal portion," or "distal-end portion" for catheters, as disclosed herein, include a portion of the catheter intended to be close to or within the patient when used in a patient. Similarly, for example, the term "distal length" of a catheter includes the length of the catheter intended to be close to or within the patient when used in a patient. For example, the term "distal end" of a catheter includes the tip of the catheter intended to be close to or within the patient when used in a patient. A distal portion, distal portion, or distal length of a catheter may include the distal end of the catheter; however, a distal portion, distal portion, or distal length of a catheter does not necessarily include the distal end of the catheter. That is, unless the context otherwise requires, a distal portion, distal portion, or distal length of a catheter is not the distal portion or distal length of the catheter.

[0110] The term "pain" refers to a distressing sensation typically caused by strong or destructive stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with or similar to actual or potential tissue damage." The terms "pain" and "discomfort" are used interchangeably. The Visual Analogue Scale (VAS) and the Numerical Rating Scale (NRS) are most commonly used to assess the current intensity of acute pain.

[0111] The term "cannula" refers to a medical or veterinary device used in minimally invasive surgery. It typically consists of an awl (which can be metal or plastic with a sharp or tapered tip), a cannula (essentially a rigid, hollow tube), and usually a seal. Some cannulas also include a valve mechanism that allows for blow-in. Cannulas are designed to be placed through the chest and abdominal walls during thoracoscopic and laparoscopic surgery, and each cannula serves as an entry point for subsequent insertion of other endoscopic instruments such as graspers, scissors, staplers, electrocautery devices, aspiration tips, etc., hence the more common colloquial term "port." Cannulas also allow for the passive drainage of excess gas or fluid from organs within the body.

[0112] The term “occluder” or “occluder rod” refers to a thin, rigid (and sometimes curved) rod that passes through a hollow channel or lumen to help insert a medical device or other medical instrument into a patient or subject.

[0113] The term "substantially" indicates the possibility of a slight deviation from the stated chemical or physical properties, and allows for a difference of up to about 20%, or up to about 10%, or up to about 5% between the actual and stated chemical or physical properties. For example, the term "substantially homogeneous" refers to a material in the form of a mixture of two or more components, wherein the material is substantially homogeneous overall, and any two discrete regions within the material differ by up to about 20%, or up to about 10%, or up to about 5% in terms of the chemical or physical properties of the material, such as the presence or absence of the components, the concentration of the components, the degree of hydrophilicity or lipophilicity, density, crystallinity, or other properties. Similarly, the terms "approximately" or "about" in any context are intended to mean a possible variation of up to about 20%. Typically, the term means a possible variation of up to about 10% or up to about 5%.

[0114] Other technical terms used herein have their general meanings in the technologies in which they are used, as illustrated in various technical dictionaries. Specific values ​​and configurations discussed in these non-limiting examples may vary and are cited merely to illustrate at least one implementation, not to limit its scope. Detailed Explanation

[0115] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory, and are intended to provide further explanation of the subject matter as claimed. Further features and advantages of the subject matter are set forth in the following description and will be apparent in part from the description, or may be learned by practice of the subject matter. The advantages of the subject matter will be realized and obtained through the structures particularly pointed out in its written description and claims.

[0116] The implementation includes a drug delivery device that can be implanted into the bladder for a sustained period while releasing the drug. A successful bladder implant must remain securely within the bladder to effectively deliver its active pharmaceutical ingredient (API) throughout the intended duration. To prevent accidental removal during normal urination, the implant may be designed with an excessively large cross-sectional area or a shape that does not allow it to pass through the urethra.

[0117] Importantly, the drug delivery device is left in the bladder only if it is therapeutically beneficial. Conventional methods involve physically removing the device after the retention period. Active removal may require responsive disassembly. The implant can be designed to disassemble into smaller parts upon specific triggering, in response to specific stimuli such as temperature, pH, salinity, and enzymes. Alternatively, surgical-based removal can be performed by a medical professional. For example, the device can be physically retrieved or disassembled via cystoscopy. The applicant describes a third method requiring passive removal. The implant and / or portions thereof are designed to gradually degrade or dissolve, eventually passing naturally with the urine flow after its therapeutic window has closed.

[0118] Embodiments of the present invention include devices, systems, and methods for administering solid pharmaceutical products for the treatment of urinary tract-related diseases. When administered to the bladder, “intravesical particles” or “pharmaceutical products” can deliver the drug locally to the bladder / urethra. This avoids the need for oral medication and systemic administration. Low doses of antibiotics are effective and therefore have fewer side effects. Improved therapeutic windows are also possible with controlled drug release. Formulations comprising particles containing an active agent, as described below, can be administered to a subject via the intravesical route (i.e., through the urethra or via bladder injection) using the devices described herein.

[0119] The implementation scheme also includes a treatment method that involves administering a pharmaceutical product into the bladder of a subject. The method may include intravesical administration of granules using a drug delivery device described herein. Thereafter, the granules may release a therapeutic agent (or multiple agents) into the bladder for a desired therapeutic process. The method may be used to treat diseases such as infections (e.g., UTIs), interstitial cystitis, overactive bladder syndrome, bladder cancer, kidney cancer, ureteral cancer, anticoagulant disorders, overactive bladder, underactive bladder, urinary retention, diabetes, heart failure, kidney failure, or cystitis.

[0120] The pharmaceutical products of the present invention may include solid pharmaceutical products (e.g., granules, spheres, rods, cartridges, cylinders, cotton plugs, drug-loaded tubular pharmaceutical products, pharmaceutical products with patterned or irregular cross-sections, etc.), fluid pharmaceutical products (e.g., foams, gels, coatings), or powdered or lyophilized pharmaceutical products contained in capsules, cartridges, granules, tablets, or any suitable encapsulation. The pharmaceutical products used with the apparatus of the present invention may also include connection forms, connection shapes, coupling forms, and coupling shapes.

[0121] Examples of connection and linkage forms, as well as connection and linkage shapes, are shown in the accompanying drawings and may include multiple pharmaceutical products or structures connected (e.g., by tethers, sutures, or other connectors). A pharmaceutical product may include one or more active agents (i.e., active pharmaceutical portions) applied as a coating onto or along the particles and / or within the particles. In this aspect, the pharmaceutical product (or a portion thereof) degrades or dissolves in the patient's bladder.

[0122] The pharmaceutical product described herein can be administered directly into the bladder via the urethra (i.e., transurethral administration). In this aspect, the pharmaceutical product remains in the bladder for the intended duration (i.e., the retention period). During the retention period, one or more active agents can be released into the bladder and urinary system. After the retention period, the product can be expelled from the bladder by urination (i.e., the elimination phase). As will be understood, particle size and urethral diameter are related to each of these phases.

[0123] Although there are differences among humans, the urethra has a normal cross-sectional diameter of approximately 6 mm and a maximum diameter of approximately 10 mm. The applicant has demonstrated that an object of 4 mm (in terms of length) can pass through the urethra with minimal irritation. Objects of 5 mm or larger, however, typically cause discomfort and / or complications upon expulsion. Therefore, the applicant proposes that the optimal cross-sectional diameter of an object introduced into the bladder through the urethra is less than or equal to 4 mm. In this aspect, the object is cylindrical with a diameter of approximately 4 mm (e.g., Figure 3A (As depicted in the image). The length of the object may be, for example, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, about 20 mm or longer.

[0124] Figure 2A The structure of individual cylindrical particles is depicted, showing their length (L) and diameter (D). From human trials, the applicant has demonstrated that objects with a 4 mm cross-section (D) do not remain in the bladder. Instead, the object is excreted with urine, with a short (or negligible) retention period. Objects with a 5 mm cross-section can have a longer retention period in the bladder but will also be excreted. The review guidelines for objects that are not easily excreted from the bladder indicate a 10 mm cutoff value for the cross-sectional diameter used for retention. Although pharmaceutical products of this size have a long retention period, they are not easily administered and must be removed surgically or significantly degraded within the bladder.

[0125] It is also worth considering that when a velocity gradient exists toward the bladder outlet (i.e., the urethra), objects in the bladder rotate to their minimum cross-sectional diameter via the excretory mechanism. This means that taking an object with a cross-sectional diameter (D) of 4 mm and increasing its length (L) (e.g., to 10 mm, 20 mm, or 30 mm) has minimal impact on its retention rate. Due to hydrodynamics, the urethra “sees” it as a 4 mm object during the excretory phase. Therefore, a drug product with a 4 mm diameter and a 10 mm length has similar properties to a drug product with a longer length (e.g., 4 mm × 30 mm).

[0126] Therefore, the implementation plan includes preventing the premature excretion of drug products of various shapes from the bladder. Figure 2B The text describes horseshoe-shaped particles. Figure 2C The image depicts "bowstring" shaped particles according to the implementation scheme. Figure 2C As shown in the diagram. In other aspects, multiple pharmaceutical products are joined together. The pharmaceutical products can be joined using absorbable sutures (e.g., suture-jointed bowstrings or suture-jointed hinges). In another aspect, the absorbable sutures can dissolve to release the individual pharmaceutical products from each other. Figure 2D The image depicts bowstring-shaped particles. Figure 2E As shown in the diagram, a larger angle (i.e., approximately 90°) can increase the relative size and retention of the drug product. Figure 2F Elbow-shaped particles are depicted. The image is in... Figure 2G As shown in the image.

[0127] The applicant further discovered that the pharmaceutical product can engage with a filamentous structure (e.g., a suture) to prevent premature excretion of the pharmaceutical product. The filamentous structure can degrade after a desired retention period, at which point the pharmaceutical product is excreted in urine. Therefore, embodiments include a drug-release rod having three or more filamentous extensions (e.g., sutures) protruding from the body, such as... Figure 5C As shown in the diagram. In this aspect, each drug product has three filaments spaced 120 degrees apart and each filament is at least 8 mm long. In this aspect, folds (i.e., folds in the bladder wall) impede the excretion of the drug product.

[0128] The filamentous structure can be foldable, allowing the drug product to be easily inserted through the urethra and expand upon entering the patient's bladder. The expansion of the filamentous structure allows the drug product to remain within the bladder throughout the treatment process. In this regard, the filamentous structure can be bioabsorbable and dissolve after a predetermined time period or a predetermined number of excretion cycles.

[0129] Conformational Change Drug Products The applicant describes herein a pharmaceutical product that is easily administered (i.e., via the urethra), retained in the bladder, and subsequently expelled upon bladder excretion. In the embodiments, the pharmaceutical product undergoes one or more conformational changes. Figure 3A A relatively small pharmaceutical product is described, consisting of a smaller one for insertion, a larger one for retention, and a smaller one for elimination. This allows the product to be administered within hours, and the expansion enables it to remain in the bladder for the desired duration (i.e., retention period). In this aspect, the particles have a cross-sectional diameter of less than or equal to 4 mm for insertion, undergo a conformational change after insertion into the bladder to a cross-sectional diameter of 10 mm or greater for retention, and then decrease to a cross-sectional diameter of less than or equal to 4 mm for elimination.

[0130] In one aspect, the first conformational change (i.e., from 4 mm to 10 mm) occurs after insertion and before the first excretion event (i.e., the first urination). In another aspect, the second conformational change (i.e., from 10 mm to 4 mm) occurs after the treatment process or gradually during the treatment process. This allows the pharmaceutical product to retain a larger conformation throughout the duration of the drug treatment (i.e., during the administration of the active agent). As will be understood, the pharmaceutical product may include materials known to swell when exposed to liquids (i.e., hygroscopic materials).

[0131] In this respect, conformational changes (after insertion) occur mechanically through the bending or articulation of the object, such as... Figure 3A As shown in the figure. In other respects, conformational changes occur chemically through expansion or swelling or through the aggregation of similar objects to form agglomerates (not shown).

[0132] Pharmaceutical products may also include an "elbow" with a deformable shape, such as... Figure 3B As shown in the diagram, the elbow can be straight or curved with an angle ranging from 10 to 180 degrees, allowing the cross-sectional diameter of the administered drug product to span those positional changes. For example, two drug products can be engaged at an angle between 10 and 180 degrees to each other via a hinge or elbow of a polymer (e.g., silicone). Upon insertion, the drug products can be parallel (i.e., about 180 degrees to each other). After insertion, the hinge or elbow can return to a second angle (e.g., about 90 degrees) for the retention phase. After a period of time following drug release, the elbow can dissolve, allowing it to be expelled through the urethra.

[0133] Figure 3CCylindrical particles joined by connectors are depicted. In one aspect, each cylinder 27 is secured to a cap 185. A bridge portion 195 is connected to the connector 195. One or more of these components are degradable. In one aspect, the bridge portion 195 degrades or dissolves to release the cylindrical particles from each other, as depicted. Alternatively, one or both caps 185 may degrade or dissolve to release cylindrical particles (not shown) from each other. In another embodiment, one or both cylindrical particles 27 degrade or dissolve to cause them to release from each other (not shown). In another embodiment, one or both cylinders swell, causing them to be released from the cap. After releasing from each other, the cylindrical particles are more easily expelled during urination.

[0134] Individual drug products can be excreted from the bladder when separated from each other (e.g., after degradation). The degradable portions of the drug product can be selected based on the desired degradation rate, such that, for example, approximately 25% of the product is cleared after one week, approximately 50% after two weeks, and so on.

[0135] Pharmaceutical products may have a preferred conformation (i.e., angle) that they present upon insertion. Position-retaining elements may be made wholly or partially of a soluble polymer. For example... Figure 3B As shown, the angle between approximately 75 and 90 degrees provides the largest area. The components of the joint can be made of a variety of materials known in the art and are selected based on factors such as solubility, buoyancy, stability, tear strength / tensile strength, moldability, elasticity, flexibility, moldability, and hardness.

