Formulations for treating urinary system disorders

Abstract

Embodiments include intravesical therapies for the treatment of diseases such as urinary system disorders. A controlled release drug delivery system is administered into the bladder of a patient. The controlled release particles in the formulation may include a pharmacologically active agent and an excipient (i.e., a controlled release carrier). The buoyancy and size of the particles in the urine ensure that the formulation remains within the bladder of the patient and releases the active agent into the bladder through the duration of an extended drug delivery period. Also described are methods of treating urinary system disorders by intracapsular administration of the particulate formulations, and including methods of treating urinary system infections, bladder cancer, incontinence, and other urinary system disorders.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 332,639, filed on April 19, 2022. The contents of the above application are incorporated herein by reference. Field of the Invention

[0003] The present invention relates generally to the treatment of urinary disorders and, more particularly, to formulations and methods for the intravesicular administration of pharmacologically active agents to treat or prevent disorders of the urinary system.

[0004] background

[0005] 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 a UTI affects the upper urinary tract, it is called a kidney infection (i.e., pyelonephritis). Symptoms of a UTI include painful urination, frequent urination, and a feeling of needing to urinate despite an empty bladder. The most common cause of infection is E. coli, although other bacteria or fungi can sometimes be the cause. Risk factors include female anatomy, sexual intercourse, diabetes, obesity, and family history. In uncomplicated cases, UTIs are treated with a short course of antibiotics (e.g., nitrofurantoin).

[0006] The prevalence of UTI risk increases with age. They are especially common in older adults who use catheters or live in nursing homes or other full-time care facilities. Other conditions common in older adults (e.g., Alzheimer's disease, Parkinson's disease, and diabetes) can lead to urinary retention or neurogenic bladder, which increases the risk of UTIs. According to recent studies, more than a third of all infections in people in nursing homes are UTIs. More than 10% of women over the age of 65 report having had a UTI in the past year. This number increases to nearly 30% in women over the age of 85. As men age, they also tend to experience more UTIs. In many cases, chronic urinary tract infections require ongoing medication, which leads to a gradual increase in tolerance levels to antibiotics and ultimately kidney problems.

[0007] If not treated promptly or appropriately, the infection from a UTI can spread. A UTI can eventually lead to a bladder infection. This presents a risk of the infection spreading to the kidneys via the ureters, which can lead to more serious consequences, including renal failure and sepsis (i.e., 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.

[0008] UTIs and complications caused by UTIs are also costly and often require hospitalization. In many cases, UTIs are treated only after the infection has developed and become symptomatic. Current treatments designed to prevent the formation of UTIs require continuous preventive oral medications that have side effects common to long-term medication. In addition, long-term antibiotic use can lead to drug-resistant bacteria. In many cases, UTIs reduce the quality of life, especially when kidney damage leads to kidney failure, requiring dialysis or transplantation of a donor kidney.

[0009] For conditions associated with urinary tract infections, bacterial clearance improves with complete bladder emptying. If the bladder cannot be emptied effectively, there is a urine retention volume known as post-void residual (PVR), which can serve as a bacterial reservoir for subsequent and persistent infections. Detecting and minimizing this PVR faces several challenges. PVR can be measured indirectly by ultrasound assessment. However, this method has limited accuracy, which depends on body habits and volumes of less than 50ml and greater than 250ml. Alternatively, PVR can be measured and removed by draining the remaining urine via a catheter inserted retrogradely through the urethra. However, this method can be painful and psychologically traumatic.

[0010] PVR can be reduced by eliminating the main cause of bladder outlet obstruction, such as enlarging the area of ​​urethral stricture. However, this approach usually requires a separate procedure or surgery. Removing PVR without treating the underlying cause of retained urine is a temporary operation because the volume will re-accumulate in the next voiding cycle. Without a procedure or surgery, this volume will remain and may become a potential reservoir for future and persistent infection.

[0011] Conventionally, UTIs are treated with oral antibiotics. High doses of antibiotics are required so that effective amounts reach the urinary tract. With systemic delivery of drugs to treat UTIs, the volume of distribution of therapy is equal to the total amount of urine that enters the bladder. Therefore, therapy becomes ineffective with each emptying of the bladder and requires continuous replenishment. In other cases, the drug target may be limited (i.e., the bladder wall), but the drug target is not physically accessible without increasing the drug concentration in the urine to the desired therapeutic concentration.

[0012] There is a need for improved methods of preventing and treating UTIs. Such methods should target bacteria within the bladder / urinary tract without the side effects or risks associated with oral administration of oral antibiotics. The compositions and methods described herein meet these objectives and may particularly benefit patients at increased risk of UTIs, such as elderly patients or incapacitated patients. The systems and methods described herein may also be used to treat other diseases, such as, for example, overactive bladder and other urinary disorders. SUMMARY OF THE INVENTION

[0014] The invention described and claimed herein has many attributes and embodiments, including but not limited to those set forth or described or mentioned in this brief summary. The invention described and claimed herein is not limited to or by the features or embodiments identified in this summary, which are included for purposes of illustration and not limitation.

[0015] Embodiments include intravesicular administration (i.e., local drug delivery in the bladder) systems with adjustable and controlled drug release via non-permanent carriers. In one aspect, the product (i.e., carrier or controlled release carrier) remains floating in the urine to allow retention in the bladder. In one aspect, the active agent (i.e., drug) is retained in the bladder to provide a therapeutic drug target concentration over the duration of therapy.

[0016] Embodiments include systems and methods for treating diseases such as urinary disorders. In one aspect, the systems and methods include a pharmaceutical formulation for intravesicular administration of a pharmacologically active agent. The formulation may include particles, each particle having an excipient portion and an active agent. In one aspect, the excipient portion is a degradable material.

[0017] The agent can be, for example, an antibiotic, an anticancer agent. The disease can be, for example, an infection (e.g., UTI), overactive bladder, interstitial cystitis, anticoagulant disease, underactive bladder, urine retention, diabetes, heart failure, renal failure, or cancer (e.g., bladder cancer, kidney cancer, ureteral cancer, or urethral cancer).

[0018] In one aspect, the agent is an anti-infective agent (i.e., an antibacterial, antiviral, antifungal, or antiparasitic agent). In one aspect, the active agent is an antimicrobial agent, such as, for example, silver sulfadiazine, amikacin, tobramycin, cefoperazone-sulbactam, cefoperazone-avibactam, cefoperazone-tazobactam, piperacillin-tazobactam, chlorhexidine, doripenem, ertapenem, imipenem, meropenem, cefepime, cefoxitin, ceftazidime, tigecycline, colistin, polymyxin B, or aztreonam.

[0019] In aspects, the particles are cylindrical or spherical. In aspects, the particles have a hollow core. In aspects, the particles have an average diameter of about 2 mm to 8 mm. Alternatively, the particles have an average diameter of about 2 mm to 4.5 mm or about 2 mm to 6 mm.

[0020] In aspects, the particles comprise fatty acids and / or waxes. In aspects, a mucoadhesive material is included in the particles.

[0021] In aspects, the particles comprise a matrix, and the pharmacologically active agent is dispersed in the matrix.

[0022] In one aspect, the controlled release carrier gradually dissolves, degrades or erodes in urine to release the active agent from the microparticles in the bladder. In one aspect, the particles are modified to modulate the time period of drug delivery.

[0023] In aspects, a primary population of particles and a secondary population of particles are implanted, each having a different quality (eg, a different active agent).

[0024] In aspects, the particles include a color indicator (eg, methylene blue) that is excreted in the urine and allows the patient to visualize one or more stages of treatment.

[0025] In aspects, the system includes a first subset of particles and a second subset of particles, each having a different quality (eg, size, shape, composition, active agent, etc.).

[0026] In aspects, the product is cleared from the bladder over time, for example, by behavioral changes (loss of buoyancy) and urination from the bladder, or mechanical changes (micronization, surface erosion) or chemical changes (biodegradable), within two to six months after implantation. In aspects, the product is delivered to the patient via the urethra using a syringe having a diameter of less than six millimeters. In aspects, the product and its materials are biocompatible.

[0027] In embodiments, the density of the carrier particles is less than the urine specific gravity of 1.030.

[0028] Embodiments also include methods of extending the retention duration of a pharmaceutical agent in the bladder. In aspects, the retention duration can be adjusted / modulated by, for example, changing the shape, size, excipient composition, and / or production method of the particles.

[0029] In embodiments, the active agent is locally released in the urine in the bladder at a zero-order steady state at or above therapeutic levels for a period of time (e.g., up to three months from implantation). In aspects, the active agent is released for a duration appropriate for the particular disease to be treated (e.g., about one week, about two weeks, about three weeks, about one month, about six weeks, about two months, about three months, about four months, about five months, about six months, or longer).

[0030] Embodiments also include methods of treating an infection (eg, a UTI). In aspects, the method comprises intravesicularly administering an effective amount of a composition comprising the controlled release particles described herein conjugated to an antibiotic (eg, amikacin).

[0031] Embodiments include methods of treating bladder cancer (eg, urothelial carcinoma). In aspects, the method includes intravesicularly administering an effective amount of a composition including a controlled release particle described herein conjugated to an anti-tumor agent (eg, a taxane).

[0032] Additional embodiments include methods of treating or preventing UTI by administering the formulations described herein. In aspects, the methods are for patients at risk for and / or with a history of UTI.

[0033] Thus, embodiments include methods of treating and / or preventing disease. The methods may include the steps of: (a) providing more than one particle, each particle having a buoyancy that causes the more than one particle to float in urine contained in a bladder, (b) delivering the more than one particle to a subject's bladder, and (c) allowing the more than one particle to be excreted and / or degraded over a period of time. Each particle may include an excipient portion and an active agent, and wherein the active agent is released into the bladder.

[0034] In aspects, the disease is urinary tract infection (UTI), bladder cancer, kidney cancer, ureteral cancer, urethral cancer, anticoagulant disease, overactive bladder, underactive bladder, urinary retention, diabetes, heart failure, renal failure, or cystitis.

[0035] In aspects, the active agent is released into the urine in a substantially stable state. In aspects, the step of delivering more than one particle into the bladder disrupts the biofilm of the urethra or bladder.

[0036] In aspects, the method includes the step of diagnostic imaging.