[0136] Figure 3D A pharmaceutical product in a retention configuration is depicted, along with three components: a connector, a hinge, and an API-embedded cylindrical rod. As shown, the free end of each cylinder has a diameter of approximately 4 mm. The capped portion has a diameter of approximately 5 mm. As described above, degradation of one or more of the components (i.e., the connector, hinge, or cylindrical rod) can trigger the release of the cylinders from each other. In this aspect, the connector is a soluble, degradable, or bioresorbable material; the hinge includes a silicone connecting piece that connects to the rod and improves retention in the bladder; and the rod is embedded in a polymer matrix. In this aspect, the hinge may also include a) a socket (where the rod is inserted), b) a cap (the flat dome of the socket), and c) a connector (a flexible link or joint bridging two caps).

[0137] In one embodiment, the drug product is passively excreted from the bladder with urine. In another aspect, the product dissolves / degrades into smaller sizes or fragments, allowing it to 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 engages in the socket and detaches, thereby causing disassembly of the embodiment. Alternatively, the silicone material of the hinge may be replaced with a bioresorbable elastomer that is flexible and elastic like silicone and dissolves over time.

[0138] In this implementation, the drug product is disassembled into individual parts for excretion with urine. The disassembly function can be isolated to individual components of the implant without interfering with other functions. This approach allows different segments of the implant to perform different roles, enabling independent adjustment of each component with minimal impact on overall performance. For example, the implant may include a rod made of a base material optimized for API diffusion, primarily comprising a flexible, non-degradable silicone connector, and a third component designed to ensure the connector between the rod and hinges fails at a predetermined rate or time. This third component, the connector, may be critical because it connects the different parts of the implant and ultimately triggers its disassembly. When the implant fragments are intact, their size or shape may prevent natural excretion during urination. Alternatively, the connector between the two hinges may be replaced from silicone with an erodible elastic material that, upon erosion, causes disassembly of the socket and rod, allowing the rod to be excreted.

[0139] Figure 3E It describes the three stages of a drug product (i.e., implantation, drug delivery, and dismantling and elimination). Figure 3F Different mechanisms for particle separation according to different implementation schemes are depicted. In one aspect, a hole in the hinge allows water to enter. The cylinders gradually swell until they are released. In another aspect, a slit in the hinge increases the degree of freedom of movement. The cylinders are released when the adhesive material loses its strength. In yet another aspect, adhesive material in a butt joint connects the cylinders. The cylinders are released when the adhesive material dissolves.

[0140] tethered / connected drug products In the implementation scheme, multiple drug products are joined by a tether or similar structure. This "grouping" of drug products increases their effective size. Due to their larger size, they are more resistant to excretion from the bladder in urine. Figure 4A Multiple pharmaceutical products (e.g., two cylinders) are depicted that are joined by tethers or otherwise connected (e.g., by hinges).

[0141] In this aspect, the tethered drug products are stacked on top of each other for administration (i.e., insertion). The cylindrical product 27 can be easily administered using a syringe or other device. After administration (e.g., upon exposure to urine), they can form a “tethered group.” This arrangement increases the size and prevents the drug product from being excreted in the urine. In this aspect, the active agent is released from the drug product during this “retention phase.”

[0142] In this aspect, the tether 175 gradually degrades or dissolves. The tether dissipates until the drug products are released from each other. Thereafter, the drug products can be excreted in the patient's urine. In this aspect, the tethered drug products can follow three phases: (a) administration phase, (b) retention phase, and (c) excretion phase. In this aspect, the duration of the retention phase is controlled by the size and / or composition of the tether. For example, a tether used for ten days of antibiotic treatment would require at least ten days to dissolve. Tethers that dissolve more quickly (i.e., a shorter retention phase) can be used for shorter antibiotic treatments.

[0143] In one aspect, the embolized drug product (in the administration phase) has a diameter smaller than the diameter of the urethra (i.e., less than 5 mm or about 5 mm). In another aspect, the embolized drug product (in the retention phase) is larger than the ureteral orifice (i.e., greater than 10 mm or about 10 mm). Furthermore, the diameter of the individual drug product (in the excretion phase) is smaller than the diameter of the ureteral orifice (i.e., less than 5 mm or about 5 mm).

[0144] In this aspect, the cylindrical products have different compositions and / or functions. For example, a first cylinder containing an active agent can be paired with a second cylinder that provides buoyancy. In this aspect, the first cylinder and the second cylinder each have different active agents.

[0145] In this embodiment, more than two particles are connected or linked by a tether. For example, a pharmaceutical product may include three, four, five, six, seven, eight, nine, ten, or more cylindrical particles. The particles may be stacked or arranged in another compact position for transurethral administration.

[0146] In other embodiments, multiple pharmaceutical products are joined together by connectors. The connectors can be flexible and / or rigid. Figure 4B The "connected" drug product shown has a relatively large effective size. The connector keeps the cylinders parallel to each other for administration. After administration (i.e., upon exposure to fluid in the bladder), the connector creates an angle between the particles. Due to this angle, the particles are more resistant to excretion from the bladder. The connector can degrade, causing the particles to separate from each other.

[0147] Similarly, Figure 4C Multiple drug products are depicted joined by connectors. Here, the cylinder degrades during the retention phase. After degradation, the individual drug products can be separated for excretion from the bladder. As described above, the degradable portions can be selected based on the desired degradation rate, such that, for example, approximately 25% of the product is cleared after one week, approximately 50% after two weeks, and so on.

[0148] Figure 5A This is an image of particles (e.g., two cylinders 27) joined by tethering 175. Similarly, Figure 5B This is an image of particles joined together by a hinge connector.

[0149] The conformational arrangement of connected drug products Figure 6 An arrangement of six pharmaceutical products is depicted. The pharmaceutical products are stacked for easy administration (i.e., insertion). This configuration facilitates administration into the bladder using a syringe or similar device. After administration (e.g., upon exposure to urine), they can form a “tethered group.” The cylinders can be arranged in a zigzag pattern as depicted. The increased surface area of ​​this conformation prevents the pharmaceutical products from being excreted with urine. In this aspect, the active agent is released from the pharmaceutical products during this “retention phase.” As described above, the tethered portions can gradually degrade or dissolve until the individual pharmaceutical products are released from each other. In this aspect, the pharmaceutical products are held on a single axis (i.e., flat). Alternatively, the pharmaceutical products can be arranged in a multi-axis configuration. Furthermore, as shown, the rods can be connected in series at their ends. The angle of this connection can be free (e.g., on a string) or fixed (e.g., using a hinge). Alternatively, a single connector (e.g., two rods joined at an angle) or multiple connectors connected in series can be present.

[0150] In the implementation plan, the tether dissolves or degrades over a period of approximately two days, five days, ten days, two weeks, three weeks, one month, two months, three months, or longer. In this aspect, the tether is stable and does not dissolve.

[0151] The implementation scheme includes other shapes and configurations of the pharmaceutical product. In one aspect, the tether material is rigid (e.g., or semi-flexible) so that the pharmaceutical product returns to its preferred shape. Figure 7A A cylindrical pharmaceutical product with a circular shape is described. As can be understood, a circular shape has a larger diameter and higher retention. Similarly, Figure 7BThe text describes spherical drug products with a circular shape. In other aspects, drug products are shaped like cotton plugs, sticks, cartridges, cylinders, drug-loaded tubes, pretzels, horseshoes, and drug products with patterned or irregular cross-sections. Grouping can form various three-dimensional shapes, such as coils, hexagons, open loops, and closed loops.

[0152] As can be understood, the tethered portion of a pharmaceutical product can determine its three-dimensional shape upon conformational change. Therefore, the material, the number of hinges, tear strength / tensile strength, moldability, elasticity, flexibility, and stiffness can influence the three-dimensional arrangement. Materials can be, for example, monoclonal sutures, catgut suture materials, vichy sutures, PDS (polydioxanone sutures), etc. In this regard, the material is either bioabsorbable or biodegradable.

[0153] In this configuration, the pharmaceutical product is connected in an orientation such that all rods are aligned in the same plane. Alternatively, the pharmaceutical product may be oriented out of plane, or may have a periodic alternation. In these configurations, the connectors may share both a common plane and a common orientation with other connectors. For example, rods connected in series via hinged connectors (all sharing the same plane and orientation) will bend to form a coil overall. In another instance, the hinges of the connection may regularly alternate between two orientations in the same plane with a period of 2, forming a zigzag arrangement.

[0154] The connector can be incorporated into, attached to, or retain the cylinder. Connectors can exist between or more cylinders. Connectors can take the form of two caps joined by a bridge, such as... Figure 3B As shown in the figure. The cap 185, bridge 190, and the connector between the cap and bridge 195 can be made of materials that vary in substance, behavior, size, polarity, stiffness, angle, and quantity.

[0155] Figure 7C Heterogeneous grouping of pharmaceutical products is described. Particles can have homogeneous or heterogeneous functions. For example, rods can vary in buoyancy, length, material, drug payload, drug release kinetics, drug loading, degradation rate and kinetics, surface erosion relative to the whole, cohesion (the cohesion between them), adhesion (adhesion to tissues), etc. In this example, cylinders are connected to spheres. The active agent can be contained within the cylinder; the spheres can provide buoyancy. For example, the spheres can contain materials that expand due to buoyancy and degrade in urine.

[0156] Bladder regulation In other aspects, the entry site from the bladder to the urethra is adjusted during the retention phase. Implementation methods include changing the threshold of the cross-sectional diameter used to retain the object in the bladder after insertion therapy (not shown). In other aspects, a filter is placed at the bladder neck, a filler is injected around the bladder neck to induce urethral wall juxtaposition, or a flow-limiting object within the urethra reduces the flow rate and thus serves to retain the object within the bladder.

[0157] Intravesical drug delivery device In one aspect, the device of the present invention is a handheld application device comprising a loading funnel for receiving solid pharmaceutical products (e.g., granules, spheres, cotton plugs, sticks, cartridges, cylinders, drug-loaded tubular pharmaceutical products, pharmaceutical products having patterned or irregular cross-sections, etc.). Figure 8 A delivery device 5 according to an embodiment is depicted. The delivery device may include a body 10 having components. In one aspect, the body includes a substantially linear cylinder 15 and an insertion tip 20. The insertion tip is inserted into the subject's urethra and secured in place. Thereafter, a drug product can enter the cylinder 15 from a funnel region 25. A pressure source 30 (e.g., compressed water or air) can drive the drug product through the device into the bladder. In one aspect, 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 change the pressure applied to the trigger to regulate the pressure entering the device (and thus regulate the rate of drug product expulsion).

[0158] 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 for the patient during insertion and use of the device. Therefore, in this aspect, the device's barrel has a length of approximately 1 cm to approximately 15 cm or greater. The insertion tip may have an outer diameter (“OD” or maximum cross-sectional dimension) of approximately 9 mm or less. In addition to the inner diameter of the barrel (“ID”), the size / flexibility of the drug product and the amount of pressure applied can affect the delivery rate of the drug product.

[0159] Therefore, the ID of the lumen of the tube body 15 and the insertion tip 20 can be determined based on the expected size of the drug product to be delivered. In this aspect, the ID is between about 0.3 mm and about 2 mm. In this aspect, the lumen is elastomeric, allowing it to be flexible / elastically deformable. In this aspect, the insertion tip 20 is tapered at the distal end for insertion through the urethra. In this aspect, the insertion tip is for single use and can be disposed of after use.

[0160] The body 10 can be any suitable biocompatible material for connecting / accommodating components. In one aspect, the drug capsule body 10 is constructed of plastic or silicone. The loading funnel may have a funnel shape, but other forms are contemplated. The funnel can deliver a drug product, a pharmaceutical preparation, or any suitable substance or structure known in the art and within the scope of the practitioner's authority over the device. In other embodiments, the funnel is a high-capacity delivery device configured to store up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 125, 135, 150, 175, 200, 250, 300, 350, 400, 500, 750, 1000, or more units of a drug product. In other embodiments, the funnel is a rapid delivery device capable of delivering multiple units of pharmaceutical product simultaneously or rapidly and continuously.

[0161] The loading funnel 25 may also include grooves, ridges, obstructions, pegs, springs, switches, latches, manifolds, valves, or labyrinth structures to throttle or alter the delivery rate of the drug product / drug / excipient. In one aspect, the loading funnel is an integral component of the handheld delivery device body. In another aspect, the loading funnel is a modular component configured for detachable attachment to the handheld delivery device body. Multiple funnels may be provided to deliver a variety of drug products, excipients, drugs, or combinations thereof, or to deliver drug products, excipients, or drugs at a faster or more optimized delivery rate. The loading funnel can be operatively attached to any contemplated device of the present invention.

[0162] A loading funnel feeds the drug product into a hollow channel within a cylinder, which is operatively connected to or integrally formed within the body of a handheld application device. For example... Figure 8As shown, a desired quantity of pharmaceutical product can be placed / poured into loading funnel 25. In this aspect, the pharmaceutical product in solution is fed into the loading funnel. Alternatively, a cassette or loading tray (not shown) can be used to feed the pharmaceutical product into the funnel. The cylinder can be constructed in any known shape and with any known inner and outer diameters. The cylinder capacity can match the capacity of the loading funnel, or it can contain a capacity larger or smaller than the loading funnel's capacity. The cylinder can be smooth, semi-smooth, or partially smooth along its inner periphery, or it can include ridges, notches, grooves, knurling, springs, or any known geometric protrusions to optimize the delivery of the pharmaceutical product or any other suitable substance through its hollow channels. The cylinder can also be tapered, truncated, or have a uniform, inconsistent, or irregular diameter along its entire length, substantially its entire length, or a portion or repeating extension of its length. The cylinder can also include one or more locking mechanisms to throttle, alter, and / or optimize the delivery rate of the pharmaceutical product. In this aspect, the funnel is shaped (i.e., wider at the top and narrower towards the bottom) so that individual drug products are fed into the lumen of the cylinder.