[0037] definition

[0038] In this specification, reference to "an embodiment / aspect" or "an embodiment / aspect" means that a particular feature, structure or characteristic described in conjunction with the embodiment / aspect is included in at least one embodiment / aspect of the present disclosure. The use of the phrases "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 is it a separate or selectable embodiment / aspect that is mutually exclusive with other embodiments / aspects. In addition, various features are described that may be exhibited by some embodiments / aspects but not by other embodiments / aspects. Similarly, various requirements are described that may be requirements of some embodiments / aspects but not requirements of other embodiments / aspects. Embodiments and aspects may be used interchangeably in some cases.

[0039] The terms used in this specification generally have their ordinary meaning in the art, in the context of the present disclosure, and in the specific context in which each term is used. Certain terms used to describe the present disclosure are discussed below or elsewhere in this specification to provide additional guidance to practitioners regarding the description of the present disclosure. It should be understood that the same thing can be stated in more than one way.

[0040] Therefore, optional language and synonyms can be used for any one or more terms discussed herein. Whether a term is elaborated or discussed herein does not have any special meaning. Synonyms for certain terms are provided. The description of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any term discussed herein, is illustrative only and is not intended to further limit the scope and meaning of the present disclosure or any exemplary term. Likewise, the present disclosure is not limited to the multiple embodiments given in this specification.

[0041] Without further intention to limit the scope of the present disclosure, the following provides examples of instruments, devices, methods and related results thereof according to the embodiments of the present disclosure. It should be noted that, for the convenience of the reader, titles or subtitles can be used in the examples, which should never limit the scope of the disclosure. Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. In the event of a conflict, the present document including the definition will prevail.

[0042] The term "overactive bladder" or "OAB" refers to a group of urinary symptoms (not a disease). The most common symptom is a sudden, uncontrolled need or urge to urinate. Some people will leak urine when they feel the urge. Another symptom is the need to urinate many times during the day and night. OAB can be described as a constant urge to urinate. Leaking urine is called "incontinence."

[0043] The term "stress urinary incontinence" or "SUI" refers to another common bladder problem. Subjects with SUI leak urine when they sneeze, laugh, or perform other physical activities.

[0044] The terms "interstitial cystitis," "IC," or "painful bladder 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 feel mild discomfort, pressure, or tenderness in the pelvic area. Others may have severe bladder pain or struggle with urinary urgency, the sudden need to urinate, or urinary frequency, the need to urinate more often. Health care professionals diagnose IC by ruling out other conditions with similar symptoms.

[0045] The term "active agent" or "active ingredient" refers to a substance, compound or molecule that is biologically active or otherwise induces a biological or physiological effect on a subject to which it is administered. In other words, an "active agent" or "active ingredient" refers to one or more components of a composition to which all or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, a component of a composition to which all or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, a component of a composition to which an additional portion of the composition is attributed and / or to which other effects of the composition are attributed.

[0046] The term "pharmaceutically acceptable" means that it is not biologically or otherwise undesirable material, i.e., the material can be incorporated into a pharmaceutical composition as provided herein, and does not cause any substantial undesirable biological effect or interact with any other component of the composition in a harmful manner. When the term "pharmaceutically acceptable" is used to refer to a solid carrier or semisolid carrier, a liquid vehicle or other excipient, i.e., any inactive ingredient herein, this means that the carrier or excipient meets the required standards for toxicology and production testing, and / or it is included in the inactive ingredient guide formulated by the U.S. Food and Drug Administration and is designated as "Generally Considered to be Safe (Generally Considered as Safe)" ("GRAS").

[0047] The term "controlled release" refers to a mechanism of drug delivery, wherein the administration of a preparation containing an active agent or its fraction does not result in 100% of the active agent being released immediately. This allows the drug level to remain at an effective level over a period of time. The term can be 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, pulse release and delayed release preparations, and preparations combining two or more types of release profiles, such as the immediate release of a bolus dose, followed by pulse release or sustained release. "Sustained release" (synonymous with "extended release") refers to a preparation providing a gradual release of an active agent over an extended period of time, and preferably, although not necessarily, produces a substantially constant dose level in a distributed volume (e.g., urine, bladder, total body water, etc.), and is generally referred to as "zero-order" release. "Controlled release" also includes "delayed release," which refers to a formulation that, after 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 form herein is generally a sustained release type.

[0048] The term "particle" or "microparticle" refers to a carrier or controlled release carrier described herein that is formulated to contain a pharmacologically active agent. The particles can be substantially spherical, cylindrical or rod-shaped or have some other shape. The particle size is given as the average particle size in a particle population. The particle size distribution in a particle population is relatively narrow (i.e., the specified average particle size is associated with a fairly low deviation standard, which is typically less than 30%, such as less than 20% or less than 15%). The particles in the formulation may or may not have substantially the same shape and size.

[0049] The term "intravesical administration" or "intravesical therapy" refers to treatment in which the therapeutic agent is placed directly into the bladder (ie, through a catheter) rather than given orally or injected into a vein. Similarly, intravesical drugs are administered directly into the bladder via a urinary catheter.

[0050] The term "mucoadhesion" refers to adhesion between two materials, one of which is a mucosal surface. Mucoadhesive drug delivery systems extend the residence time of a dosage form at the site of application or absorption. Mucoadhesive drug delivery systems interact with the mucus layer and mucin molecules covering the mucosal epithelial surface and increase the residence time of the dosage form at the absorption site.

[0051] The term "spherical" refers herein to a precisely spherical particle, or more generally, to a particle having a rounded surface, which may or may not be substantially spherical.

[0052] The terms "average diameter", "average longest dimension" and "particle size" are used interchangeably herein. As used herein, the particle size is given by the average diameter of spherical particles and the average longest dimension of non-spherical particles. It should be noted that the term "average diameter" technically corresponds to substantially spherical particles; however, other particle shapes can also be incorporated into the particle formulation, provided that the particles have at least one dimension (i.e., at least one average dimension in the entire particle population) greater than 2.0 mm, such as in the range of 2.0 mm to about 12.0 mm, such as about 2.5 mm to about 6.5 mm, such as 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 described above. Elongated particles, such as cylindrical particles or rod-shaped particles, can, for example, have a length of about 9.0 and still be narrow enough to pass through a catheter and urethral opening.

[0053] The terms "effective amount" and "therapeutically effective amount" of an active agent, combination of active agents, or pharmaceutical formulation refer to a nontoxic amount or concentration sufficient to produce the desired result. The exact amount required will vary from subject to subject, depending on factors such as the age, weight, and general condition of the subject, the specific condition being treated, the severity of the condition, the specific active agent, and the judgment of the clinician.

[0054] The term "urinary system" is used in a conventional sense to refer to the lower as well as the upper urinary tract, and thus includes the bladder, urethra, kidneys, and ureters.

[0055] The term "disorder" refers to a clinically relevant physiological condition and thus includes symptomatic conditions or asymptomatic conditions regardless of etiology. Thus, a disorder includes an adverse condition caused by disease or injury. The disorder to which the present invention relates is a disorder of the urinary system.

[0056] "Drug delivery period" refers to the period of time, typically an extended period of time, over which the pharmacologically active agent is released from a formulation or a fraction thereof.

[0057] The term "substantially" represents the possibility of slightly deviating from the stated chemical or physical properties, and allows a difference of at most about 20%, or at most about 10%, or at most about 5% between the actual chemical or physical properties and the stated chemical or physical properties. For example, the term "substantially homogeneous (homogeneous)" refers to such a material in the form of a mixture of two or more components, wherein the material is substantially uniform as a whole, and any two discrete regions in the material differ at most about 20%, or at most about 10%, or at most about 5% in terms of the chemical or physical properties of the material, the chemical or physical properties of the material such as the presence or absence of components, the concentration of components, the degree of hydrophilicity or lipophilicity, density, crystallinity or other properties. Similarly, the term "approximately (approximately)" or "about (about)" in any context is intended to mean a possible change of at most about 20%. Typically, the term means a possible change of at most about 10% or at most about 5%.

[0058] The term "subject" or "patient" refers to any single animal in need of treatment, 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.

[0059] As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, etc. that are 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 supplementary, additional or enhanced therapeutic functions.

[0060] As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0061] The terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting pathology or symptoms of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptoms); (2) ameliorating a disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or exhibiting pathology or symptoms of the disease, condition or disorder (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0062] The term "specific gravity" refers to the ratio of the density of a material to the density of water at 4°C. It is therefore a relative quantity without units. The specific gravity of urine refers to the electrolytes and osmolality of the urine. The normal range of urine specific gravity is 1.005 to 1.030. In the context of clinical pathology, specific gravity is a urinalysis parameter commonly used to assess renal function and can help diagnose a variety of renal diseases.

[0063] The term "effervescence" refers to the escaping of gas from an aqueous solution and the fizzing or bubbling (fizzing) produced by the release. In aspect, the particles described herein include effervescent substances. For example, the effervescent reaction between carbonate / bicarbonate and citric acid / tartaric acid releases carbon dioxide, which is trapped in the gelatinous hydrocolloid layer of the system, thereby reducing its specific gravity and making it float over time. Resin beads can be loaded with bicarbonate and coated with ethylcellulose. The coating (which is insoluble but permeable) allows water to penetrate. Therefore, carbon dioxide is released, causing the beads to float in urine. Another method is to directly incorporate sodium bicarbonate into a polymer and a drug melt. When urine / water contacts sodium bicarbonate, the preparation floats.

[0064] The term "biocompatibility" refers to the ability of a material to mount an appropriate host response under specific circumstances. A biocompatible material will not have toxic or deleterious effects on a biological system. For example, an implanted device will exist harmoniously with tissues without causing deleterious changes.

[0065] the term Refers to a NF grade, hard fat suppository base in the form of small lozenges containing vegetable derived glycerides that have a history of use in a range of APIs.

[0066] The term "amikacin" refers to an antibiotic drug used for a variety of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections (UTIs). It is also used to treat multidrug-resistant tuberculosis. It is usually administered by injection into a vein using an IV or by injection into a muscle.

[0067] The term "excipient" refers to a pharmacologically inert ingredient intentionally added to a drug product for a variety of functional effects, such as to enhance dosage form bulk or size, disintegration of solid dosage forms, binding of particulates, lubrication during processing, taste masking, or modifying drug release.