[0163] In one embodiment, a "hopper mechanism" is operatively attached to a loading funnel. The hopper mechanism is configured as a dispenser for drug particles. It ensures that drug particles (e.g., rods) enter the cylinder in the correct orientation to avoid blockage. One design is a conical hopper with a narrow opening at the bottom leading to the cylinder. The cylinder can be shaped to properly hold the drug product. This allows the rods to enter the cylinder through the funnel in the correct orientation. Another design includes a series of small channels or tubes leading from the hopper to the cylinder. The channels can be angled / bent to guide the rods into the cylinder in the correct orientation. In this aspect, the device automatically stops dispensing after a specific dose (i.e., a specific volume or number of particles) has been administered.

[0164] In an embodiment, the handheld delivery device includes a trigger for actuating the delivery of a pharmaceutical product from the handheld delivery device. The trigger can be spring-loaded using a tension spring, compression spring, leaf spring, or any suitable and known spring in the art. The trigger can be attached to a housing of the handheld device body and can be surrounded by a hollow trigger housing. The trigger housing can be formed in any shape to accommodate the trigger of the handheld delivery device. In an embodiment, the trigger housing is arcuate. In other aspects, the trigger housing is substantially square. In yet another aspect, the trigger housing is a low-profile hollow protrusion, which provides optimal clearance for trigger actuation. The trigger housing is designed to provide clearance for the practitioner's or user's fingers to approach the trigger. The trigger may also include a grip or gripping surface. The grip or gripping surface can be made of any suitable material, such as elastomeric materials, plastics, polymers, metals, alloys, or blends of alloys, or any of the materials mentioned above or any suitable material known in the art. The trigger's grip may include modified geometry to aid in holding. The altered geometry can take the form of concave, convex, undulating, recessed, or raised surfaces. The handle of the trigger can also include multiple protrusions, undulations, or recesses to aid the user's or practitioner's ability to grip the trigger. Such protrusions can take the form of raised grooves, notches, knurling, raised dots, spheres, studs, or any other suitable gripping surface or geometry known in the art. Such undulations can take the form of a wave pattern with rounded crests, sharp crests, plateaus, or any suitable form to aid the user's or practitioner's grip on the trigger.

[0165] The trigger can provide automated, semi-automatic, or delivery of pharmaceutical products from a handheld delivery device at any frequency known in the art. One or more pharmaceutical product units can be dispensed with a single trigger actuation, or can be dispensed at the following rates: one pharmaceutical product per trigger actuation, two pharmaceutical products per trigger actuation, three pharmaceutical products per trigger actuation, four pharmaceutical products per trigger actuation, five pharmaceutical products per trigger actuation, six pharmaceutical products per trigger actuation, seven pharmaceutical products per trigger actuation, eight pharmaceutical products per trigger actuation, nine pharmaceutical products per trigger actuation, ten pharmaceutical products per trigger actuation, twelve pharmaceutical products per trigger actuation, fifteen pharmaceutical products per trigger actuation, and so on. 17 drug products, triggering 20 drug products per trigger, triggering 25 drug products per trigger, triggering 30 drug products per trigger, triggering 40 drug products per trigger, triggering 50 drug products per trigger, triggering 65 drug products per trigger, triggering 75 drug products per trigger, triggering 100 drug products per trigger, triggering 125 drug products per trigger, triggering 150 drug products per trigger, triggering 200 drug products per trigger, triggering 500 drug products per trigger, triggering 1,000 drug products per trigger, or triggering 1,000 or more drug products per trigger.

[0166] In another aspect, the drug products can be dispensed at the following rates or volumes: approximately one drug product per trigger, approximately two drug products per trigger, approximately three drug products per trigger, approximately four drug products per trigger, approximately five drug products per trigger, approximately six drug products per trigger, approximately seven drug products per trigger, approximately eight drug products per trigger, approximately nine drug products per trigger, approximately ten drug products per trigger, approximately twelve drug products per trigger, approximately fifteen drug products per trigger, approximately seventeen drug products per trigger, approximately twenty drug products per trigger, and approximately twenty-five drug products per trigger. Each trigger activates approximately 30 drug products, approximately 40 drug products, approximately 50 drug products, approximately 65 drug products, approximately 75 drug products, approximately 100 drug products, approximately 125 drug products, approximately 150 drug products, approximately 200 drug products, approximately 250 drug products, approximately 300 drug products, approximately 350 drug products, approximately 400 drug products, approximately 500 drug products, approximately 1,000 drug products, or more.

[0167] In another aspect, the drug products may be dispensed at the following rates or volumes: no more than one drug product per trigger activation; no more than two drug products per trigger activation; no more than three drug products per trigger activation; no more than four drug products per trigger activation; no more than five drug products per trigger activation; no more than six drug products per trigger activation; no more than seven drug products per trigger activation; no more than eight drug products per trigger activation; no more than nine drug products per trigger activation; no more than ten drug products per trigger activation; no more than twelve drug products per trigger activation; no more than fifteen drug products per trigger activation; no more than seventeen drug products per trigger activation; no more than twenty drug products per trigger activation; no more than one drug product ... The trigger may activate no more than 25 drug products per trigger, no more than 30 drug products per trigger, no more than 40 drug products per trigger, no more than 50 drug products per trigger, no more than 65 drug products per trigger, no more than 75 drug products per trigger, no more than 100 drug products per trigger, no more than 125 drug products per trigger, no more than 150 drug products per trigger, no more than 200 drug products per trigger, no more than 250 drug products per trigger, no more than 300 drug products per trigger, no more than 350 drug products per trigger, no more than 400 drug products per trigger, or no more than 500 drug products per trigger.

[0168] In another aspect, multiple drug products (i.e., different drug products) can be administered each time a trigger is activated. Multiple drug products can be administered simultaneously, sequentially, or in an alternating or patterned manner.

[0169] The handheld application device may also include a hose or catheter connected to its proximal end for delivering compressed air or pressurized fluid from a pressure source and advancing a solid drug product from the outlet port of the funnel through a hollow cylindrical channel toward its distal end and exiting through its distal opening. The hose or catheter may be constructed of any suitable material or any combination of materials within the scope of those skilled in the art. The hose or catheter may be elastomeric, polymeric, rubbery, metallic, comprising a combination of alloys, or a combination of elastomeric or polymeric materials. The hose or catheter may also include clamps, supports, locks, or other peripheral devices positioned along its length. The pressurized fluid or compressed air fed through the hose or catheter also serves to advance the solid drug product distally beyond the outlet of the hollow cylindrical channel and through a gentle insertion tip attached to the distal end of the handheld application device, delivering the solid drug product to a treatment area of ​​the patient or subject, such as the urethra, bladder, or kidney. The hose or catheter may be connected to a supply of compressed air or compressed fluid, or alternatively, may be connected to a disposable device containing compressed air or compressed fluid. The hose or conduit is also adapted to connect to any suitable port for delivering compressed air or compressed fluid, including wall-mounted ports for delivering compressed air or compressed fluid.

[0170] Pressure relief valve 35 may be present on the handheld delivery device. Pressure relief valve 35 may be located above the coupling between the catheter and the handheld device, below the coupling between the catheter and the handheld device, attached to the funnel of the handheld device, or attached to any other suitable location preferred by the user or practitioner of the device, and in any location known in the art. Pressure relief valve 35 serves to release pressure accumulated within the handheld device during actuation and drug product delivery. Pressure release may occur through a single outlet, a single port, a single perforation, or a manifold with a port, outlet, or perforation.

[0171] Suitable forms and shapes for delivery of pharmaceutical products via the apparatus of the present invention include drug-loaded tubular cartridges filled with rod-shaped pharmaceutical products or other pharmaceutical products and formulations disposed within the drug-loaded tubular cartridges, such that the drug-loaded tubular cartridges are positioned within the hollow cylindrical channel of the present invention. Other forms and shapes include, for example, spheres, cubes, pyramids, polyhedra, tracks, cylinders, truncated cylinders, irregular cylinders, planar spheres, teardrops, spikes, pretzels, horseshoes, and any suitable shapes or forms known in the art. Combined forms, combined shapes, coupled forms, and coupled shapes are also contemplated. Examples of combination and connection forms, as well as combination and connection shapes, include two or more cylindrical drug products or structures connected by tethers; two or more rod-shaped drug products connected by tethers; two or more spherical drug products connected by tethers; two or more cubic drug products connected by tethers; two or more elliptical drug products connected by tethers; two or more prism-shaped 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; two or more spherical drug products connected by hinges; and two or more cylindrical drug products or structures connected by hinges. This includes one or more cubic drug products, two or more elliptical drug products connected by hinges, two or more prism-shaped 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 cubic drug products connected by sutures, two or more elliptical drug products connected by sutures, two or more prism-shaped drug products connected by sutures, two or more pyramidal drug products connected by sutures, etc. The forms and shapes mentioned above are also contemplated for storing active agents and excipients, or any arrangement or combination thereof. Furthermore, the combined and linked forms of the drug products can be connected via a bioabsorbable polymer or other suitable bioabsorbable material (e.g., sutures), said bioabsorbable material dissolving at a predetermined rate or after a predetermined number of excretion cycles.

[0172] In this aspect, the entry portion of the device's cylinder (i.e., the insertion tip 20) is made of a flexible material (e.g., silicone) that is more comfortable for the patient. These materials allow for greater flexibility in the device's design and can be molded into different shapes to fit different patients. The pressure used for delivery can be determined to effectively deliver the drug product while avoiding patient discomfort.

[0173] The insertion tip 20, attached to the distal end of the cylinder, can be a bladder sheath, a lubricating tip, a Luer lock or taper for connection to a drug delivery device, or any known insertion or coupling device in the art. The mild insertion tip can also be rigid, disposable, soluble, bioabsorbable, single-use, etc. The mild insertion tip can also be in the form of a catheter, cannula, or needle and can be attached to the distal end of the cylinder or any other component of the device of the present invention. The insertion tip can be made of a single material, multiple materials, or a mixture of materials. In another aspect, the insertion tip comprises a different material along its length, comprises a repeating material pattern, or comprises an irregular material pattern along its length. For versatility and functionality, the insertion tip can also be configured for attachment to an adapter or additional tip. The insertion tip can be a modular component, detachably attached to the distal end of the cylinder or any other component of the device of the present invention. The insertion tip can also be integral with the device of the present invention, attached or engaged to the distal tip of the cylinder or any component of the device of the present invention.

[0174] Deep locking flexible catheter In this aspect, the insertion tip 20 includes an anchoring mechanism. An anchoring mechanism is already used with conventional catheters. An example of such a device is the Foley catheter. Conventional Foley catheters typically have a balloon that prevents the inner tip from slipping out once it has been inserted to the appropriate depth. However, these catheters are not designed to deliver any products, and therefore their lumen (i.e., the channel) is narrow and has relatively high frictional resistance because they are made of a certain grade of silicone.

[0175] In one embodiment, the delivery device includes a depth-locking flexible catheter 50 having an anchoring mechanism to reduce / prevent tip movement after the tip is inserted into the urethra. Figure 9A catheter 50 is depicted having a distal end 55 including an anchoring mechanism (e.g., a balloon) and a proximal end 60 including a locking mechanism (e.g., threads and nuts). In one aspect, the threaded portion extends longer than the required length of the locking ring assembly, allowing the assembly to be variably tightened at different depths along the longer threaded portion. In another aspect, the locking ring assembly consists of a relatively wide mudguard washer 65 resting against the patient's skin and two locking nuts (70, 75) that tighten together at a precise desired depth outside the mudguard washer. The locking nuts may have a high surface area (one convex and the other concave) so that they can be tightened together by friction, helping to prevent disassembly. In another aspect, the locking nuts are large enough that they can be easily separated by hand, but are smaller in width compared to the mudguard washer. The nearest side of the device may be a connector (such as a threaded lock or a Luer sliding lock) allowing other devices to be attached while the bladder sheath remains stationary between sections of the procedure. The inner diameter (ID) of the catheter lumen can be, for example, from about 1 mm to about 9 mm wide or smaller / larger, depending on the size of the particles applied. In this aspect, the length of the catheter is determined by the patient's sex (i.e., male or female).

[0176] As shown, the catheter may include a balloon or other structure protruding from the distal end 55. The balloon may be inflated or expanded by any suitable medium, including, for example, fluids, air, gases, or any mixtures mentioned above. The catheter may be a modular component that is detachably attached to any part of the device of the present invention. Alternatively, the catheter may be an integral component forming part of the overall device and operatively associated with parts of the device.

[0177] The depth-locking flexible catheter 50 may include any number of lumens. In embodiments, the depth-locking flexible catheter includes a single lumen for passage of a pharmaceutical product, drug substance, excipient, carrier, or any suitable substance, product, particle, mechanism, or device known in the art. The depth-locking flexible catheter and other devices may also include two, three, four, five, six, seven, or more lumens. The lumens may be coaxial, concentric, arrayed, patterned, irregularly offset, discontinuous, or completely continuous, and may have any length, circumference, diameter, gradient diameter, or variable diameter considered suitable for the purposes of the invention.

[0178] The depth-locking flexible conduit may further include an internal portion and an external portion. In this aspect, the external portion is a semi-rigid plastic with threads / nuts. The external components may include a rotatable washer 65, a clockwise convex nut (right-hand thread) 70, and a counterclockwise concave nut (left-hand thread) 75. The rotatable washer, clockwise convex nut, and counterclockwise concave nut are threadedly engaged to the threaded proximal end 60 of the depth-locking flexible conduit. The rotatable washer, clockwise convex nut, and counterclockwise concave nut may be engaged to the proximal end of the depth-locking flexible conduit in any suitable manner known in the art or within the scope of the user or practitioner. The rotatable washer, clockwise convex nut, and counterclockwise concave nut may be replaced with equivalent fasteners and gaskets known in the art.

[0179] Concentric multi-lumen static sheath In another embodiment, the delivery device includes an insertion tip having a concentric multi-lumen static sheath 80, such as Figure 10 As shown in the figure, a concentric multi-lumen static sheath may include an outer tubular member 90 and an inner tubular member 85 arranged concentrically and coaxially.

[0180] In this aspect, the inner tubular member 85 includes a flexible portion at its distal end. The flexible portion can inflate or deform upon insertion into the urethra or bladder of a patient or subject to act as a locking member by maintaining the position of the outer and inner tubular members. The flexible portion can be shaped like a "shoehorn" and unfold at its distal end 95 to secure the catheter in place. The flexible portion can comprise any suitable material known in the art. Inflatable and expandable materials can include, for example, polymers, elastomers, plastics, latex, paraffin wax, malleable metals, malleable alloys, or any combination thereof. An inflation lumen, pull cord, pulling mechanism, or actuator (not shown) can be operatively connected to the flexible portion to actuate its inflation or deformation. The flexible portion can deform into a lobe or wing that overlaps with the outer tubular member and locks the inner tubular member into position within the patient and / or locks and attaches the inner tubular member relative to the outer tubular member. The flexible portion can be coated or impregnated with pharmaceutical products and serve as a component for drug and pharmaceutical delivery.

[0181] In this aspect, the insertion tip includes an external locking ring 100 that gently screws onto the patient's skin to lock the sheath in place, such as... Figure 11A As depicted in the image. The locking ring allows for a universal and adjustable sheath length, which can be set with depth according to the urethral length of a specific patient.

[0182] In optional designs, the catheter has a "cotton plug" structure made of flexible, sterile material, such as... Figure 11BThe device, as depicted, can internally contain a drug product 27. The internal drug product can be any of the shapes and conventions mentioned above, including a bowstring arrangement where two drug products are connected by a bioabsorbable tether. The bowstring arrangement allows the two drug products to enter at a 180-degree angle relative to each other and provides a minimum diameter for easy access to the patient's urethra. After entry, the bioabsorbable bowstring allows the drug products to be at an angle less than 180 degrees, ensuring the drug products remain in the patient's bladder for a predetermined number of excretion cycles. Finally, the bioabsorbable bowstring tether slowly dissolves, allowing each previously connected drug product to leave the patient's bladder and urethra after a predetermined dissolution period. Once the device is inserted into the urethra, a push-button spring mechanism at the bottom of the device can open the device outwards. This mechanism can comfortably hold the device in place for the duration of drug administration. It can also be used for consistent and uniform delivery of the drug product. The device can have a cord / thread that can be pulled after administration to close the device and allow for easy and comfortable removal. Unlike a cystoscope, the device provides patient comfort because it is made of flexible and / or lubricating materials (e.g., rayon, blends of rayon and cotton, and synthetic fibers or similar materials). In this aspect, the catheter is inserted together with the applicator (not shown).

[0183] Soft hook component In another embodiment, the insertion tip includes one or more soft gripping hook members 105. Figure 12 A soft gripper member that can be used as a depth setting and locking mechanism is described. The soft gripper member serves to hold a bladder sheath in place while simultaneously setting the depth of drug delivery. Each soft gripper member may include a longitudinal body terminating at a ball-shaped end, the width of which is greater than the width of the longitudinal body. The ball-shaped end can be made of any gripping member novel or known in the art, including cup arrays, suction members, arrays of suction members, barbs, arrays of barbs, etc.

[0184] The soft hook member 105 may originate within the wall of a tubular member of the delivery device, operate coaxially with or within the delivery device, and project distally from the distal end of the delivery device of the present invention. The soft hook member is typically flexible and adapted to bend into an arc or bow shape so that its ball-shaped end contacts the interior of a patient's orifice or anatomical structure, such as the inner wall of the urethra, bladder, or kidney. To establish depth, the soft hook member is deployed into the treatment area and pulled back via a connected pull member, pull line, or actuator that deforms the distal end of the hook member into a curved or bow shape, thereby allowing the ball-shaped end of the hook member to contact the inner surface of the patient's orifice or anatomical structure.

[0185] In embodiments, the soft hook member is part of a soft hook member array. The soft hook member array may include two or more soft hook members connected to two or more pulling members or pulling devices. The soft hook member array may include equally spaced soft hook members or randomly spaced and categorized soft hook members. The device of the present invention may include any number of soft hook members or an array of soft hook members. The soft hook member may also be contemplated as a filamentous element such as a suture, and may include an array of sutures for gripping the interior of the patient's bladder wall.

[0186] The soft gripper component can comprise any suitable material, such as elastomeric materials, polymeric materials, plastics, metals, metal alloys, or any or all combinations thereof. The material configuration of the soft gripper component can be uniform, patterned, or comprise alternating and distinguishable materials. The flexural modulus of the soft gripper component can vary along its length. For example, the soft gripper component can comprise a more rigid material at its base and a more flexible material at its distal tip. Any arrangement of flexural modulus or flexural modulus strength known in the art and / or within the scope of practitioners or users can be employed.

[0187] Delivery device with ratchet mechanism In another embodiment, the delivery device is a handheld delivery device that includes a drug product loading chamber, a container chamber, a drug product delivery chamber, and an actuation mechanism including a piston, a plunger, and a threaded connection member. The drug product loading chamber, container chamber, and drug product delivery chamber can be designed to fit any suitable size and be capable of handling different types of drug products. Figure 13A , Figure 13B and Figure 13C Different views of the loading mechanism are depicted (i.e., first-person view, top-down view, and side view, respectively).

[0188] The drug product delivery chamber 110 can be sized to any size and shape suitable for its intended use, as well as any size and shape known in the art. In one embodiment, the drug product delivery chamber 110 is sized and shaped to receive a threaded piston and plunger 115 threadedly connected to a threaded throttling device within the drug product delivery chamber. In one aspect, the threaded throttling device receives the piston in a threaded connection and is located proximal to the interior of the drug product delivery chamber. In other aspects, the threaded throttling device is located in other portions of the drug product delivery chamber, such as at the midpoint of the chamber, near the midpoint of the chamber, proximal to the exterior of the chamber, in any location deemed appropriate by the user or practitioner, or in any location suitable for the purposes of the invention and / or known in the art.

[0189] The drug product delivery chamber may also include a pull trigger 40 connected to a rotating, spring-loaded ratchet mechanism. The spring-loaded ratchet mechanism may be operatively connected to a loading pin 120 and an unloading pin 125. When an operator pulls or actuates trigger 40, the trigger acts on both pins, releasing the drug product unit from the loading area (loaded drug-loaded canister) 130 into the container compartment (empty drug-loaded canister) 135. The trigger and pins then return to their original positions via spring retraction, holding the next consecutive drug product unit in place.

[0190] In the implementation, the container compartment is positioned opposite the drug product loading compartment and operatively connected to the drug product delivery chamber. The container compartment can receive cartridges, empty ampoules, empty capsules, empty granules, empty cartridges connected or attached by a tether, empty ampoules connected or attached by a tether, empty capsules connected or attached by a tether, empty granules connected or attached by a tether, empty structures connected or attached by a tether, or equivalents acting by an unloading pin operatively connected to a trigger of the handheld delivery device. Upon trigger actuation, the unloading pin displaces, thereby allowing empty drug product to enter the container compartment after ejection from the drug product delivery chamber. The connection between the unloading pin and the trigger of the handheld delivery device varies in design. The unloading pin and the trigger can be connected directly, indirectly, via a spring, via a tension member, via a pulling mechanism, via a pushing mechanism, or via any suitable means known in the art. The unloading pin can be electronically coupled to the trigger, and in other respects, it can be fastened without physical connection, but via near-field communication, wireless communication, RFID, Bluetooth, Wi-Fi, or any suitable equivalent that allows the trigger to communicate with and act on the unloading pin.

[0191] The cartridge spring 145 of the drug product loading chamber can both retract to receive the drug product unit and expand to eject the drug product unit into the drug product delivery chamber. The drug product delivery chamber is operatively attached to the drug product loading chamber and receives the ejected drug product unit for delivery to a patient or subject via an actuation mechanism. The actuation mechanism can be any type of actuator known in the art, including pistons, pistons coupled to plungers, threaded pistons, threaded pistons coupled to plungers, occluder rods, needle pins, threaded needle pins, threaded rods, pneumatic actuators, spring-loaded actuators, piezoelectric actuators, electronic actuators, etc.

[0192] Figure 13BA top-down view of the drug product delivery chamber is depicted. The chamber can be attached to catheter 50. When the trigger is pulled, the drug product unit is released from the loading area (loaded drug-loaded cannula) 130 into the empty drug-loaded cannula 135. A screw piston 140 guides the drug product through the connector and into the catheter area. Similarly, Figure 13C A side view of a drug product delivery chamber is depicted, showing a screw piston 140 and plunger 115 that guide the drug product to the connector / catheter.

[0193] The drug product loading compartment can be manufactured, designed, and engineered for different capacities. In implementations, 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-five, up to thirty, up to thirty-five, up to forty, up to forty-five, up to fifty, up to sixty, up to seventy-five, up to one hundred, up to one hundred and twenty-five, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, up to one hundred and fifty, or up to one hundred and fifty or more drug product units can be loaded into the drug product loading compartment at any time.

[0194] In other implementations, no more than 5 drug product units, no more than 10 drug product units, no more than 15, no more than 20, no more than 25, no more than 30, no more than 35, no more than 40, no more than 50, no more than 60, no more than 75, no more than 100, no more than 125, no more than 150, no more than 175, no more than 200, no more than 250, no more than 300, no more than 350, no more than 400, no more than 450, or no more than 500 drug product units may be loaded into the drug product delivery compartment.

[0195] In other respects, approximately two drug product units, approximately three drug product units, approximately four drug product units, approximately five, approximately seven, 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 compartment at any time.

[0196] The container can be manufactured, designed, and engineered for an unlimited number of capacities. In implementations, up to one, two, three, four, five, six, seven, eight, nine, ten, twelve, fifteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, fifty, sixty, seventy, seventy, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, forty-five, or forty-five or more drug product units can be received into the drug container at any given time.

[0197] In other implementations, no more than 5 drug product units, no more than 10 drug product units, no more than 15, no more than 20, no more than 25, no more than 30, no more than 35, no more than 40, no more than 50, no more than 60, no more than 75, no more than 100, no more than 125, no more than 150, no more than 175, no more than 200, no more than 250, no more than 300, no more than 350, no more than 400, no more than 450, or no more than 500 drug product units may be accepted into the container.

[0198] In other respects, approximately two pharmaceutical product units, approximately three pharmaceutical product units, approximately four pharmaceutical product units, approximately five, approximately seven, 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 pharmaceutical product units may be accepted into the container.

[0199] In another aspect, at least one pharmaceutical product unit, at least two pharmaceutical product units, at least three pharmaceutical product units, at least four pharmaceutical product units, at least five pharmaceutical product units, at least seven pharmaceutical product units, at least nine pharmaceutical product units, at least 10, at least 12, at least 15, at least 17, at least 20, at least 23, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 70, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, at least 700, at least 800, at least 900, at least 1000 or more drug product units may be accepted into the container.

[0200] tubular delivery device equipped with valves In another aspect, the delivery device of the present invention may further include valves at both the inlet and outlet ports of the delivery device body. The delivery device may terminate at a blunt distal end, which is sealed by the valve when not actuated or used. A stopper rod, needle, piston, or other insertion device may be used to indirectly open the valve seal at the distal end of the device by pushing the drug product against the inner surface of the distal valve and acting to open the valve as the drug product is pushed through it. A proximal valve may also be present and seal the proximal opening of the delivery device of the present invention. When a stopper rod, needle, piston, or other insertion device is inserted into the channel of the delivery device of the present invention, the proximal valve may be opened by the action of the stopper rod, needle, piston, or other insertion device.

[0201] In another embodiment, a tubular member is provided, comprising an open proximal end and an open distal end, and a plurality of drug product units are loaded in a hollow channel extending therebetween. A valve is attached to the proximal end of the tubular member and surrounds the open proximal end. A second valve is attached to the distal end of the tubular member and surrounds the open proximal end. A stopper rod, core needle, etc., is provided as a drug product propulsion and ejection tool, capable of entering the proximal opening of the tubular member through the first valve, propelling a batch of drug product units or particles to be processed through the hollow channel, and ejecting the drug product units away from the open distal end of the tubular member through the second valve. In one aspect, the valve may be selectively opened or activated by a push-button spring mechanism attached to the distal end of the tubular member. In other aspects, the push-button spring mechanism may be attached along the length of the tubular member to the underside of the tubular member, or attached at any location deemed suitable by a person skilled in the art. Drug products used with a valved tubular delivery device can have any of the shapes and conventions mentioned above, including a bowstring arrangement in which two drug products are connected by a bioabsorbable tether. The bowstring arrangement allows the two drug products to enter at a 180-degree angle relative to each other and provides a minimum diameter for easy access to the patient's urethra. After entry, the bioabsorbable bowstring allows the drug products to maintain an angle of less than 180 degrees, ensuring that the drug products remain in the patient's bladder for a predetermined number of excretion cycles. Finally, the bowstring tether slowly dissolves, allowing each previously connected drug product to exit the patient's bladder and urethra after a predetermined dissolution period.

[0202] For the purpose of establishing proper or correct orientation of the device during use, marking members or marking indices may be provided along the outer wall of the tubular member. Marking members may be in the form of colored lines extending along the length of the outer wall of the tubular member. Marking members may also be in the form of phrases indicating the correct placement of the tubular member within the subject or patient. Marking members may also be in the form of marking indices, provided as numbers, letters, symbols, colors, words, arrows, coded indicators, or other known symbols, for indicating the correct placement of the tubular member during use of the device.