[0068] The term "zero order" refers to a delivery system that releases a drug at a constant rate (i.e., the release rate is independent of the concentration or amount of the drug retained in the delivery system). When a constant amount of drug is eliminated per unit time, but the rate is independent of the concentration of the drug, the drug release kinetics is referred to as zero-order kinetics. Zero-order drug delivery systems (DDS) can overcome the problems faced by immediate release and first-order systems by releasing the drug at a constant rate, thereby maintaining the drug concentration within the therapeutic window over an extended period of time.

[0069] The term "first order" refers to a 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 a drug over an extended period of time after administration of a single dose.

[0070] The term "therapeutic index", "TI" or "therapeutic ratio" refers to a quantitative measure of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes a therapeutic effect to the amount that causes toxicity. The therapeutic window or safety window refers to the dose range optimized between efficacy and toxicity, achieving maximum therapeutic benefit without causing unacceptable side effects or toxicity. The TI is determined by the incidence / severity of adverse reactions that are incompatible with the target indication (e.g., the toxic dose in 50% of subjects, the TD 50 ) is related to the dose that results in the desired pharmacological effect (e.g., the effective dose in 50% of subjects, ED 50 ) is calculated by the ratio.

[0071] Other technical terms used herein have their ordinary meanings in the technologies in which they are used, as exemplified by various technical dictionaries. The specific values ​​and configurations discussed in these non-limiting examples may vary, and are cited only to illustrate at least one embodiment, and are not intended to limit the scope thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 The method for preparing particles as described in Example 4 is schematically illustrated.

[0074] Figure 2 The results of the evaluation of the antimicrobial efficacy of silver sulfadiazine (SSD) and cefpodoxime as described in Example 2 are presented.

[0075] Figure 3 is a graph illustrating the percentage of SSD released from particles of the present invention over time as determined in Example 5. As discussed in the Examples, the results indicate that a zero order release profile is achieved.

[0076] Figure 4is a graph illustrating the cumulative amount of SSD released over time as a percentage of the amount of drug initially present for a glyceryl tristearate (GTS) / SSD particle formulation prepared in phosphate buffered saline (PBS) at pH 7.5 as explained in Example 6.

[0077] Figure 5 is a graph illustrating the cumulative amount of SSD released over time as a percentage of the amount of drug initially present for a glyceryl tristearate (GTS) / SSD particle formulation prepared in artificial urine medium at pH 7.5 as explained in Example 6.

[0078] Figure 6 The graph shows the results obtained for the degradation assay of Example 7, in which carrier degradation of GTS / SSD particles over time was assessed.

[0079] Figure 7 Scanning electron microscope (SEM) images of the particles evaluated in Example 7 are provided and show that the surface of the microspheres appeared unchanged after seven days.

[0080] Figure 8 A list of vectors and vehicles evaluated as described in Example 8 is provided.

[0081] Fig. 9 Results of mucoadhesive testing performed as described in Example 8 are provided.

[0082] Fig.10 The graph shows the mucoadhesion and degradation rates observed for particles formulated with different controlled release vehicles.

[0083] Fig.11 The figure shows the Fig.10 Mucoadhesive capacity of particles formulated with several different controlled release vehicles identified in.

[0084] Fig.12 The graph shows the effect of carrier loading on drug release rate for particles prepared with SSD and stearyl alcohol as described in Example 8.

[0085] Fig.13 Results of buoyancy studies conducted with various controlled release vehicles and combinations, also as described in Example 8, are provided.

[0086] Fig.14 The retention of the formulation over time was simulated, also as described in Example 8.

[0087] Fig.15A A cylindrical hollow rod is depicted.

[0088] Fig. 15BThe buoyancy of the rods (cylindrical and solid) after 14 days is shown.

[0089] Fig. 15C Shown is the effect of carrier loading (SSD in μg / ml versus time) for particles prepared as solid rods and rods with a hollow core.

[0090] Fig.15D The effect of carrier loading (percent release versus time) is shown for particles prepared as solid rods and rods with a hollow core.

[0091] Fig.16A The chemical structure of amikacin is shown.

[0092] Fig. 16B The chemical structures of amikacin and pamoic acid are shown.

[0093] Fig. 16C The graph shows the release rate of amikacin over time (μg / ml vs. time).

[0094] Fig.17A The shape, volume and surface area of ​​the particles tested are shown.

[0095] Fig. 17B The graph shows the effect of different shapes (cylinders and rods of different sizes) on drug release (percent released versus time).

[0096] Fig. 17C The graph shows the effect of different shapes (cylinders and rods of different sizes) on drug release (concentration versus time).

[0097] Fig.18A The graph shows the effect of different excipients on drug release (percent released versus time) using spheres.

[0098] Fig.18B The graph shows the effect of different excipients on drug release (concentration vs. time) using spheres.

[0099] Fig.19A The graph shows the effect of different excipients on drug release (percent released versus time) using cylinders.

[0100] Fig.19B The graph shows the effect of different excipients on drug release (concentration vs. time) using cylinders.

[0101] Fig. 20A The graph shows the effect of different excipients on drug release (percent released versus time) using spheres.

[0102] Fig. 20BThe graph shows the effect of different excipients on drug release (percent released versus time) using spheres.

[0103] Fig.21A The graph shows the effect of using different amounts of PAA in the formulation on drug release (μg / ml vs. time).

[0104] Fig. 21B The graph shows the effect of using different amounts of PAA in the formulation on drug release (percent released versus time).

[0105] Fig.22A The graph shows the difference in drug release over time (μg / ml vs. time) for stirred and homogenized particles.

[0106] Fig. 22B The graph shows the difference in drug release over time (percent released vs. time) for stirred and homogenized granules.

[0107] Fig. 22C is a comparison of the results for particles prepared by (a) stirring and (b) homogenization.

[0108] Fig.23 The graph shows the release profile of amikacin from the particles (μg / ml vs. time).

[0109] Fig.24 The graph shows the effect of formulation process variables.

[0110] Fig.25 The figure shows a rapid release formulation of amikacin.

[0111] Details

[0112] 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 technology as claimed. Additional features and advantages of the subject technology are set forth in the following description, and in part will be apparent from the description, or may be learned through practice of the subject technology. The advantages of the subject technology will be realized and obtained through the structures particularly pointed out in its written description and claims.

[0113] Embodiments of the present invention include platforms and methods for treating diseases associated with the urinary system. Intravesicular particles deliver drugs to specifically increase drug concentrations in the bladder / urethra. This avoids the need for oral medications and systemic administration. With intravesicular administration, lower doses of antibiotics are effective and therefore there are fewer side effects. With controlled drug release, an improved therapeutic window is also possible.

[0114] Therefore, the present invention provides a preparation and method for controlled release of pharmacologically active agents in the bladder to treat disorders of the urinary system. The preparation comprising particles containing active agents is administered to the subject via an intravesical route (i.e., through the urethra or via bladder injection). Because the particles float in the urine, they float to the surface of the urine present in the bladder. The particles can be retained in the bladder over the duration of the extended drug delivery time period. As they gradually degrade, the particles gradually dissolve / rupture and are discharged in the bladder.

[0115] In aspects, the type of particles used (e.g., size, shape, composition, and method of generation) can be selected based on the proposed treatment. For example, two millimeter cylindrical particles (with antibiotic active agents) may be optimal for treating female patients with UTI. These relatively large particles (where 2 mm is the average longest dimension) can be retained in the bladder in three ways. First, most of the particles in the formulation (i.e., greater than about 90%) float in the urine. During the first half of the excretion cycle, when the urethral opening is at its maximum, the buoyancy keeps the particles away from the urethral opening. Second, as the bladder empties and the urethral opening gradually narrows, in the second half of the excretion cycle and as the excretion approaches completion, the particle size is wider than the narrowed urethral opening. Third, at the end of the excretion cycle (when the urethral opening narrows and the floating particles are brought to the level of the urethral opening), the particles tend to gather in the bladder and thereby prevent the particles from flowing out.

[0116] In aspects, the particles may include a mucoadhesive material. During voiding, the bladder contracts, and the thick, irregular mucosal tissue (i.e., folds) on the inner wall of the bladder may trap the microparticles in the resulting folds. During a series of cycles of refilling and emptying the bladder, the active agent is continuously released within the bladder. In addition, the particle size, degradation or aggregation of the microparticles and other factors may be varied to promote retention within the bladder without necessarily trapping the microparticles in the folds when the bladder contracts. Any of these retention means may be used in combination, and some retention means may exhibit synergy in terms of enhancing the mechanical process of the optional retention means.

[0117] Another benefit involves the penetration of biofilms. Contact between the particles and the inner wall of the bladder or urethra and particle movement within the bladder can disrupt biofilms. The particles can cause turbulence, preventing biofilm formation and promoting mechanical disruption of any already existing biofilm, which in turn reduces the likelihood of bacterial cells adhering to the biofilm matrix. By disrupting biofilms in the bladder and urethra, the formulations and methods can further minimize or eliminate bacterial growth within the bladder and urethra.

[0118] Typically, the pharmacologically active agent is a drug used to treat a disorder of the urinary system (i.e., a disorder of the bladder, ureters, urethra, kidneys, or a combination). The choice of the pharmacologically active agent incorporated into the formulation depends on the specific disorder being treated. Urinary tract infections, particularly treatment of complicated urinary tract infections, require the administration of an anti-infective agent, which is an antibacterial agent when the urinary tract infection is a bacterial infection. According to some embodiments, the antibacterial agent is elemental silver, silver ions, silver salts, or silver coordination compounds.

[0119] The preparation can also be used to treat urinary disorders other than bacterial infections, in which case the pharmacologically active agent is a drug other than an antibacterial agent. The active agent can be an antifungal or antiviral agent; a chemotherapeutic agent; an anti-inflammatory agent; an anesthetic; an analgesic; a diuretic; a procoagulant or anticoagulant; a biological product; an agent for treating incontinence; a renin-angiotensin-aldosterone system (RAAS) inhibitor; an agent for treating kidney stones; or any other pharmacologically active agent that is effective in treating urinary disorders. In another aspect, the active agent is a contrast agent for diagnosis and monitoring.

[0120] The particles (i.e., controlled release carriers) can include a variety of materials that allow them to float in the bladder (i.e., float in urine). Suitable carriers for allowing the particles to float in urine provide a particle specific gravity of less than about 1.03, more typically less than about 1.005. Typically, although not necessarily, and depending on the active agent and any excipients present, this means that the carrier itself has a specific gravity of less than about 1.03, such as less than about 1.005.