[0203] In this regard, the type of particle or pharmaceutical product used (e.g., size, shape, composition, and manufacturing method) can be selected based on the proposed treatment. For example, cylindrical particles (containing an antibiotic active agent) two millimeters in length may be optimal for treating female patients with UTIs. These relatively large particles (where 2 mm is the average longest size) can remain in the bladder in three ways. First, the majority of the particles in the formulation (i.e., greater than about 90%) float in the urine. During the first half of the excretory cycle, when the urethral opening is at its maximum, this buoyancy pulls the particles away from the urethral opening. Second, as the bladder empties and the urethral opening gradually narrows, in the second half of the excretory cycle and as excretion nears completion, the particle size is wider than the narrowing urethral opening. Third, at the end of the excretory cycle (when the urethral opening narrows and the floating particles are brought to the level of the urethral opening), the particles tend to aggregate within the bladder, thus preventing the particles from flowing out.

[0204] Many catheters (intravesical or otherwise) or cystoscopes can easily slip or dislodge after they have been inserted. They can also be inserted too deeply. This risk of device slippage complicates procedures involving extended intravesical manipulation. Complications can be caused by a number of factors, including but not limited to an increased risk of tearing or irritation; by preventing hands-free operation by the clinician; by increasing the risk of needing to reinstall the device after it has been inadvertently removed, which could lead to increased adverse effects on tissues; or by altering the depth to which it has been fully inserted.

[0205] How to use In the implementation scheme, the particles within the drug formulation comprise (a) a pharmacologically active agent and (b) a controlled-release carrier. Through gradual reduction in mass and / or other means, the particles release the active agent into the bladder over an extended drug delivery period. The composition of the particles is further described herein.

[0206] As will be understood, the selection of pharmacologically active agents depends on the indication. Although not mandatory, the active agents that can be administered via intracapsular administration of the granular formulation of the present invention are generally selected from the following categories: anti-infective agents, including antibacterial, antifungal, and antiviral agents; chemotherapeutic agents; anti-inflammatory agents; anesthetics; analgesics; diuretics; procoagulants and anticoagulants; biological products; agents for the treatment of incontinence, including overactive bladder (including antimuscarinic agents, β3-adrenergic receptor agonists, anesthetics, and analgesics); renin-angiotensin-aldosterone system (RAAS) inhibitors; agents for modulating immune responses; agents for the treatment of kidney stones; agents for gene therapy; and contrast agents for diagnosis and monitoring.

[0207] As described above, the drug formulation is most conveniently administered to the patient in compacted form. In the bladder, the capsule can expand or conform to a larger size, which prevents entry into the urethra during the desired retention period. In this case, the granules have a diameter of approximately 10 mm. 3 Up to 50 mm 3 The combined volume. In this aspect, the particle has approximately 1 mm. 3 Approximately 2 mm 3 Approximately 3 mm 3 Approximately 5 mm 3 Approximately 7mm 3 Approximately 10 mm 3 Approximately 12 mm 3 Approximately 15 mm 3 Approximately 20 mm 3 Approximately 25 mm 3 Approximately 30 mm 3 Approximately 35 mm 3 Approximately 40 mm 3 Approximately 45mm 3 Approximately 50 mm 3 Approximately 60 mm 3 Approximately 70 mm 3 Approximately 80 mm 3 Approximately 90 mm 3 Approximately 100 mm 3 Or a larger combination of volumes. In this aspect, the particles have a hollow core.

[0208] In another aspect, the drug particles described herein are a group of cylindrical (i.e., tubular or cylindrical) particles or substantially cylindrical particles connected or linked together by tethers. In this aspect, the particles have a diameter of no more than 1 mm. 3 No more than 2 mm 3 No more than 3 mm 3 No more than 5 mm 3 No more than 7 mm 3 No more than 10 mm 3 No more than 12 mm 3 No more than 15 mm 3 No more than 20 mm 3 No more than 25 mm 3 No more than 30 mm 3 No more than 35 mm 3 No more than 40 mm 3 No more than 45 mm 3 No more than 50 mm 3 No more than 60 mm3 No more than 70 mm 3 No more than 80 mm 3 No more than 90 mm 3 or not exceeding 100 mm 3 The volume of the combination.

[0209] In another aspect, the particles have a diameter of approximately 2 mm. 2 Approximately 3 mm 2 Approximately 5 mm 2 Approximately 7 mm 2 Approximately 10 mm 2 Approximately 12mm 2 Approximately 15 mm 2 Approximately 20 mm 2 Approximately 25 mm 2 Approximately 30 mm 2 Approximately 35 mm 2 Approximately 40 mm 2 Approximately 45 mm 2 Approximately 50 mm 2 Approximately 60mm 2 Approximately 70 mm 2 Approximately 80 mm 2 Approximately 90 mm 2 Approximately 100 mm 2 Or a larger combination of surface areas.

[0210] In another aspect, the drug product is connected by a bioabsorbable tether or hinge, which is designed to maintain its integrity (i.e., not dissolve) until one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-five, thirty, thirty-five, forty, forty-five, and fifty cycles of excretion. After 1000, 55, 60, 65, 70, 75, 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500, 600, 700, 800, 900, 1000 or more excretion cycles.

[0211] Bioabsorbable tethers or hinges can have a fixed or variable stiffness. The stiffness of bioabsorbable tethers or hinges can be approximately 1A, approximately 2A, approximately 3A, approximately 4A, approximately 5A, approximately 6A, approximately 7A, approximately 8A, approximately 9A, approximately 10A, approximately 11A, approximately 12A, approximately 13A, approximately 14A, approximately 15A, approximately 16A, approximately 17A, approximately 18A, approximately 19A, approximately 20A, approximately 21A, approximately 22A, approximately 23A, or approximately 24A. Shore A hardness, approximately 25A, 26A, 27A, 28A, 29A, 30A, 35A, 40A, 45A, 50A, 55A, 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 96A, 97A, 98A, 99A, or 100A.

[0212] Bioabsorbable tethers or hinges can have a fixed or variable stiffness. The stiffness of bioabsorbable tethers or hinges can be 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, or at least 24A. Shore A hardness of at least 25A, at least 26A, at least 27A, at least 28A, at least 29A, at least 30A, at least 35A, at least 40A, at least 45A, at least 50A, at least 55A, at least 60A, at least 65A, at least 70A, at least 75A, at least 80A, at least 85A, at least 90A, at least 95A, at least 96A, at least 97A, at least 98A, at least 99A, or at least 100A.

[0213] Bioabsorbable tethers or hinges can have a fixed or variable hardness. The hardness of bioabsorbable tethers or hinges can be no more than 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, or 24A. Shore A hardness not exceeding 25A, 26A, 27A, 28A, 29A, 30A, 35A, 40A, 45A, 50A, 55A, 60A, 65A, 70A, 75A, 80A, 85A, 90A, 95A, 96A, 97A, 98A, 99A, or 100A.

[0214] In this respect, the administration of the pharmaceutical product and device of the present invention can improve urinary incontinence in a subject or patient 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%.

[0215] In this respect, the administration of the pharmaceutical products and devices of the present invention can reduce the signs / symptoms of bladder / urinary tract / kidney diseases 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%.

[0216] In this respect, the administration of the pharmaceutical product and device of the present invention can reduce the signs / symptoms of bladder / urinary tract / kidney diseases 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%.

[0217] In this respect, intravesical administration of a drug product using the device / method of the present invention can reduce reported patient discomfort (compared to the use of a conventional catheter) 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 this aspect, compared to conventional methods (e.g., manually loading a catheter), the administration of the pharmaceutical product and device of the present invention reduces the time required for intravesical administration of the pharmaceutical product (e.g., including 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%. In this aspect, the device and method allow intravesical administration to be performed by less trained personnel (i.e., by a single healthcare professional / technician).

[0219] In the implementation, the apparatus / method described herein can deliver drug particles, wherein the average diameter of the particles or drug delivery product is about 50 nanometers, about 100 nanometers, about 200 nanometers, about 350 nanometers, about 500 nanometers, about 1,000 nanometers, about 2,000 nanometers, about 3,000 nanometers, about 5,000 nanometers, about 10,000 nanometers, about 10 micrometers, about 20 micrometers, about 30 micrometers, about 50 micrometers, about 100 micrometers, about 150 micrometers, or about 250 micrometers. Meters, approximately 500 micrometers, approximately 750 micrometers, approximately 1,000 micrometers, approximately 1,500 micrometers, approximately 2,000 micrometers, approximately 3,000 micrometers, approximately 5,000 micrometers, approximately 10,000 micrometers, approximately 1 millimeter, approximately 1.25 millimeters, approximately 1.35 millimeters, approximately 1.45 millimeters, approximately 1.5 millimeters, approximately 1.65 millimeters, approximately 1.75 millimeters, approximately 1.85 millimeters, approximately 2 millimeters, approximately 2.15 millimeters, approximately 2.25 millimeters, approximately 2.5 millimeters, or approximately 3 millimeters or larger.

[0220] In this context, the controlled-release particles described herein are cylindrical (i.e., cylindrical or cylindrical) or substantially cylindrical. In this context, they have a diameter of approximately 10 mm. 3 Up to 50 mm 3 The volume. In this aspect, the particle has approximately 1 mm. 3 Approximately 2 mm 3 Approximately 3 mm 3 Approximately 5 mm 3 Approximately 7 mm 3 Approximately 10 mm 3 Approximately 12 mm 3 Approximately 15 mm 3 Approximately 20 mm 3 Approximately 25 mm 3 Approximately 30 mm 3 Approximately 35 mm 3 Approximately 40 mm 3 Approximately 45 mm 3 Approximately 50 mm 3 Approximately 60mm 3 Approximately 70 mm 3 Approximately 80 mm 3 Approximately 90 mm 3 Approximately 100 mm 3 Or larger in volume. In this aspect, the particles have a hollow core.

[0221] In this regard, the drug particles described herein are cylindrical (i.e., cylindrical or cylindrical) or substantially cylindrical. In this regard, the particles have a diameter not exceeding 1 mm. 3 No more than 2 mm 3 No more than 3 mm 3 No more than 5 mm 3 No more than 7 mm 3 No more than 10 mm 3 No more than 12 mm 3 No more than 15 mm 3 No more than 20 mm 3 No more than 25 mm 3 No more than 30 mm 3 No more than 35 mm 3 No more than 40 mm 3 No more than 45 mm 3 No more than 50 mm 3 No more than 60 mm 3 No more than 70 mm 3 No more than 80 mm 3 No more than 90 mm 3 or not exceeding 100 mm 3 The volume.

[0222] In this aspect, the particles have a diameter of approximately 2 mm. 2 Approximately 3 mm 2 Approximately 5 mm 2 Approximately 7 mm 2 Approximately 10 mm 2 Approximately 12 mm 2 Approximately 15mm 2 Approximately 20 mm 2 Approximately 25 mm 2 Approximately 30 mm 2 Approximately 35 mm 2 Approximately 40 mm 2 Approximately 45 mm 2 Approximately 50 mm 2 Approximately 60 mm 2 Approximately 70mm 2 Approximately 80 mm 2 Approximately 90 mm 2 Approximately 100 mm 2 Or a larger surface area. Example

[0223] The following non-limiting examples are provided for illustrative purposes only to help to provide a more complete understanding of the representative embodiments now contemplated. These examples are intended to be merely a subset of all possible combinations of the components of the formulation. Therefore, these examples should not be construed as limiting any embodiments described in this specification, including those relating to the types and amounts of the components of the formulation and / or their methods and uses.

[0224] Example 1 Comparison of different polymorphs Polymorphs occur when polymers solidify with different chemically identical crystal lattice structures, resulting in different tertiary and quaternary structures. Adjusting the crystallinity of a product or creating different polymorphs allows for modification of drug release, buoyancy, density, and material properties such as hardness, stability, packing, and appearance. In this embodiment, alpha (α) crystalline structures, beta prime (β') crystalline structures, and beta (β) crystalline structures were generated, and their buoyancy over time was compared.

[0225] Alpha (α) particles are cured at 4°C. They appear shiny / glossy because the lattice is highly ordered and the carbon chains are laid in parallel, resulting in smooth surfaces in the quaternary structure. To produce alpha, the energy of the system must be lowered to reduce motion along the monomer degrees of freedom and to reduce intramolecular hindrance.

[0226] Beta prime (β') particles harden at 51°C. They are more randomly packed and "chalky" because the monomers have bent glycerol carbon chains. If the beta particles are more randomly packed, then energy must be stored between the polymer units during the polymerization process. Similarly, beta (β) melt-solidifies at 51°C. They appear chalky (i.e., without luster).

[0227] The characteristics of each type of crystal structure are Figure 1 A comparison was made. The β-rod maintained its buoyancy throughout the four-day process. Almost none of the β-rods sank to the bottom of the flask. In contrast, both the α-rod and β-rods lost their buoyancy after approximately three days.

[0228] Example 2 Comparison of absorbable sutures In this embodiment, the drug product is attached to absorbable sutures (e.g., suture-attached bowstrings or suture-attached hinges). After the absorbable sutures have fully dissolved, the individual drug products separate from each other and are excreted during excretion.

[0229] Therefore, the length of retention time will depend 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 sutures are made from twisted strands of purified collagen taken from the small intestine of domestic ruminants or beef tendons. Catgut sutures are naturally degraded by the body's own proteolytic enzymes. Full tensile strength is maintained for at least 7 days and absorption is complete within 90 days. Vicryl sutures are rehydrolyzed in the body into glycolic acid and lactic acid in about 7-10 days. Vicryl sutures retain about 50% of their breaking strength at 5 days and have almost no breaking strength at 14 days, and eventually the entire suture disappears. PDS (polydioxanone) sutures are more stable. They retain about 70% of their initial strength for two weeks, 50% for four weeks, and 25% for six weeks. They are absorbed through simple hydrolysis and are completely absorbed within 180-210 days.

[0230] Table 1 shows the properties of different materials and their stability in the bladder.

[0231]

[0232] Example 3 Intravesical administration of controlled-release particles (using a conventional catheter) In this embodiment, a female patient visits a healthcare provider to administer intravesical controlled-release particles. The use of intravesical particles allows for drug delivery at a specified controlled rate and at the target site for greater efficacy and safety. As depicted in Figure 7, the particles can be inserted using a catheter / drug-loaded cannula with a blunt end for insertion. The catheter / drug-loaded cannula may also include a valve for directional control.

[0233] Surgical preparation 1. Set up a sterile table (e.g., to the right of the patient table base).

[0234] 2. Place four sterile drug-loaded cannulas on the table (two of the cannulas contain 5 grams of therapy).

[0235] 3. Empty the two 5-gram packets onto the table.

[0236] 4. The rods are placed into the drug-loaded cannula one by one.

[0237] 5. Lay four filled drug-loaded cannulas on the table for administering the drug product to the patient.

[0238] 6. Open the device to advance the rod from the drug-loaded cannula into the cystoscopic sheath: a. A 6 Fr bracket pusher can be used.

[0239] b. A 7 Fr vascular sheath can be used.

[0240] c. A 5 Fr vascular catheter with a soft tip can be used.

[0241] Application procedure 1. The patient lies supine with their legs placed in the stirrup.

[0242] 2. Ensure the vaginal opening is sterile and cover the area in a sterile manner.

[0243] 3. Treat the urethra with viscous lidocaine. The sheath is coated with viscous lidocaine as a lubricant.

[0244] 4. Insert the cystoscope sheath into the bladder: a. A 19.5 Fr sheath can be used.

[0245] b. A 22 Fr sheath can be used.

[0246] c. A 17.5 Fr sheath can be used.

[0247] 5. Attach the bridge, insert the cystoscope, and fill the bladder with saline.

[0248] 6. The bladder is filled and checked for any damage or disease.

[0249] 7. Remove the endoscope, leaving the sheath in place.

[0250] 8. Adjust the sheath angle from approximately 45 degrees to approximately 0 degrees to the ground (this prevents the rod inside the bladder from floating out of the sheath).

[0251] 9. The assistant prepares the insertion rod: a. The assistant holds the distal end of the drug-loaded cannula to prevent the rod from falling off.

[0252] b. The assistant inserts the "pusher" into the proximal end of the drug-loaded cannula. The rod is now secured between the distal pinch point and the proximal pusher.

[0253] 10. The assistant inserts the distal end of the drug-loaded cannula into the cystoscope funnel and engages the cannula with the narrowed groove: i. Advance the drug-loaded cannula as far as possible into the cystoscope groove, and then push the rod through the drug-loaded cannula into the bladder, or ii. The pusher is used to push the rod out of the drug-loaded cannula and into the sheath.

[0254] b. The assistant retracts the drug-loaded cannula, advancing the pusher into the cystoscope groove to prevent rod reflux.

[0255] 11. A urologist's stick for clearing the sheath: a. The urologist places the occluder into the cystoscope funnel, adjacent to the pusher.

[0256] b. When the assistant retracts the pusher, the squeegee prevents any pellets from leaving, and then the squeegee is pushed through the sheath to expel all the rods into the bladder.

[0257] c. This completes the insertion of the first drug-loaded cannula.

[0258] d. The sheath is at a 0-degree angle, and the occluder is removed.

[0259] 12. Repeat a. Repeat the procedure (steps 8-10) for the remaining drug-loaded cannulas.

[0260] 13. Confirm a. The urologist removes the occluder, reattaches the bridge using an endoscope, and then examines the bladder to confirm the presence of the rod and the absence of damage.

[0261] b. If there is retained air in the bladder, the urologist will bleed the air.

[0262] 14. End of surgery a. The urologist removes the endoscope, sheath, and bridge.

[0263] b. The surgical drape was removed, and the patient was helped off the operating table.

[0264] Example 4 Intravesical administration of controlled-release particles (delivery device) In this embodiment, the device of the present invention is used to administer intravesical controlled-release granules to a female patient. The procedure is summarized below for two different amounts of the product.

[0265] 1. Urethral Custody maintenance × 4, Product delivery × 1 = 10 grams a. Load a 10-inch sheath (drug-loaded cannula) with 2.5 grams of product measuring 200 mm (approximately 8 inches).

[0266] b. The sheath has a blunt inlet tip and acts as a one-way valve (e.g., flap valve, duckbill valve, Heimlich valve, etc.).

[0267] c. The sheath is inserted into the bladder through the urethra.

[0268] d. Urine returns through the sheath to prove it has entered.

[0269] e. The sheath has a one-way valve at the outer end to prevent the product from flowing back out of the sheath during transport or during surgery.

[0270] f. A stopper (pushing mechanism) is used to advance through an external valve and deliver the loaded product antegradely into the bladder.

[0271] ----i. The force from the occluder is transmitted along the product column and forces the guide tip to open.

[0272] ----ii. The force must not exceed the fragility of the drug product.

[0273] g. The occluder is advanced to its full length to mate with the rear portion of the sheath.

[0274] h. The sheath and occluder are removed together.

[0275] i. Repeat the process, delivering the target product quantity in increments of 2.5 grams.

[0276] j. The sheath has stiffness to resist upward bending forces observed during packaging, transport, and user operation.

[0277] k. The sheath may have a distal bulge or ramp that guides the product away from the propulsion axis as it leaves the sheath.

[0278] l. The sheath may have an expanded section (e.g., 4-6 cm) from the end of the guide to restrict the advancement of the sheath into the bladder.

[0279] m. In this respect, the sheath can hold the product while it undergoes electron beam sterilization (or other methods) without compromising the product's sterility.

[0280] 2. Urethra patency maintenance ×1, product delivery ×4 = 10 grams a. Insert the distal tip of the gun-shaped device into the urethra.

[0281] b. Several "cartridges" of the drug product are loaded and docked with the device in such a way that they can be delivered sequentially through the urethra: ----i. In one implementation, they are horizontal (i.e., aligned with the delivery axis) and aligned with the main channel of the device one at a time. Once aligned, the drug product is discharged from the cartridge, through the main channel, and into the bladder. The used cartridge is then replaced with a full cartridge, and the process is repeated.

[0282] ----ii. In one embodiment, the cartridge is a drug-loaded tubular sheath.

[0283] -----iii. In one embodiment, the hopper is discharged via a mechanical slider (operated by hand, by a robotic piston, or by other means).

[0284] -----iv. In one embodiment, the hopper is discharged by the force of a gas or liquid.

[0285] 3. Urinary tract access maintenance ×1, product delivery ×1 = 10g a. A French horn filled with product, which can be delivered using a mechanical slide.

[0286] In one aspect, the device includes a sheath orientation indicator with color, texture, or distinctive features to alert the operator to the orientation of the sheath inside the patient via external cues. In another aspect, an internal anchoring mechanism prevents retrograde movement of the delivery mechanism (e.g., a flap or balloon) during the procedure.

[0287] The provider may use the following procedure to insert a catheter into a patient's urethra. The catheter is operatively attached to a handheld delivery device that includes a funnel for feeding a cylindrical, floating drug product into the body of the handheld delivery device. The provider actuates a trigger attached to the underside of the housing of the handheld delivery device, delivering a timed release of the drug product into the patient's bladder through the urethra.

[0288] Example 5 Treatment of chronic UTI In this example, a female patient visits a healthcare provider due to signs / symptoms of a UTI. The provider notes that the patient has experienced three UTIs within a six-month period. She has previously been prescribed oral antibiotics (i.e., amoxicillin or nitrofurantoin). Although prophylactic oral antibiotics are an option, the patient wishes to avoid them. Furthermore, the healthcare provider acknowledges the risk of antibiotic resistance.

[0289] The provider has proposed the option of using intravesical controlled-release particles. Conventional drug delivery systems (e.g., tablets, capsules, etc.) can suffer from poor bioavailability and fluctuations in plasma drug levels. The use of intravesical particles allows for drug delivery at a specified controlled rate and at the target site, resulting in greater efficacy and safety.

[0290] Cannulas are used during laparoscopic surgery and other minimally invasive procedures to create small puncture-like incisions in the outer tissue layer. These incisions allow the surgeon to insert a cannula, through which surgical instruments can be introduced. In this embodiment, the provider inserts cannula 112 into the patient's urethra, such as... Figure 15 As depicted, the cannula may include a distal (internal) flange that opens to hold the cannula in place. It may also include a one-way valve to prevent fluid from being released from the bladder during the procedure. As depicted, the cannula may be approximately 8 cm long (based on a urethral length of approximately 6 cm).

[0291] The provider uses a cannula as the entry point for the particles. Figure 16A A container filled with granules is depicted; Figure 17 An occluder is also depicted. The cartridge may include a one-way valve. The cartridge may also include markings or a shroud for indicating length. For example, a shroud (i.e., an external plastic / rubber structure) 160 may be inserted / attached 6 cm from the distal tip. This can indicate a safe insertion point in the cannula and prevent over-insertion and injury to the bladder. An occluder is also depicted. In this aspect, the occluder is matched to the length of the cartridge. It may also include markings or a shroud 165 for preventing over-insertion and injury to the bladder. In this embodiment, the provider follows the steps described below.

[0292] a) Insert the cannula 112 through the patient's urethra; b) Secure and open the cannula; c) Pass the hopper through the sleeve needle to mark 160; d) Insert the stopper into the hopper to mark 165 to discharge the particles; e) Remove the stopper and the hopper; f) Repeat steps (c)-(e) until the full dose is administered (e.g., four cartridges); g) Remove the cannula 112 from the patient.

[0293] In summary, the provider carefully inserts the container into the cannula to avoid contact with the distal bladder. Next, an occluder is used to drain the particles from the container into the bladder. This process is repeated for a total of four containers. The cannula is then removed from the patient's urethra. The provider assesses the patient's discomfort throughout the procedure.

[0294] The patient reported symptom relief within six hours of the procedure. She experienced no discomfort or sensation of granules. She was evaluated one week later and showed no signs / symptoms of infection. Furthermore, the provider noted that although amikacin was present in the bladder at an effective concentration, there was no detectable circulating amikacin. The patient was subsequently advised to maintain regular visits to her healthcare provider and report any signs / symptoms of possible UTIs.

[0295] Example 6 Administer intravesical granules using a pre-loaded occluder. A female patient residing in a nursing home experienced recurrent urinary tract infections due to her inability to completely empty her bladder. After assessing the patient's condition, the physician recommended treatment with anti-infective drug capsules. These capsules are buoyant and float in the urine within the patient's bladder, allowing the drug to release its active ingredient in a timed manner without premature excretion.

[0296] In this embodiment, the occluder is preloaded with particles ( Figure 17 The provider inserts the occluder into the cannula, carefully avoiding contact with the distal bladder. Next, a handle or lever is used to expel particles from the occluder into the bladder. The occluder is then removed. These steps are repeated for a total of four occluders. Finally, the cannula is removed from the patient's urethra. Figure 17 A variation of the occluder design is depicted. In one aspect, the occluder includes a thumb buckle 170. The thumb buckles can be arranged in pairs at positions of 0° and 180° or 90° and 270° relative to each other.

[0297] In the implementation scheme, the apparatus and method described herein allow for intravesical administration as a single-person procedure. In this aspect, the pharmaceutical product can be administered without the healthcare provider's visibility (i.e., as a blinded procedure).

[0298] In the implementation scheme, the device and method described herein can deliver fragments of a pharmaceutical product (e.g., 160 4×5 mm fragments, 80 4×10 mm fragments, or 40 5×15 mm fragments to achieve a delivery dose of 10 grams, etc.) into the bladder via the female or male urethra.

[0299] In the implementation, the devices and methods described herein prevent lateral, antegrade, and / or retrograde catheter movement to improve comfort or reduce pain during intravesical administration procedures.

[0300] In the implementation, the apparatus and methods described herein have tactile feedback. This can alert the healthcare provider to adjust / terminate the procedure if a blockage is present.

[0301] Example 7 Intravesical granules are administered using a device with an intravesical sheath. In this example, a female patient reported multiple and recurrent urinary tract infections to her healthcare provider. After assessing the patient's condition, the provider recommended treatment with a group of anti-infective drug product capsules. These capsules are buoyant and float in the urine within the bladder, allowing the drug product to be released over a period of time (e.g., five days).

[0302] The provider inserts an intravesical sheath 80 into the patient's urethra and secures the sheath in place using the leaf-shaped distal end 95. Once the intravesical sheath is locked in place, the delivery chamber 110 is connected to the sheath (e.g., by securing it to a threaded portion). The provider inserts a packet of anti-infective drug product through the lumen of the intravesical sheath by twisting the proximal handle of a threaded piston operably connected to the proximal end of the intravesical sheath. Figure 4A The piston pushes the anti-infective drug product package through the inflatable depth-locking member 55 of the bladder sheath and into the patient's bladder. The practitioner repeats this procedure, using a total of four cartridges. The bladder sheath is then removed from the patient, and the provider schedules a follow-up appointment for the patient.

[0303] The provider followed up with the patient two weeks after the procedure. The patient reported no discomfort, and the provider found no evidence of urinary tract infection.

[0304] Example 8 Application of "tethered" bladder granules A female patient residing in a nursing home experienced recurrent urinary tract infections (UTIs) due to her inability to completely empty her bladder. After assessing her condition, the physician recommended treatment with intravesical antibiotics. The physician recommended a course of treatment with amikacin via suppositories (i.e., granules or cylinders).

[0305] like Figure 4A As shown, the tethered drug products are stacked and administered through the urethra in the form of cylinders (i.e., the administration phase). Upon exposure to urine in the bladder, the cylinders separate but remain attached to each other by the tether (i.e., the retention phase). Due to the combined size of the cylinders, the tethered cylinders resist excretion during urination.

[0306] The tether gradually dissolves during the period when the active agent (e.g., amikacin) is released from the granules. In this embodiment, the tether remains intact for approximately 10 days when amikacin is released into the bladder. The concentration of amikacin in the bladder remains relatively constant during this period.

[0307] The patient was assessed regularly during the treatment process. Approximately 48 hours after administration, she had no signs / symptoms of UTI, and more than 90% of the particles remained in her bladder (via ultrasound). After ten days, most of the particles had separated from each other and were excreted during urination. After two weeks, no cylinders remained in the bladder.