[0121] The controlled release carrier includes materials that not only provide buoyancy within the bladder but also promote retention of the particles by the bladder wall (i.e., mucoadhesive materials). The particle material may be selected from waxes; 24 Fatty acid esters of fatty acids; C8-C 24 Fatty acids; C8-C 24 Fatty alcohol; hydroxylated C8-C 12 Alkanes; polymers and copolymers of hydroxylated vinyl monomers; polymers and copolymers of carboxylated vinyl monomers; cellulosic polymers and derivatives thereof; and combinations of any of the foregoing. In embodiments where two or more mucoadhesive materials are used in combination, the combination may include a blend of two or more mucoadhesive materials of the same type (e.g., two or more waxes, or two or more fatty acid esters) or a combination of two or more different types of mucoadhesive materials (e.g., triglycerides and fatty alcohols).

[0122] Thus, in addition to buoyancy and larger sized particles (ie, particles having an average diameter greater than 2.0 mm), mucoadhesion can help ensure that the particles are retained within the bladder to provide sustained release of the active agent over an extended drug delivery period.

[0123] According to further embodiments, the controlled release carrier comprises a matrix, and the pharmacologically active agent is dispersed in the matrix. According to other embodiments, the particle is a coated core-type controlled release dosage form, wherein the controlled release carrier coats a core containing the active agent, or wherein the active agent coating surrounds a core of the controlled release carrier.

[0124] In any of these embodiments, in addition to providing buoyancy and retention, the controlled release carrier can be selected so that it gradually dissolves, degrades or erodes in urine to gradually release the pharmacologically active agent from the particles into the bladder.

[0125] In another embodiment, the particles are designed to agglomerate within the bladder. In one example of such a formulation, the microspheres can be hemispherical, agglomerating from plane to plane to provide a sphere of particles within the bladder.

[0126] In another embodiment, the preparation includes a first subset of particles and a second subset of particles. The first subset of particles and the second subset of particles may differ in two or more aspects of average diameter (or in one or more other dimensions), shape, buoyancy, deformability, or such properties. According to some embodiments, the first subset of particles and the second subset of particles differ in size. According to other embodiments, the first subset of particles and the second subset of particles differ in buoyancy. In still another embodiment, the first subset of particles and the second subset of particles differ in both size and buoyancy. In each of the above examples, it is generally desired that at least 90% of the particles of the preparation are floating.

[0127] According to another embodiment, the first subset of particles, the second subset of particles, or both the first subset of particles and the second subset of particles are reversibly deformable. In some embodiments, the first subset of particles, the second subset of particles, or both the first subset of particles and the second subset of particles are deformable to the extent that they allow flow within a chute having an inner diameter in the range of about 4 mm to about 6 mm, i.e., the diameter of a standard intrasaccular catheter.

[0128] In any of the foregoing embodiments, the second subset of particles may include a different pharmacologically active agent, a different amount of the same or different pharmacologically active agent, a different controlled release carrier, a different amount of a controlled release carrier, or have a different controlled release profile relative to the first subset of particles.

[0129] The particles can be stored in a solution (i.e., a liquid vehicle) and applied in a solution (i.e., a liquid vehicle). Therefore, in another embodiment, the preparation further includes a liquid vehicle in which the particle group is dispersed. The liquid vehicle generally includes one or more excipients (i.e., at least one of a viscosity modifier, a tension modifier, a buffer, and a dispersant). Since the preparation is intended for intracapsular administration, the liquid vehicle should be suitable for delivery via this approach. As will be appreciated by those of ordinary skill in the art, low-viscosity liquid vehicles are generally not suitable for intracapsular administration; the liquid vehicle used in the preparation should have a viscosity lower than the viscosity of castor oil or mineral oil, for example, within the range of normal body temperature (about 36° C. to about 37° C.). In addition, the use of hydrophilic vehicles or components should be avoided because they may impair the buoyancy of particles in urine.

[0130] In another embodiment, the present invention provides a controlled release pharmaceutical formulation for intravesicular administration to a subject to treat a bacterial infection of the bladder, which formulation may include:

[0131] (a) a population of particles having an average diameter in the range of 2.5 mm to 4.0 mm and an average specific gravity less than 1.005, wherein the particles comprise from about 50 wt.% to about 95 wt.% of a controlled release carrier that provides sustained release of an active agent in the bladder over a drug delivery period of at least about one month, wherein the carrier is effective to cause the particles to float in the urine and comprises a mucoadhesive material to promote retention by the bladder wall; and

[0132] (b) from about 5 wt. % to about 50 wt. % silver sulfadiazine dispersed in a controlled release vehicle.

[0133] In another embodiment, a method for treating a urinary disorder in a subject is provided, wherein the method comprises administering a controlled release pharmaceutical formulation to the bladder, the controlled release pharmaceutical formulation comprising a population of particles having an average diameter (or at least one dimension) greater than 2.0 mm and comprising about 2.5 wt.% to about 95 wt.% of a pharmacologically active agent effective for treating the urinary disorder and 5 wt.% to 97.5 wt.% of a controlled release carrier effective to cause the particles to float in the urine and provide sustained release of the active agent in the bladder over a drug delivery period of about one month to at least about three months. The urinary disorder can be a disorder of the bladder, ureter, urethra, kidney, or a combination thereof.

[0134] In some embodiments, the urinary system disorder is a urinary tract infection (commonly referred to as "UTI"), such as a bacterial infection, a fungal infection, or a viral infection. According to other embodiments, the method is used to treat cancer or benign tumors of the urinary system; urinary incontinence (including stress urinary incontinence and overactive bladder, "OAB") and urinary retention; urinary system inflammation, injury or scarring; bladder pain syndrome; neurogenic bladder dysfunction; vesicoureteral reflux; sexually transmitted diseases, such as chlamydia, gonorrhea or syphilis; bladder stones; or kidney stones, diabetic nephropathy, pyelonephritis or renal failure.

[0135] Preparation particles

[0136] In an embodiment, the particles within the pharmaceutical formulation include (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 components of the particles are further described below.

[0137] A. Active Agent

[0138] As can be understood, the choice of pharmacologically active agents depends on the indication. Although not required, 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 agents, antifungal agents and antiviral agents; chemotherapeutic agents; anti-inflammatory agents; anesthetics; analgesics; diuretics; procoagulants or anticoagulants; biological products; agents for treating incontinence, including overactive bladder (including antimuscarinics, β3-adrenergic receptor agonists, anesthetics and analgesics); renin-angiotensin-aldosterone system (RAAS) inhibitors; agents for treating kidney stones; and contrast agents for diagnosis and monitoring. Specific examples of active agents that can be administered to treat urinary disorders as provided herein are as follows:

[0139] Anti-infective agents:

[0140] Anti-infective agents include tetracycline antibiotics and related compounds (e.g., chlortetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline, minocycline, and roli-tetracycline);

[0141] Anti-infective agents also include macrolide antibiotics such as erythromycin, clarithromycin and azithromycin; streptogramin antibiotics such as quinupristin and dalfopristin; β-lactam antibiotics including penicillins (e.g., penicillin G, penicillin VK), anti-staphylococcal penicillins (e.g., cloxacillin, dicloxacillin, nafcillin and oxacillin), broad-spectrum penicillins (e.g., aminopenicillins such as ampicillin, amoxicillin and benzathine benzylpenicillin), and antipseudomonal penicillins. penicillins such as carbenicillin), cephalosporins (e.g., cefoperazone, cefepime, cefpodoxime, cephalexin, cefazolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriaxone), and carbapenems such as imipenem, meropenem, and aztreonam; aminoglycoside antibiotics such as streptomycin, gentamicin, tobramycin, amikacin, and neomycin; glycopeptide antibiotics such as teicoplanin; sulfonamide antibiotics such as sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, and sulfadiazine. ine), sulfamerazine, sulfamethazine, sulfamethizole and sulfamethoxazole; silver-based active agents such as elemental silver, silver ions and silver salts, and silver coordination compounds; quinolone antibiotics such as levofloxacin, trovafloxacin, ciprofloxacin, nalidixic acid and ofloxacin; anti-mycobacterials such as isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic acid and cycloserine; nitrofurans such as nitrofurazone and nitrofurantoin.

[0142] Anti-infective agents also include antifungal agents such as itraconazole, ketoconazole, fluconazole, and amphotericin B; antiseptics such as the biguanides chlorhexidine and Alexidine; and miscellaneous antimicrobial agents such as trimethoprim, chloramphenicol, fosfomycin, spectinomycin, polymyxin B (colistin), bacitracin, nitrofurantoin, methenamine, and hydroxyclosan sodium.

[0143] Agents for treating viral infections of the urinary system include, by way of example, anti-herpetic agents such as acyclovir, famciclovir, foscarnet, ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir and vidarabine; antiretroviral agents such as didanosine, stavudine, zalcitabine, tenofovir and zidovudine; other antiviral agents include amantadine, interferon-α, ribavirin and rimantadine. Of particular interest for the treatment of viral infections of the urinary system are cidofovir and leflunomide.

[0144] The antibacterial agent of particular concern herein is oligodynamic active agent (i.e., agent based on metal of biological killing). Many such agents are based on silver, and as mentioned above, include elemental silver, silver ions, silver salts and silver coordination compounds. Silver salts can be inorganic, such as silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate and silver tetrafluoroborate. Organic silver-containing compounds include both organic silver salts and coordination compounds, such as silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate and silver sulfadiazine (SSD). It has also been found that other metals such as gold, zinc, copper and cerium both individually and in combination with silver have antimicrobial properties.

[0145] SSD degradation products

[0146] Also of interest as antibiotic agents herein are SSD degradation products formed in situ following intravesicular administration of SSD. These degradation products include, for example, sulfanilic acid; sulfonamide; sulfaguanidine, a guanidine derivative of sulfonamide; and 2-aminopyridine. It has now been discovered that these degradation products have comparable antibacterial properties to the original compounds (i.e., prior to degradation in the bladder). The above-mentioned SSD degradation products—which may result from enzymatic degradation, hydrolysis, physical erosion or degradation, or any mechanism—are therefore promising as active agents in their own right. This in turn means that when the SSD in the granular formulation of the present invention is released into the bladder, the SSD and its degradation products may combine to provide an enhanced and prolonged therapeutic effect.