[0308] Example 9 Application of "conformational change" granules in the bladder A female patient visited a healthcare professional complaining of recurrent urinary tract infection (UTI). The healthcare provider noted that the patient had recently been treated with a broad-spectrum antibiotic (oral) for the UTI. After assessing her condition, the physician recommended treatment with an intravesical antibiotic. The use of intravesical particles allows for the delivery of the drug at a specified controlled rate and to the target site (i.e., the urinary tract) for greater efficacy and safety. Specifically, the provider recommended a course of administration of amikacin via a conformationally modified drug product (i.e., a connected cylinder).

[0309] like Figure 3A As shown, the drug product is stacked and administered through the urethra in a cylindrical shape (i.e., the administration phase). Upon exposure to urine in the bladder, the cylinders separate but remain attached to each other at or near the capping area by connectors or tethers (i.e., the retention phase). Due to the combined size of the particles, they resist excretion during urination.

[0310] As amikacin is released from the cylinder into the bladder, the connector portion gradually dissolves. In this embodiment, the connector portion remains intact for approximately ten days. The concentration of amikacin in the bladder remains relatively constant during this period.

[0311] The patient was assessed regularly during the treatment process. Approximately 48 hours after administration, she had no signs / symptoms of UTI, and more than 90% of the cylinders remained in her bladder (as observed by ultrasound). After ten days, most of the cylinders had separated from each other and were expelled during urination. After two weeks, there were no cylinders in the bladder.

[0312] Example 10 Administer intravesical granules with bioabsorbable polymer connectors. As in the example above, a female patient visits a healthcare professional complaining of recurrent urinary tract infection (UTI). The physician recommends treatment with intravesical antibiotics. Specifically, the provider recommends a procedure of administering amikacin via a conformational drug product (i.e., a connected cylinder).

[0313] As described above, the drug product is stacked and administered through the urethra in a cylindrical shape (i.e., the administration phase). When exposed to urine in the bladder, the cylinders are held attached to each other by connectors or tethers (i.e., the retention phase).

[0314] like Figure 3G As shown, at least a portion of the cylinder comprises a material that swells upon exposure to a liquid. This occurs during the retention phase. Swelling causes the cylinder to be released from the cap. Subsequently, the individual cylinder and cap portion are readily excreted with urine (i.e., the elimination phase).

[0315] In this embodiment, the composition of the cylinder is modified to extend the duration of the retention phase. The cylinder and cap assembly can be modified or "adjusted" to extend the retention phase. One method involves the use of enteric coating. Figure 3H As shown, the rod can be coated. The outer layer reduces water movement / absorption. The coating gradually dissolves upon exposure to urine in the bladder.

[0316] Figure 3I The comparison results of different coatings are shown (i.e., the percentage of bars retained over a 21-day time period). Poly(acrylic acid) (“PAA”) cylinders with the following coatings were compared:

[0317] In this study, PAA cylinders coated with 60% LT460 provided the optimal retention period. In some cases, the cylinders were coated multiple times (i.e., multiple layers) to extend the retention period.

[0318] Alternatively, the cylinder can be made of composite materials. Swellable (i.e., hygroscopic) materials can be combined with hydrophobic materials. This reduces the swelling rate and prolongs the retention period. For example... Figure 3J Other methods described herein include: "Dissolved hinge" – that is, using dissolved hinge components. For example, the silicon material of the hinge can be replaced with a bioresorbable elastomer.

[0319] "Push Out Rod" - The holes in the hinge allow water to diffuse and then the material swells to push out the rod.

[0320] "Weakened hinge" - the slits in the hinge increase the degree of freedom of movement because the adhesive material loses its strength.

[0321] "Release bar" - a butt joint (the bar has no overlapping sockets), so that the bar is released when the adhesive dissolves.

[0322] "Disassemble the hinge" - use an erodible / soluble material as the hinge connector.

[0323] Example 11 Use of floating medical devices In one implementation, a device placed in a fluid-filled organ, such as a bladder for drug delivery (or other therapeutic effects), floats in the body fluid.

[0324] In this embodiment, the device for intravesical drug delivery minimizes stimulation of sensory nerves in the trigone of the bladder to provide therapeutic treatment within the bladder. This improvement reduces the pressure on the intravesical therapeutic device when placed on the trigone of the bladder, which is defined by the space defined by the central urethral opening and the bilateral ureteral orifices.

[0325] For example, U.S. Patent No. 11,135,161 teaches an implantable device for delivering a drug to a patient, wherein the device includes: a first drug portion having a first drug shell containing a first drug formulation in solid form; and a second drug portion including a second drug shell containing a second drug formulation. Variations also include a device having a drug reservoir component having a resilient tube having at least one lumen defined 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 unfolded shape and a relatively expanded retaining shape.

[0326] Implantable devices, including those discussed above, can be modified to reduce any stress caused by delivering the device to the triangular region. For example, the buoyancy or flotation of the 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).

[0327] In another variation, the floating object may include a central chamber (e.g., a balloon or other gas reservoir) wherein the floating object has a large amount of low-density material, such as lipids (e.g., tristearate). In yet another variation, the intravesical drug delivery device comprises part or all of a gas, liquid, or solid with a density less than urine, wherein a portion of the drug reservoir or retention reservoir is filled with a gas, such as oxygen, nitrogen, carbon dioxide, carbon tetrafluoride, etc.

[0328] Example 12 Drug products are delivered to the bladder of male patients. In this embodiment, the drug product is delivered into the bladder of a male patient. This procedure is preferably for outpatient use and requires the use of a flexible device (single-use). The maximum outer diameter of the device passing through the urethra is 10 mm, preferably 7 mm or less. The inner diameter of the device must be sufficient to deliver the drug product. As described herein, the drug product can have a diameter of approximately 5 mm. The thinner the catheter wall, the easier these goals are to achieve. Devices made of polytetrafluoroethylene (PTFE) are preferred because of their good rigidity with respect to thickness, and for this reason, they are used in vascular sheaths.

[0329] The catheter must be able to pass through the male urethra, which undergoes a 0-60 degree bend beneath the prostate. The catheter must not twist during this bend; therefore, it needs to be deformable within the ranges of 0-15 degrees, 15-30 degrees, 30-45 degrees, or 45-60 degrees. To prevent twisting, the walls can be reinforced with coiled metal bands, plastic ribs, metal springs, etc.

[0330] When products are inserted into the catheter, each product must be able to push forward the product in front of it. This means the inner diameter of the catheter must allow two drug products to move forward only in a single file and not jam or stack on top of each other. You might be able to place the products side-by-side, but they must not jam or block the pair in front of them, etc. This causes blockage and product damage. Friction within the catheter must be minimized in humid environments; therefore, hydrophobic coatings and PTFE are preferred materials.

[0331] Throughout the catheter, from inlet to outlet, the inner diameter must not have a large abrupt change; otherwise, it will allow the drug product to become stuck, fragmented, etc. In existing vascular sheaths, there is a proximal enlarged chamber to allow for fluid injection.

[0332] Clearing the catheter from the medication and delivering all medication to the bladder is a challenging process. The leading edge of the "occluder" must not slip across the gap on either side of the medication, which could lead to entrapment and product damage. Instead, the diameter difference between the medication and the catheter's ID must be less than the cross-sectional area of ​​the occluder's leading edge.

[0333] If the occluder is in the male urethra, it will have to advance through a bend in the catheter. It is important that the occluder is deformable. This can be achieved using compliant materials or by using an occluder with a distal “head-on-aneck” structure, where the head provides a large surface area for advancing the drug product, and the neck allows the head to be angled relative to the proximal portion of the advancing occluder.

[0334] The components delivered for the product can be summarized as follows: 1. Catheter insertion a. Entering the urethral opening b. Crossing the urethra ----i. Spongy urethra ----ii. Membranous urethra ----iii. Prostatic urethra 2. Confirmation of bladder access a. Return of urine b. Pressure changes 3. Continuous maintenance of the urethral-bladder pathway a. Balloon inflation b. End anchoring fin c. Transmural expansion, pressure, or friction 4. Preparation of the bladder for receiving drug products a. Fluid dripping ----i. An additional infusion port that is part of the sheath? 5. Place the product into the tubing. a. Connecting the material boxes b. Manual loading c. Pre-filled catheter d. Mechanical loading 6. The product is delivered into the bladder via a catheter. a. Advancing and delivering pharmaceutical products (next step) b. Advancement of the occluder to clear the duct ----i. The breaker design must smoothly navigate bends. 7. Repeat steps 5 and 6, ensuring no backflow of product or bladder fluid. a. A valve located at the proximal or distal end that allows the drug product to travel in one direction. 8. Catheter removal Example 13 Treatment of bladder cancer In this example, a 75-year-old male patient visited a healthcare provider complaining of hematuria, painful urination, and lower back pain. The provider performed a visual examination of the bladder via cystoscopy. Pathological examination confirmed the presence of tumor cells.

[0335] The provider has proposed the option of using intravesical controlled-release particles. Conventional drug delivery systems (e.g., tablets, capsules, etc.) can suffer from poor bioavailability and fluctuations in plasma drug levels. The use of intravesical particles allows for drug delivery at a specified controlled rate and at the target site, resulting in greater efficacy and safety.

[0336] The patient received intravesical chemotherapy. Specifically, he received a single infusion of intravesical chemotherapy. The cylindrical particles, as described herein, comprise mitomycin C (MMC) as the active agent. The particles are administered in a stacked arrangement (i.e., two cylinders joined by a soluble connective). After insertion, the particles undergo a conformational change in size (i.e., from 4 mm to 10 mm). The particles remain in the bladder while the MMC is released into the bladder and surrounding tissues.

[0337] Approximately five days later, the particles underwent a second conformational change following the treatment process (i.e., from 10 mm to 4 mm). The particles (and their components) were excreted in the patient's urine. The provider performed a second visual examination of the bladder via cystoscopy. The number and size of the tumors were significantly reduced (i.e., reduced by approximately 85%). The provider recommended immunotherapy and regular monitoring of the patient's bladder.

[0338] Example 14 Use of pharmaceutical products with filamentous extensions An 88-year-old female patient was experiencing recurrent urinary tract infections (UTIs) due to her inability to completely empty her bladder. After assessing her condition, the physician recommended treatment with intravesical antibiotics. The physician recommended administration of amikacin via a drug product with an extended filamentous structure (i.e., sutures) and delivery the drug product into the patient's urethra using a handheld delivery device.

[0339] like Figure 5B As shown, the drug product is a cylinder joined with a filamentous extension. Prior to administration, the filamentous extension is folded around the periphery of the cylindrical drug product, providing ease of use for loading a handheld delivery device and administering the drug through the patient's urethra and into the bladder.

[0340] The physician administered the medication to the patient via a handheld delivery device and followed up one week later. During the follow-up appointment, the physician noted that the medication remained in the bladder washout solution and that the patient's UTI symptoms had lessened. At the subsequent appointment (three weeks after administration), the physician performed an ultrasound on the bladder. The filamentous extensor had dissolved, and over 90% of the medication had been excreted in the urine.

[0341] The above non-limiting embodiments are provided for illustrative purposes only to help to better understand the disclosed subject matter. These embodiments should not be construed as limiting any implementations described in this specification, including those relating to pharmaceutical compositions or methods and uses for treating diseases or infections.

[0342] This document describes certain embodiments of the invention, including the mode known to the inventors as the best mode for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors contemplate that those skilled in the art may employ such variations as appropriate, and the inventors envision that the invention may be practiced in other ways than expressly described herein. Therefore, the invention includes all modifications and equivalents of the subject matter set forth in the appended claims that are permitted by applicable law. Furthermore, any combination of all possible variations of the above embodiments is covered by the invention, unless otherwise stated or otherwise clearly contradicted by the context.

[0343] The grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each member of the group disclosed herein may be mentioned and claimed individually or in any combination with other members of the group. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, this specification is deemed to contain the group as a modification, thereby achieving the written description of all Markush groups as used in the appended claims.

[0344] Unless otherwise indicated, all figures used in this specification and claims to represent characteristics, items, quantities, parameters, properties, terms, etc., should be understood to be modified in all cases by the term "about". As used herein, the term "about" means that the characteristic, item, quantity, parameter, property, or term described so far covers a range of plus or minus 10% above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Therefore, unless indicated to the contrary, the numerical parameters stated in this specification and the appended claims are approximate values ​​that may vary. To a minimum, and without attempting to limit the application of the doctrine of equivalence to the scope of the claims, each numerical indication should be interpreted at least based on the number of significant figures reported and by applying common rounding techniques. Although the numerical ranges and values ​​stating the broad scope of the invention are approximate, the numerical ranges and values ​​stated in specific embodiments are reported as precisely as possible. However, any numerical range or value inherently contains certain errors that are necessarily caused by the standard deviation found in their respective test measurements. The description of numerical ranges of values ​​herein is intended only as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value of the numerical range is incorporated into this specification as if it were described separately herein.

[0345] The terms “a,” “an,” “the,” and similar pronouns used in the context of describing the invention (particularly in the context of the following claims) should be interpreted to cover both the singular and plural forms, unless otherwise indicated herein or clearly contradicted by the context. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. The use of any and all embodiments provided herein, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and not to limit the scope of the further claimed invention. The language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing the invention.

[0346] All patents, patent publications, and other publications referenced and identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methods described in such publications that can be used in conjunction with the present invention. These publications are provided only for their disclosures prior to the filing date of this application. In this respect, nothing should be construed as an admission by virtue of a prior invention or for any other reason prior to such disclosure. All statements regarding dates or the content of these documents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or content of these documents.

[0347] Finally, it should be understood that although aspects of this specification are highlighted by reference to specific embodiments, those skilled in the art will readily understand 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 by no means limited to the specific methodologies, schemes, and / or reagents described herein. Consequently, various modifications or alterations to the disclosed subject matter, or alternative configurations of the disclosed subject matter, can be made based on the teachings herein without departing from the spirit of this specification. Finally, the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the invention, which is solely defined by the claims. Therefore, the invention is not limited to the precise contents shown and described.