[0147] In any particular case, the choice of anti-infective agent will depend on the nature of the infective agent as well as other factors. Urinary tract infections are commonly caused by the microorganisms Escherichia coli (E. coli), Klebsiella pneumonia, Staphylococcus saprophyticus, Proteus mirabilis, Enterococcus faecalis, Staphylococcus aureus, Candida albicans, Streptococcus agalactiae, Mycoplasma genitalium, Pseudomonas aeruginosa, Chlamydia trachomatis, and the herpes simplex viruses human alphaherpesvirus 1 (HSV-1) and human alphaherpesvirus 2 (HSV-2).

[0148] Chemotherapeutic agents:

[0149] Chemotherapeutic agents that can be administered via the intravesicular route using the particle formulations of the present invention include, but are not limited to, apaziquone; aldesleukin; Bacillus Calmette-Guérin (BCG) immunotherapy; cisplatin; docetaxel; doxorubicin; erdafitinib; everolimus; fosfomycin; gemcitabine; methotrexate; mitomycin C; mitoxantrone; paclitaxel, thiotepa; camptothecin and its analogs and derivatives (e.g., 9-aminocamptothecin, 9-nitrocamptothecin, 10-hydroxycamptothecin, irinotecan, meglumine, topotecan, and 20-O-β-pyranosylglucopyranosylcamptothecin); taxanes (e.g., baccatins, cephalidine, omannine and its derivatives); carboplatin; interleukin (IL)-2 and IL-12; interferon alpha-2a, interferon alpha-2b, interferon alpha-n3 and other agents of the interferon family; levamisole; altretamine; cladribine; tretinoin; procarbazine; dacarbazine; mitotane; asparaginase; porfimer; amifostine; mitotic inhibitors, including the podophyllotoxin derivatives teniposide and etoposide; and the vinca alkaloids vinorelbine, vincristine and vinblastine. Drugs of particular interest for the treatment of cancers of the urinary system (including bladder cancer, kidney cancer, and cancers of the urethra and ureter) include, but are not limited to, apaquilone; aldesleukin, axitinib, BCG immunotherapy, cisplatin, doxorubicin, erdafitinib, everolimus, fosfomycin, gemcitabine, IL-2, IL-12, methotrexate, mitomycin-C, thiotepa, vinblastine, and the monoclonal antibody drug bevacizumab Avelumab cabozantinib-S-malate, ipilimumab, nivolumab, sunitinib malate, and pembrolizumab, among others.

[0150] Anti-inflammatory agents:

[0151] Active agents useful in treating urinary tract inflammation include nonsteroidal anti-inflammatory agents (NSAIDs), such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen, apazone, diclofenac, difenpiramide, diflunisal, etodolac, indomethacin, ketorolac, meclofenamic acid ( meclofenamate, nabumetone, phenylbutazone, piroxicam, sulindac, and tolmetin; COX-2 inhibitors such as celecoxib, rofecoxib, and valdecoxib; and steroidal anti-inflammatory agents, such as hydrocortisone, hydrocortisone-21-monoesters (e.g., hydrocortisone-21-acetate, , hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-valerate), hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21-diacetate, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate), alclometasone, betamethasone, dexamethasone, flumethasone, prednisolone, methylprednisolone, and triamcinolone acetonide.

[0152] Anti-inflammatory agents of particular interest in the treatment of urinary tract inflammation are sodium cromolyn, sodium pentosan polysulfate and the glycosaminoglycans chondroitin sulfate, hyaluronic acid and heparin.

[0153] Anesthetics:

[0154] Representative anesthetics that can be administered using the particle formulations described herein include lidocaine, bupivacaine, benzocaine, acetylcaine, tetracaine, and prilocaine, among others.

[0155] Representative analgesics that can be incorporated into the granule formulation include nonsteroidal analgesics such as acetaminophen, acetylsalicylic acid, and the anti-inflammatory agents described above, as well as opioid analgesics such as buprenorphine, butorphanol, codeine, diamorphine, dihydrocodeine, ethylmorphine, fentanyl, hydrocodone, hydromorphone, isomethadone, levorphanol, lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, and tramadol. As is known in the art, opioid receptors are present in bladder tissue (Westerling et al. (2007), "Opioids and Bladder Pain / Function," in Schmidt et al. (Eds.), Encyclopedia of Pain (Springer, Berlin)), and therefore using the formulations and methods of the present invention, these agents can be used to treat bladder pain syndrome (BPS) and other pain within the urinary system, regardless of the underlying etiology.

[0156] Diuretics

[0157] Diuretics that can be administered with the formulations of the invention include, by way of example, loop diuretics such as furosemide, ethacrynic acid, bumetanide, and torasemide; thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide; potassium-sparing diuretics such as spironolactone, epierenone, potassium canreonate, amiloride, and triamterene; and xanthenes such as theophylline and theobromine.

[0158] Biological products:

[0159] Biological agents that can be administered using the particle formulations of the invention include, for example, proteins, peptides, peptide fragments, monoclonal antibodies, enzymes, amino acids, nucleic acids (e.g., DNA, modified DNA, mRNA), cytokines, hormones, and chimeric antigen receptor (CAR) T cell therapy.

[0160] Other examples of active agents that can be incorporated into the granule formulation include RAAS inhibitors for the treatment of diabetic nephropathy, such as the angiotensin-converting enzyme (ACE) inhibitors captopril, zofenopril, fosinopril, enalapril, lisinopril, benazepril, and imidapril; antimuscarinics for the treatment of overactive bladder, such as darifenacin, hyoscyamine, oxybutynin, tolterodine, solifenacin, trospium, fesoteridine, benztropine mesylate, and pheniramine; mesylate, orphenadrine, procyclidine, and trihexyphenidyl; and β3-adrenergic receptor agonists for the treatment of overactive bladder, such as amibegron, mirabegron, nebivolol, solabegron, and vibegron.

[0161] Other active agent groups include bladder relaxants (e.g., for the treatment of incontinence caused by detrusor overactivity). Relaxants include, for example, oxybutynin, ipratropium, and tricyclic antidepressants such as amitriptyline, imipramine, and desipramine; capsaicin, baclofen, and other GABA B receptor agonists; and drugs used to treat incontinence due to sphincter defects (such as alpha-adrenergic agonists, beta-adrenergic agents, estrogen agents, and tricyclic antidepressants).

[0162] Any of the above-mentioned active agents and active agent types can be administered in combination, and any such combination can be particularly advantageous for treating certain urinary disorders. For example, in the treatment of urinary tract infections, intravesicular co-administration of an antibiotic agent with an anesthetic will both treat the infection and relieve pain. Combinations of two or more antibiotic agents are also contemplated, such as an antibiotic with a higher solubility and an antibiotic with a lower solubility to provide different drug release rates. Examples of suitable combinations include, but are not limited to, SSD plus lidocaine, SSD with meropenem, or SSD plus silver nitrate. As another example, the treatment of bladder cancer associated with inflammation will benefit from intravesicular co-administration of a chemotherapeutic agent with an anti-inflammatory agent. Additional examples include: administration of anti-infective agents in conjunction with delivery of healthy urinary bacteria such as lactobacilli to treat urinary tract infections; administration of adjuvants that act as oxidants to increase the efficacy of the primary active agent, particularly when the primary active agent is an oligokinetic agent; administration of agents that are released to dissolve organic matter surrounding the particle, such as a layered structure in which one layer contains the active agent, the next layer contains potassium citrate or allopurinol to dissolve "stone" material, the next layer contains the active agent, and so on; administration of synergistic agents such as urease, which prevent bacteria from changing the pH of urine to ensure that the active agent is within its effective pH range; and administration of agents that are released to promote dissolution of the particle, such as lipase, in order to promote release of the active agent.

[0163] Pharmacologically active agents used to treat kidney stones can also be therapeutically administered according to the present invention. For example, intravesicular delivery of allopurinol using the formulations of the present invention facilitates the breakdown of uric acid-based stones and prevents recurrence of stones, as does intravesicular administration of alkalinizing agents such as acetazolamide, sodium bicarbonate, potassium citrate, and magnesium citrate, or thiazide and thiazide-like diuretics such as chlorthalidone or indapamide.

[0164] In a variation of the embodiment, wherein the pharmacologically active agent is administered via an intravesicular route, the diagnostic agent is administered in the same manner with a granular formulation as provided herein. Diagnostic agents are agents that can be identified, quantified or monitored using conventional imaging equipment. Diagnostic agents can include iodine-based contrast agents (e.g., iopromide, iohexol, iothalamate, ioxaglate, iopramidol, iosimenol, iodixanol, lipiodol, metrizoate and the like) used with voiding cystourethrography, intravenous urography, X-ray computed tomography (CT) and other diagnostic techniques; lanthanide-based contrast agents (e.g., dysprosium and gadolinium chelates, particularly gadopentetate; and iodine-based contrast agents (e.g., dysprosium and gadolinium chelates, particularly gadopentetate; and iodine-based contrast agents (e.g., iopromide, iohexol, iothalamate, ioxaglate, iopramidol, iosimenol, iodixanol, lipiodol, metrizoate and the like); and lanthanide-based contrast agents (e.g., dysprosium and gadolinium chelates, particularly gadopentetate; and iodine ... dimeglumine), gadobutrol and the like) and superparamagnetic iron oxide contrast agents commonly used in magnetic resonance imaging (MRI); silver-containing contrast agents and gold-containing contrast agents proposed for CT imaging, such as pegylated (polyethylene glycol-functionalized) silver nanoparticles and gold nanoparticles; microbubble-type contrast agents such as those used in ultrasound imaging; and others, as will be appreciated by those of ordinary skill in the art.

[0165] B. Controlled Release Vectors:

[0166] Controlled release particles (i.e., formulation particles, nanoparticles or particles) include pharmacologically active agents combined with controlled release carriers. The carrier can be in the form of a matrix, and the activating agent is dispersed or embedded in the matrix. Alternatively, the particle can be a coated core type, wherein the controlled release carrier is in the coating on the core containing the activating agent, or wherein the activating agent is present in the coating on the core of the controlled release carrier. In aspect, matrix type particles can be advantageous, and the core containing the activating agent of the carrier coating is also advantageous. As explained in the following article section C, different shapes and structures (e.g., particles, tablets, capsules, expandable systems and contractible systems, etc.) are expected.

[0167] The selection of controlled release carrier depends on many factors. First, the carrier is selected to make the specific gravity of the particles prepared with a specific active agent and the carrier lower than the specific gravity of urine. Since the specific gravity of urine is in the range of about 1.005 to 1.03, the specific gravity of the particles prepared with the selected active agent should be less than 1.03 or less than 1.005. Usually, this also means that the specific gravity of the controlled release carrier is less than 1.03 or less than 1.005. The carrier should also provide the controlled release of the desired type (that is, it should be gradually soluble in urine). The carrier should be bioerodible (for example, by enzymatic activity), physically degradable or some combination thereof. Hydrophilicity and hydrophobicity are also considerations. Usually, hydrophilic carriers are used together with hydrophilic active agents, and hydrophobic carriers are used together with hydrophobic active agents. The controlled release carrier is solid or semisolid, although viscous liquid carriers can be used, condition is that suitable particles can be provided therewith in the selected liquid vehicle.

[0168] In embodiments, triglyceride is the main component of granule.Triglyceride is the most common fat form in blood flow and is also present in the urine of bladder.Triglyceride and other lipids are well established as drug carriers, and are frequently used for implants with controlled release of active ingredients.Therefore, triglyceride can be preferred, this is due to their biocompatibility, good safety profile, low toxicity, easy to manufacture and prepare, for the prediction thing (predicate) in the preparation of mucosal surface and application, for enhancing the low density of buoyancy and for the hydrophobicity of slowly degrading and controlled drug release in urine.

[0169] Applicants have tested several materials for use in particle compositions, including These materials differ according to their melting point and hydroxyl value. Materials with lower melting points closer to body temperature (30°C-39°C) will degrade faster than materials with higher melting points. Hydroxyl value is defined as the milligrams of potassium hydroxide (KOH) required for neutralizing the acetic acid absorbed by the acetylation of one gram of chemical substances containing free hydroxyl groups. Hydroxyl is a common hydrophilic group and can be used to modify the surface and change the wettability of the excipient due to its ability to form hydrogen bonds with surrounding water. The density of hydrogen bonds formed between hydroxyl and water molecules in the adsorption layer contributes to the overall wettability of the excipient. The increase in wettability can increase the degradation of the excipient via hydrolysis, and thereby achieve drug release. These two properties can be considered to select the basis, main excipient or a combination of several excipients for the formulation to achieve ideal degradation and drug release profile and drug release rate.

[0170] In one aspect, the primary polymer material comprises a hydrophobic material with a high melting point, such as tripalmitin (e.g., Dynasan ) or glyceryl tristearate (Dynasan ), glyceryl monostearate (Dynasan ) is mixed with excipients in the relative range of 1%-50% (w / w) to enhance degradation and drug release. The polymer can be melted and then mixed with the drug (or API) in the range of 1%-25% (w / v). Listed below are additional materials that have been tested for analyzing degradation rate, drug release, and compatibility with other excipients.

[0171] Other representative support materials suitable for forming the particles herein include, for example, the following:

[0172] (1) Saturated C6-C 30 Fatty acids such as caproic acid, heptanoic acid, caprylic acid, capric acid, hexanoic acid, nonanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, cerotic acid, montanic acid, and nonacosylic acid, and salts thereof, for example sodium caprylate, sodium laurate, sodium myristate, and the like;

[0173] (2) Unsaturated C6-C 30 fatty acids, such as crotonic acid, myristoleic acid, palmitoleic acid, oleic acid, eicosenoic acid, linoleic acid, docosadienoic acid, eicosadienoic acid, and linolenic acid;

[0174] (3) Saturated or unsaturated C 10 -C 30 Fatty alcohols, typically monohydric fatty alcohols, such as undecanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, oleyl alcohol, nonadecanol, behenyl alcohol, cetyl alcohol, and beeswax alcohol;

[0175] (4) Fatty acid esters, i.e., usually derived from monohydric alcohols, dihydric alcohols or polyhydric alcohols and at least one C8-C 30 Fatty acids, including:

[0176] (a) lower alcohol fatty acid esters, i.e. esters of lower (C2-C6) alcohols and fatty acids, such as ethyl oleate, isopropyl myristate and isopropyl palmitate;

[0177] (b) triglycerides such as tributyrin, tricaproin, tricaprylin, tricaprin, glyceryl triundecanoate, trilaurin, trimyristin, tripalmitin, tristearin, glyceryl trimyristoleate, triolein and mixtures thereof such as tricaprylin / tricaprin / trilaurin, tricaprylin / tricaprin / trilinolein, tricaprylin / trilaurin tristearin and the like;

[0178] (c) mono- and di-glycerides such as ricinoleylglyceryl, laurinylglyceryl, dilaurinylglyceryl, monooleylglyceryl, dioleylglyceryl, monostearic acid glyceryl, behenic acid glyceryl (e.g. Gattefosse), distearin, monopalmitin, glyceryl palmitostearate (eg Gattefosse), Glyceryl Caprylate / Caprate ( Abitec), caprylic mono- and di-glycerides (e.g. Imwitor 998) and mono- and di-acetylated mono- and di-glycerides (e.g. Myvacet 9-45);

[0179] (d) polyglycerolated fatty acids, i.e. polyglycerol esters of fatty acids, such as polyglycerol-2 stearate, polyglycerol-2 oleate, polyglycerol-2 isostearate, polyglycerol-6 oleate, polyglycerol-10 laurate, polyglycerol-10 laurate, polyglycerol-10 stearate, polyglycerol-6 dioleate, polyglycerol-10 trioleate, polyglycerol polyricinoleate, tetraglycerol pentastearate and tetraglycerol monostearate;

[0180] (e) propylene glycol fatty acid esters, i.e. esters of propylene glycol and fatty acids, such as propylene glycol monolaurate, propylene glycol ricinoleate, propylene glycol monooleate, propylene glycol dicaprylate, propylene glycol stearate and propylene glycol myristate;

[0181] (f) Polyethoxylated fatty acids, i.e., polyethylene glycol (PEG) fatty acid esters, such as PEG-1 stearate, PEG-2 stearate, PEG-2 oleate, PEG-4 laurate, PEG-4 oleate, PEG-4 stearate, PEG-6 laurate, PEG-6 oleate, PEG-6 stearate, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, PEG-12 stearate, PEG-12 laurate, PEG-12 ole ...oleate, PEG-12 stearate, PEG-12 oleate, PEG-12 stearate, PEG-12 laurate, PEG-12 oleate, PEG-12 stearate, PEG-6 oleate, PEG-6 stearate, PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-10 laurate, PEG-10 oleate, PEG-10 stearate, PEG-12 Laurate, PEG-12 oleate, PEG-12 ricinoleate, PEG-200 oleate, PEG-400 oleate, PEG-4 dilaurate, PEG-4 dioleate, PEG-4 distearate, PEG-10 dipalmitate, PEG-8 dilaurate, PEG-8 dioleate, PEG-8 distearate, PEG-10 dipalmitate, PEG-12 dilaurate, PEG-20 distearate, PEG-32 distearate, and PEG-400 distearate;

[0182] (g) polyethoxylated glyceryl fatty acid esters, i.e. compounds in which two of the three glyceryl hydroxyl groups are esterified with fatty acids and the third bears a PEG substituent, such as PEG-20 laurin, PEG-30 laurin, PEG-40 laurin, PEG-20 stearin, PEG-20 olein and PEG-30 olein; and

[0183] (h) sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sorbitan sesquioleate and sorbitan trioleate, and polyethoxylated sorbitan fatty acid esters such as PEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitan monostearate (Tween-60) and PEG-20 sorbitan monooleate (Tween-80);

[0184] (i) From C8-C 30 Fatty acids and C8-C 30 Diesters of fatty alcohols and carboxylic acids with hydroxyl groups, such as 4-hydroxycinnamic acid (coumaric acid) and ω-hydroxy acids, such as 16-hydroxypalmitic acid, 18-hydroxystearic acid and the like;

[0185] (5) phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphorylated diacylglycerides, in particular phospholipids selected from diacylphosphatidylcholine, diacylphosphatidylethanolamine, diacylphosphatidylserine, diacylphosphatidylinositol, diacylphosphatidylglycerol, diacylphosphatidic acid and mixtures thereof, wherein each acyl group contains from about 10 to about 30 carbon atoms and is saturated or unsaturated, and phospholipid mixtures, such as lecithin, hydroxylated lecithin and lysolecithin;

[0186] (6) sterols (including sterol derivatives), such as cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether, PEG-30 cholestanol and phytosterols;

[0187] (7) Polyethylene glycol alkyl ethers, i.e., ethers of PEG and fatty alcohols, such as PEG-3 oleyl ether and PEG-4 lauryl ether;

[0188] (8) Polyoxyethylene-polyoxypropylene (POE-POP) block copolymers, i.e., hydrophilic surfactants with different POE-POP ratios, are generally referred to as poloxamers and include poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 218, poloxamer 219, poloxamer 220, poloxamer 221, poloxamer 222, poloxamer 223, poloxamer 224, poloxamer 225, poloxamer 226, poloxamer 227, poloxamer 228, poloxamer 229, poloxamer 230, poloxamer 231, poloxamer 232, poloxamer 233, poloxamer 234, poloxamer 235, poloxamer 236, poloxamer 237, poloxamer 238, poloxamer 239, Poloxamer 231, Poloxamer 234, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 282, Poloxamer 284, Poloxamer 288, Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403 and Poloxamer 407 and combinations of the foregoing and with other compounds, such as Poloxamer 407 (45%) and ammonium bicarbonate (6%). The latter combination is advantageous because ammonium bicarbonate decomposes at high temperatures to produce carbon dioxide bubbles, which in turn facilitates the flotation of the granular formulation in the bladder.