Claims

1. A method for treating and / or preventing a disease in a subject, the method comprising: a) Provide more than one connected particle, each connected particle containing a first particle that is bonded to a second particle. b) Delivering the more than one connected particle into the subject's bladder. c) Allowing at least a portion of the connected particles to degrade during the retention phase to form individual particles. d) Allow the individual particles to be excreted during urination. Each of the more than one connected 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 phase.

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

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

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

5. The method of claim 1, wherein each of the more than one connected particles is substantially cylindrical.

6. The method of claim 1, wherein each of the more than one connected particles floats in the urine.

7. The method of claim 1, wherein each of the more than one connected particles has a hollow core.

8. The method of claim 1, wherein each of the more than one connected particles has a solid core.

9. The method of claim 1, wherein the excipient portion comprises a biodegradable material.

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

11. The method of claim 1, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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 of claim 11, wherein the anti-infective agent is an antibacterial agent.

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

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

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

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 fosfomycin degradation products generated in situ.

17. The method of claim 1, wherein the step of delivering the more than one connected particle into the subject's bladder includes intraurethral delivery.

18. The method of claim 1, wherein a syringe is used in the step of delivering the more than one connected particle into the subject's bladder.

19. The method of claim 1, wherein the retention period is longer than one month.

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

21. The method of claim 1, wherein each of the more than one connected particles comprises a matrix and a pharmacologically active agent dispersed therein.

22. The method of claim 1, wherein each of the more than one connected particles is coated on a core, the core containing a pharmacologically active agent dispersed therein.

23. The method of claim 1, wherein the more than one connected particle is dispersed in a liquid medium for delivery to the subject's bladder.

24. The method of claim 22, wherein the liquid medium comprises at least one selected from viscosity modifier, tension modifier, buffer, and dispersant.

25. The method of claim 1, wherein the active agent is released into the bladder in a substantially stable state.

26. The method of claim 1, wherein the step of delivering the more than one connected particle into the subject's bladder further comprises disrupting the biofilm using the urethra or bladder.

27. The method of claim 1, wherein the more than one connected particle is stacked and applied to the patient's bladder.

28. A method for treating and / or preventing a disease in a subject, the method comprising: a) Provide more than one particle arranged in a first conformation, each particle comprising an excipient portion and an active agent. b) Delivering more than one particle into the subject's bladder. c) Allowing more than one particle to transform into a second conformation in the bladder. d) Release the active agent from more than one particle into the subject's bladder, and e) Allow more than one particle to separate from each other so that they are excreted during urination.

29. The method of claim 28, wherein each particle is shaped as a cylinder, sphere, teardrop, horseshoe, pretzel, rod, pyramid, cube, prism, or drug-loaded cannula.

30. The method of claim 28, wherein the disease is a urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, inactive bladder, urinary retention, diabetes, heart failure, kidney failure, chronic inflammatory disease, or cystitis.

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

32. The method of claim 28, further comprising the step of observing a change in urine color when more than one particle is excreted.

33. The method of claim 28, wherein each of the more than one particle is substantially cylindrical.

34. The method of claim 28, wherein each of the more than one particle floats in the urine.

35. The method of claim 28, wherein each of the more than one particle has a hollow core.

36. The method of claim 28, wherein each of the more than one particle has a solid core.

37. The method of claim 28, wherein the excipient portion comprises a biodegradable material.

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

39. The method of claim 28, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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 of claim 39, wherein the anti-infective agent is an antibacterial agent.

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

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

43. The method of claim 39, wherein the anti-infective agent comprises elemental silver, silver ions, silver salts, or silver coordination compounds.

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 fosfomycin degradation products generated in situ.

45. The method of claim 28, wherein the step of delivering the more than one connected particle into the subject's bladder includes intraurethral delivery.

46. ​​The method of claim 28, wherein a syringe is used in the step of delivering the more than one connected particle into the subject's bladder.

47. The method of claim 28, wherein the more than one particle remains in the second conformation for more than a week or longer.

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

49. The method of claim 28, wherein each of the more than one particle comprises a matrix and a pharmacologically active agent dispersed therein.

50. The method of claim 28, wherein each of the more than one particle is included in a coating on a core, the core containing a pharmacologically active agent dispersed therein.

51. The method of claim 28, wherein the more than one particle is dispersed in a liquid medium for delivery to the subject's bladder.

52. The method of claim 51, wherein the liquid medium comprises at least one selected from viscosity modifier, tension modifier, buffer, and dispersant.

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

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

55. The method of claim 28, wherein the step of delivering the more than one particle into the bladder of the subject further comprises disrupting the biofilm using the urethra or bladder.

56. The method of claim 28, wherein the first conformation of the more than one particle is a stacked arrangement.

57. The method of claim 28, wherein the first conformation of the more than one particle is a stacked arrangement with a diameter of about 4 mm or less.

58. The method of claim 28, wherein the second conformation of the more than one particle is a zigzag arrangement or a circular arrangement.

59. The method of claim 28, wherein the second conformation of the more than one particle is a zigzag arrangement or a circular arrangement with a diameter of about 10 mm or greater.

60. An intravesical drug delivery system comprising more than one particle, each particle having an excipient portion and an active agent, The particles mentioned above float in the urine.

61. The intravesical drug delivery system of claim 60, wherein the particles are substantially cylindrical.

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

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

64. The intravesical drug delivery system of claim 60, wherein the particle has a solid core.

65. The intravesical drug delivery system of claim 60, wherein the excipient portion comprises a biodegradable material.

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

67. The intravesical drug delivery system of claim 60, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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 of claim 67, wherein the anti-infective agent is an antibacterial agent.

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

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

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

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

73. An intravesical delivery system, the system comprising: a) Insert the tip. b) Main body c) Pressure source, and d) Loading the funnel, The intravesical preparation passes through the loading funnel, through the body, and exits the insertion tip into the subject's bladder.

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

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

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

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

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

79. The intravesical delivery system of claim 78, wherein the active agent is a medicament for treating urinary system disorders.

80. The intravesical delivery system of claim 78, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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 intravesical delivery system of claim 73, wherein the insertion tip comprises an inflatable balloon.

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

83. The intravesical delivery system of claim 73, wherein the insertion tip comprises a threaded locking ring assembly.

84. The intravesical delivery system of claim 83, wherein the threaded locking ring assembly is adjusted to the size of the subject's urethra.

85. The intravesical delivery system of claim 73, wherein the insertion tip comprises an internal sheath.

86. The intravesical delivery system of claim 73, wherein the insertion tip comprises more than one soft hook member.

87. The intravesical delivery system of claim 83, wherein the threaded locking ring assembly is adjusted to the size of the subject's urethra.

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

89. A method for delivering a substance or formulation into the bladder of a subject, the method comprising: a) Insert the tip of the catheter through the urethra and into the bladder. b) Fix the tip region, and c) Using a pressure source to force the substance or preparation from the loading funnel into the bladder.

90. The method of claim 89, wherein the substance or formulation comprises particles.

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

92. The intravesical delivery system of claim 88, wherein the particles are contained within two cylindrical structures connected by a tether.

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

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

95. The method of claim 92, wherein the active agent is a medicament for treating disorders of the urinary system.

96. The method of claim 92, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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.

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

98. The method of claim 89, further comprising the step of adjusting the length of the tip region of the catheter using a threaded locking ring kit.

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

100. The method of claim 89, wherein more than one soft hook member is used in the step of securing the tip region.

101. A method for delivering an active agent into the bladder of a subject, the method comprising: a) Insert the distal end of the lumen device through the patient's urethra and into the patient's bladder, wherein the opposite proximal end of the lumen device remains outside the patient; b) Secure the distal end of the lumen device; b) To drive more than one particle out of the lumen of the distal end of the lumen device, into the bladder, and out of the lumen. c) Remove the lumen device from the patient's urethra; as well as d) Allow more than one particle to degrade or dissolve, thereby releasing the active agent into the patient's bladder.

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

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

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

105. The method of claim 99, wherein each of the more than one particle has an excipient portion and an activator.

106. The method of claim 103, wherein the active agent is a medicament for treating disorders of the urinary system.

107. The method of claim 103, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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.

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

109. The method of claim 99, further comprising the step of adjusting the length of the tip region of the catheter using a threaded locking ring kit.

110. The method of claim 99, wherein an inner sheath is used in the step of securing the tip region.

111. The method of claim 99, wherein more than one soft hook member is used in the step of securing the tip region.

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

113. The method of claim 99, wherein the urinary disorder is one or more of the following: urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, inactive bladder, urinary retention, diabetes, heart failure, kidney failure, or cystitis.

114. The method of claim 99, further comprising the step of treating a disorder of the subject's urinary system.

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

116. The method of claim 99, wherein the particles are substantially cylindrical.

117. The method of claim 99, wherein the particles float in the urine.

118. The method of claim 99, wherein the particles comprise an excipient portion that has been degraded in the bladder.

119. The method of claim 116, wherein the excipient portion degrades over a period of more than one month.

120. The method of claim 103, wherein the active agent is a medicament for treating disorders of the urinary system.

121. The method of claim 103, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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.

122. The method of claim 103, wherein the active agent is an antibacterial agent, an antifungal agent, or an antiviral agent.

123. The method according to claim 103, wherein the activator comprises elemental silver, silver ions, silver salts, or silver coordination compounds.

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

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

126. The method of claim 103, wherein the particles are coated on a core, and the core contains the active agent dispersed therein.

127. The method of claim 99, wherein the particles are dispersed in a liquid medium for delivery to the subject's bladder.

128. The method of claim 125, wherein the liquid medium comprises at least one selected from viscosity modifier, tension modifier, buffer, and dispersant.

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

130. A system for intravesical administration of an active agent, the system comprising: a) More than one particle arranged in a first conformation, each particle containing an excipient portion and an active agent. b) wherein the more than one particle is configured to expand to a second conformation upon exposure to a fluid. c) wherein the more than one particle is configured to release an active agent from the more than one particle upon exposure to a fluid, and d) wherein the more than one particle is configured to separate into individual particles after a retention period in the fluid.

131. The system of claim 128, wherein each of the more than one particle is substantially cylindrical.

132. The system of claim 128, wherein each of the more than one particle floats in the urine.

133. The system of claim 128, wherein each of the more than one particle has a hollow core.

134. The system of claim 128, wherein each of the more than one particle has a solid core.

135. The system of claim 128, wherein the active agent is a medicament for treating disorders of the urinary system.

136. The system of claim 128, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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.

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

138. The system of claim 134, wherein the anti-infective agent is an antifungal agent.

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

140. The system of claim 134, wherein the anti-infective agent comprises elemental silver, silver ions, silver salts, or silver coordination compounds.

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

142. The system of claim 128, wherein each particle is shaped as a cylinder, sphere, teardrop, horseshoe, pretzel, rod, pyramid, cube, prism, or drug-loaded cannula.

143. A method of treating a disease, the method comprising administering the system of claim 128 intravesically.

144. The method of claim 141, wherein the disease is urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, inactive bladder, urinary retention, diabetes, heart failure, kidney failure, or cystitis.

145. A method for treating and / or preventing a disease in a subject, the method comprising: a) Provide more than one particle, each particle containing a first particle that is joined to a second particle via a connector. b) Delivering more than one particle into the subject's bladder. c) Allow the connectors and / or particles to degrade during the retention phase. d) Allows the excretion of the connector and particles during urination. Each of the more than one particle contains an excipient portion and an active agent, and the active agent is released into the bladder during at least a portion of the retention phase.

146. The method of claim 143, wherein the disease is urinary tract infection, bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disorder, overactive bladder, inactive bladder, urinary retention, diabetes, heart failure, kidney failure, or cystitis.

147. The method of claim 143, further comprising the step of diagnostic imaging.

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

149. The method of claim 143, wherein each of the more than one particle is substantially cylindrical.

150. The method of claim 143, wherein each of the more than one particle floats in the urine.

151. The method of claim 143, wherein each of the more than one particle has a hollow core.

152. The method of claim 143, wherein each of the more than one particle has a solid core.

153. The method of claim 143, wherein the excipient portion comprises a biodegradable material.

154. The method of claim 143, wherein the active agent is a medicament for treating disorders of the urinary system.

155. The method of claim 143, wherein the active agent is one or more of the following: an anti-infective agent, an anesthetic, an analgesic, a diuretic, an anti-inflammatory agent, a procoagulant 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.

156. The method of claim 143, wherein the step of delivering the more than one particle into the bladder of the subject includes intraurethral delivery.

157. The method of claim 143, wherein a syringe is used in the step of delivering the more than one particle into the subject's bladder.

158. The method of claim 143, wherein the retention period is longer than one month.

159. The method of claim 143, wherein each of the more than one particle comprises a matrix and a pharmacologically active agent dispersed therein.

160. The method of claim 143, wherein each of the more than one particle is included in a coating on a core, the core containing a pharmacologically active agent dispersed therein.

161. The method of claim 143, wherein the more than one particle is dispersed in a liquid medium for delivery to the subject's bladder.

162. The method of claim 158, wherein the liquid medium comprises at least one selected from viscosity modifier, tension modifier, buffer, and dispersant.

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

164. The method of claim 143, wherein the active agent is released into the bladder in a substantially stable state.

165. The method of claim 143, wherein the step of delivering the more than one particle into the bladder of the subject further comprises disrupting the biofilm using the urethra or bladder.

166. The method of claim 143, wherein the more than one particle is applied to the patient's bladder in a stacked arrangement.

167. The method of claim 143, wherein the first of the more than one particle provides buoyancy, and the second of the more than one particle is provided for applying the active agent.

168. The method of claim 1, wherein one or more of the more than one particle has a hollow core.

169. The method of claim 1, wherein one or more of the more than one particle has a solid core.

Images