[0189] (9) gradually erodible or degradable synthetic polymers such as polylactide, polyglycolide, polycaprolactone, polyanhydrides, polyurethanes, polyesteramides, polyorthoesters, polyvinylpyrrolidone, polyhydroxycellulose, and copolymers, derivatives, and mixtures thereof;

[0190] (10) Hydrophilic polymers commonly used to prepare hydrogels, for example, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate and sodium carboxymethyl cellulose (NaCMC); acrylic polymers such as methacrylic acid, alkyl acrylates, alkyl methacrylates and the like; copolymers of acrylic acid, methacrylic acid, alkyl acrylates, alkyl methacrylates and the like, such as copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate and / or hydroxyethyl methacrylate; vinyl polymers and copolymers such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate and ethylene-vinyl acetate copolymers; and chitosan;

[0191] (11) Bile salts, such as sodium cholate, sodium deoxycholate, and the like; and

[0192] (12) Surfactants not covered by the above group, such as sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, 2-phenoxyethanol and benzoyl alcohol.

[0193] It should be understood that the aforementioned examples of controlled release carriers that can be used in the particles of the present invention include hydrophilic materials, hydrophobic materials, surfactants, naturally occurring materials, synthetically modified naturally occurring materials, synthetic materials; and materials having molecular weights within a relatively wide range.

[0194] Mucoadhesive controlled release materials:

[0195] Direct intravesical instillation of therapeutic drugs is still limited by the constant dilution and excretion elimination with urine production. These limitations require frequent and repeated administration, which reduces the patient's compliance and increases the cost of treatment. Preparations using mucoadhesive materials may potentially increase the residence time of drugs in the bladder by adhering to the bladder mucosa and enduring the flushing of urination. This can ultimately improve bioavailability and effectively reduce the required instillation frequency and dosage for therapeutic efficacy. Mucoadhesion to the inner wall of the bladder can be achieved via the electrostatic interaction of the mucosa with cationic materials or materials that form hydrogen bonds and covalent bonds with the bladder mucosal tissue.

[0196] The controlled release vehicle may include a mucoadhesive material to enhance retention of the formulation within the bladder (i.e., by adhering to the bladder wall). That is, the use of a mucoadhesive controlled release vehicle can extend the period of time during which the particle formulation is present within the bladder, and thereby also extend the duration of drug delivery. Any mucoadhesive material may be used, including those within groups (1) to (12) above, provided that the desired degree of retention is achieved, the desired level of particle buoyancy in urine is provided, and the desired sustained release profile results. Ideally, the material provides approximately zero order release, i.e., the active agent is released within the bladder at an approximately constant release rate.

[0197] Suitable mucoadhesive materials for use or as controlled release carriers herein to promote particle buoyancy, retention and sustained release include the following:

[0198] (1) Waxes, in particular paraffin, candelilla wax, beeswax and carnauba wax;

[0199] Derived from monohydric C2-C6 alcohol, dihydric C2-C6 alcohol or polyhydric C2-C6 alcohol and C8-C 24 Fatty acid esters of fatty acids, such as C8-C 22 Monoglycerides, diglycerides and triglycerides of saturated fatty acids, representative examples of which include triglycerides such as tripalmitin (such as those sold under the trade name Tripalmitin (available from Gattefossé), C8-C 22 A blend of triglycerides of saturated fatty acids (such as 378, from IOIOleo); C8-C 22 Saturated fatty acid triglycerides and C8-C 22 A blend of monoglycerides of fatty acids (such as H15); two or more C8-C 22 Blends of mono- and diglycerides of saturated fatty acids (such as palmitoyl stearin, a blend of palmitic acid glyceryl, stearic acid glyceryl and diglyceryl with two fatty acids); and C8-C 22 Monoglycerides of saturated fatty acids, especially behenyl glyceride;

[0200] (2) Fatty acids, especially C8-C 24 Fatty acids, such as saturated C8-C 18 Fatty acids, saturated C 12 -C 24 Fatty acids and saturated C8-C 22 fatty acids, such as palmitic acid and stearic acid;

[0201] (3) Fatty alcohols, especially C8-C24 Fatty alcohols, such as saturated C8-C 18 Fatty alcohols, saturated C 12 -C 24 Fatty alcohols and saturated C8-C 22 fatty alcohols, such as stearyl alcohol and cetyl alcohol;

[0202] (4) Hydroxylation of C4-C 12 Alkanes, including polyhydroxylated and dihydroxylated C4-C 12 Alkanes, such as 1,2-octanediol, 1,2-hexanediol, 1,2-pentanediol, and 1,3-butanediol;

[0203] (5) polymers and copolymers of hydroxylated vinyl monomers, such as poly(vinyl alcohol);

[0204] (6) polymers and copolymers of carboxylated vinyl monomers, such as poly(acrylic acid), cross-linked poly(acrylic acid) (carbomers), poly(methacrylic acid), copolymers of methyl vinyl ether with acrylic acid and / or methacrylic acid, and the like, particularly those sold under the trademark Carbomers and modified derivatives thereof are sold, such as Carbopol 71G NF, Carbopol 934 NF, Carbopol 934P NF, Carbopol 940 NF, Carbopol 941 NF, Carbopol 971P NF, Carbopol 974P NF, Carbopol 980 NF, Carbopol 981 NF, Carbopol 1342 NF, Carbopol 5984 EP, Noveon AA-1 polycarbophil, Carbopol Ultrez 10 NF, Carbopol Ultrez 20, Carbopol Ultrez 21, Carbopol ETD2020 NF, Pemulen TR1 NF, Pemulen TR2 NF, and others commercially available from Lubrizol Advanced Materials, Inc.

[0205] (7) Cellulosic polymers, including carboxycelluloses such as sodium carboxymethylcellulose and hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose.

[0206] It will be appreciated that other mucoadhesive materials providing the necessary buoyancy, retention and release profiles may be used instead of or in addition to any of the foregoing.

[0207] Composition / ratio of components

[0208] As will be understood by those skilled in the art of drug delivery, the ratio of active agent to controlled release carrier in the formulation depends on the active agent and the expected dose to be administered, which in turn depends on the drug delivery time period. Typically, the weight ratio of active agent to controlled release carrier is selected to provide a drug load (weight percentage of active in particles) in the range of about 5% to 50% (corresponding to a weight ratio range of 1:20 to 1:1), for example, in the range of 10% to 50% (corresponding to a weight ratio range of 1:10 to 1:1), typically in the range of 20% to 50% (corresponding to a weight ratio range of 1:5 to 1:1), and most typically in the range of 25% to 40% (corresponding to a weight ratio range of 1:3 to 2:3).

[0209] Typically, the particles completely dissolve, degrade or erode in the bladder, so there is no need to remove the preparation. The particle preparation has an internal excretion retention rate less than 1, which means that some fractional losses of the particles will occur at each excretion. In some cases, it may be desirable to promote particle degradation or particle removal before the end of the expected drug delivery time period. The particle preparation can be removed by suction or by introducing a particle degradation agent into the bladder. The degradation agent can be an enzyme, a chemical reagent such as hydrogen peroxide or a urine acidifying agent such as methenamine hippurate.

[0210] In some embodiments, the particles are coated with or contain one or more enzymes or other biofilm disruptors selected to degrade the extracellular matrix of the biofilm, e.g., dispersin B, trypsin (or other digestive enzymes), deoxyribonucleases, nitric oxide, etc. The particle coating or component may also include a material that reduces the affinity of crystals present in urine to attach to the particle surface (e.g., polyurethane or polytetrafluoroethylene), or a material that adheres to the biomaterial (e.g., acrylamidotaurate) using electrostatically charged materials and causes instability. Any of these mechanisms for biofilm disruption and prevention of further biofilm growth may be used in combination, and some may work synergistically.

[0211] C. Particle Manufacturing:

[0212] Controlled release matrix particles

[0213] The particles of the pharmacologically active agent dispersed in the matrix of the controlled release carrier herein can be manufactured as follows. First melt the selected controlled release carrier, and then add the activating agent to the molten carrier to provide an activating agent-carrier mixture. Use any suitable equipment that helps the activating agent to be substantially evenly distributed in the carrier to homogenize the mixture, and can be heated simultaneously to ensure that the mixture remains in the form of a melt. After at least a few minutes of homogenization, the homogenized molten mixture is fed into the atomizer to produce droplets of the mixture, and the droplets condense in flight to provide the desired particles, which are then collected. A rotary atomizer is generally preferred. It should be understood that particle size can be changed by controlling the viscosity of the feed material (for example, by adjusting the temperature of the melt), the rotating speed of the atomizer, the feed rate and the size of the turntable. A representative scheme is described in Example 3. Particle size is inversely proportional to the viscosity of the feed material, the rotating speed and the feed rate. Therefore, for larger particles, the feed material viscosity, the rotating speed and / or the feed rate can be reduced, and in order to obtain smaller particles, a lower feed material viscosity, the rotating speed and / or the feed rate are required.

[0214] Conventional methods known to those of ordinary skill in the art and / or described in the relevant texts and literature can be used to make coated core-type particles, wherein the controlled release carrier is provided as a coating on a core containing the active agent, or wherein the active agent is in a coating disposed on a core containing a controlled release carrier. See, for example, the description of encapsulated sustained release delivery systems in Remington: The Science and Practice of Pharmacy, 19th Edition, Vol. 2 (Mack Publishing Co., 1995), Chapter 34.

[0215] The particles can be manufactured to be at least slightly porous using techniques known in the art. Gas bubbles or air bubbles can be introduced into the matrix or coating (if present). Alternatively, or in addition, a porogen (e.g., poloxamer) can be incorporated into the controlled release coating, or for controlled release matrix particles, before, during, or after the particles are dispersed therein, the porogen is incorporated into the melt. For additional information on the preparation of porous microspheres, see Cai et al. (2013), "Porous microsphere and its applications," Int J Nanomedicine 8: 1111-1120, which is incorporated herein by reference.

[0216] Controlled release particles can also be manufactured using hot melt extrusion technology. Hot melt extrusion (HME) is well known in the field of manufacturing polymer-based preparations and dosage forms, and is described in relevant texts and literature. See, for example, Simoes et al. (2021), "Hot-Melt Extrusion: a Roadmap for Product Development," AAPSPharmSciTech 22 (5) 184; and Chivate et al. (2021), "Hot-Melt Extrusion: An Emerging Technique for Solubility Enhancement of Poorly Water-Soluble Drugs," PDAJPharm Sci Technol. 75 (4): 357-373, both of which are incorporated herein by reference. Hot melt extrusion is particularly useful when the active agent and / or carrier or excipient is poorly soluble or unstable using other manufacturing techniques, but is not limited thereto.

[0217] Shape / Form

[0218] The preparation method of lipid drug carrier includes direct compression, solid lipid extrusion and melting technology. In order to prepare drug carriers of different shapes and geometric shapes, manufacturing technology is adopted, such as injection molding, melt spray condensation, compression, solid lipid extrusion via hot melt extrusion and casting technology using 3D printing mold. The final form of cylindrical rods including the diameter ranging from 2mm-5mm and the height of 5mm-15mm is prepared with molten polymer together with the drug and injected into the silicone tube mold of the desired size. The spheroids with diameter sizes ranging from 100mm-1mm are prepared using melt spray condensation using an atomizer. The spheroids with a diameter greater than 1mm are prepared by casting the hot melt mixture of polymer and drug in the 3D printing mold.

[0219] Although it would be conventionally assumed that the shape of the controlled release particles is substantially spherical, this is not the case. The particles of the present invention may be spherical or substantially spherical, but the invention is not limited in this respect, provided that the particles may have any three-dimensional structure resulting from the selected manufacturing technique, provided that they are generally of a size and shape that does not cause urethral obstruction or obstruction of a catheter for intracapsular administration of the formulation. The particles may be cylindrical, spherocylindrical, elliptical, oval, etc., or a combination of any of the foregoing, i.e., polymorphic.

[0220] The particles are used as controlled release pharmaceutical preparations for intracapsular administration to a subject so that the preparation comprises a particle group. The substantially spherical particles in the preparation have a mean diameter greater than 2.0 mm to about 8.0 mm, for example 2.5 mm to 6.5 mm, for example 2.5 mm to 6.0 mm, 2.5 mm to 5.5 mm, 2.5 mm to 5.0 mm, 2.5 mm to 4.5 mm, 2.5 mm to 3.5 mm or 2.0 mm to 3.0 mm. For non-spherical particles, a similar metric is the length of the longest dimension of the particle (and "diameter" is generally used herein to cover the metric). As mentioned herein, the particle size distribution of the particle group in the preparation applied to the subject is relatively narrow, i.e., the particle should be within 20% of the median particle diameter, preferably within 10%. For example, if the median diameter is 4 mm, the particle size range should be between 3.2 mm and 4.8 mm (within 20% of the median diameter), preferably between 3.6 mm and 4.4 mm (within 10% of the median diameter).

[0221] A notable feature of the particles is their buoyancy. In one embodiment, all or substantially all of the particles in the particle population float in the urine. This allows the particles to float to the surface of the urine in the bladder, significantly reducing the fraction of the particle formulation that will be released each time the bladder is emptied. Buoyancy in urine is achieved by making particles with a specific gravity that is generally less than 1.03, more typically less than 1.005, as long as the specific gravity of urine is in the range of about 1.005 to 1.03. This in turn typically corresponds to the use of a controlled release carrier with a specific gravity that is generally less than 1.03, more typically less than 1.005.

[0222] The size and buoyancy of the particles provide benefits that are specific to the bladder. For example, in certain embodiments, the size and / or shape of the particles allow passage through the urethra when needed to prevent blockage. In addition to the mucoadhesive carrier, the buoyancy of the particles also helps to retain the particles in the bladder, regardless of any force acting on the particles by the bladder wall during bladder excretion. The retention of the particles is also beneficial to the patient because the particles fill any residual space after excretion of the contracted bladder, which replaces any urine that would otherwise remain in the bladder and may, for example, aggravate infection by promoting bacterial growth or fungal growth. If the contracted bladder contains excessive particles, the size of the particles allows them to pass through the urethra to avoid any increase in urination frequency. Finally, as explained earlier in this article, the contact between the particles and the inner wall of the bladder or urethra, and the particle movement that causes urine turbulence in the bladder, substantially prevent biofilm formation, and promote the mechanical destruction of any existing biofilm, which in turn reduces the possibility of bacterial cells adhering to the biofilm matrix.

[0223] The particles in the formulation can also be designed to agglomerate within the bladder. For example, in one representative example of such a formulation, the particles can be hemispherical, agglomerating plane to plane to provide a particle sphere within the bladder.

[0224] The preparation can include a first subset of particles and a second subset of particles, wherein the particles in the two subsets are different in some way, such as in two or more aspects of average diameter, shape, buoyancy, deformability or such properties. Thus, in one embodiment, the first subset of particles and the second subset of particles are different in size, so that the particles in one subset are relatively large particles of a non-tiled shape (i.e., a shape that prevents the formation of a void-free layer), for example, having a diameter or longest dimension in the range of 2.0 mm to about 8.0 mm, such as 2.0 mm to about 6.0 mm or 2.0 mm to 4.5 mm, and smaller particles in the range of about 0.5 mm to 2.0 mm. The second subset can pass through the gaps left by the non-tiled larger particles. In another embodiment, the preparation includes particles with different buoyancy levels, so that one subset of particles is very buoyant and the second subset is not very buoyant. The particles in the preparation can also be different in size and buoyancy.

[0225] According to another embodiment, the first subset of particles, the second subset of particles, or both the first subset of particles and the second subset of particles are reversibly deformable. For example, the first subset of particles, the second subset of particles, or both the first subset of particles and the second subset of particles can be deformed to the extent that allows flow within a chute having an inner diameter in the range of 6 mm to 8 mm.

[0226] Additionally, or alternatively, the particles within the formulation may include particles having different pharmacologically active agents, different amounts of the same or different pharmacologically active agents, different controlled release carriers, different amounts of controlled release carriers, particles having different controlled release profiles, or any combination of the foregoing.

[0227] D. Vehicle / Excipient

[0228] The formulation administered to a subject to treat a urinary system disorder comprises the controlled release particle population described in the previous section and typically comprises at least one pharmaceutically acceptable excipient, i.e., a formulation component that does not have pharmacological activity that imparts desired physical or chemical properties to the formulation or its components.

[0229] The particle group can be incorporated into a sterile liquid vehicle, which can be aqueous or non-aqueous, so that the preparation comprises an aqueous or non-aqueous dispersion, suspension or emulsion of particles in a liquid vehicle. The example of a non-aqueous liquid vehicle includes a fatty oil, which should be understood to include a mixture of fatty acids, fatty acid diglycerides and / or fatty acid triglycerides, such as castor oil, cottonseed oil, corn oil, linseed oil, mineral oil, olive oil, sesame oil, soybean oil and the like; a fatty acid that is liquid at room temperature, i.e., a relatively low molecular weight fatty acid and / or an unsaturated fatty acid, such as oleic acid, linoleic acid and linolenic acid; alcohols, such as propylene glycol, glycerol and relatively low molecular weight polyethylene glycol (molecular weight less than about 750 g / mol). Ideally, the liquid vehicle should have a viscosity in the range of 2 cP to 400 cP.

[0230] In addition to the particles and any liquid vehicle containing the particles, the formulation may also contain excipients such as buffers and other pH adjusters, viscosity adjusters, dispersants, tonicity adjusters, enzyme inhibitors, preservatives and stabilizers, solubilizers and emulsifiers.

[0231] The pH adjusting agent should maintain the pH of the formulation within the range of 5.8 to 7.4 so as not to affect the local pH of urine. Representative pH adjusting agents for this purpose include phosphate buffered saline (PBS) and other phosphate buffers, such as potassium dihydrogen phosphate, potassium dihydrogen phosphate, and pyrophosphate buffers; bicarbonates, such as sodium bicarbonate; histidine / histidine hydrochloride; citrates, such as disodium citrate and trisodium citrate; acetates such as ammonium acetate; tris (hydroxymethyl) aminomethane (Tris) buffer, arginine; and meglumine. The pH adjusting agent is additionally used to prevent crystallization of any solute on the particles.

[0232] Viscosity modifier is diluent or thickening agent, although in the preparation of the present invention, any viscosity modifier is usually thickening agent.Viscosity modifier herein helps preparation to be transported by selected intracapsular delivery system (such as catheter, intraurethral syringe etc.), and is selected to keep preparation viscosity in the range of 2cP to 400cP.Suitable viscosity modifier includes sodium carboxymethylcellulose (NaCMC), sorbitol, dextran, gum arabic, gelatin, methylcellulose and poly (vinyl pyrrolidone).As an example, for keeping preparation viscosity in the above-mentioned range of NaCMC, this generally means using molecular weight in the range of 90kDa to 700kDa, concentration in the range of 5mg / mL to 30mg / mL, such as CMC of 5mg / mL, 10mg / mL, 20mg / mL or 30mg / mL.Certainly, any viscosity modifier will consider molecular weight and concentration, and can select (molecular weight) or change (concentration) these parameters as required to reach target viscosity. Higher molecular weight viscosity modifiers will result in more viscous solutions, also at higher concentrations (eg, 5 mg / mL of 250 kDa CMC provides a viscosity similar to that obtained with 20 mg / mL of 90 kDa CMC).

[0233] Dispersants

[0234] The purpose of the dispersant is to prevent agglomeration and sticking of the particles and to promote dispersion of the particles in the formulation. As is well known in the art, the dispersant is typically a surfactant, although not necessarily; exemplary surfactants herein include the poloxamers identified above, and particularly Tween 20 and Tween 80, incorporated into the formulation in an amount ranging from 0.1 mg / mL to 5 mg / mL, such as 0.1 mg / mL, 0.5 mg / mL, 1.0 mg / mL, and 5 mg / mL (0.01%, 0.5%, 0.1%, and 0.5%, respectively). Another dispersant of interest herein is poly(vinyl pyrrolidone) (PVP), such as povidone K12 and povidone K17.

[0235] Incorporate a tonicity adjuster to make the formulation isotonic in urine. Common tonicity adjusters can be used herein and include dextrose, glycerol, D-mannitol, and sodium chloride. Exemplary tonicity adjusters that can be incorporated into the formulations of the present invention are D-mannitol, sodium chloride, and combinations thereof; an aqueous solution containing 5% D-mannitol and 0.9% sodium chloride makes the solution isotonic in urine.

[0236] Another excipient group includes enzyme inhibitors, including inhibitors of enzymes that may degrade pharmacologically active agents, inhibitors of enzymes present at pathological levels in other areas of the bladder or urinary system; and urease inhibitors. Since urease is a known virulence factor of some urinary pathogens (including saprophytic streptococci (S.saprophyticus) and Proteus mirabilis (P.mirabilis)), incorporating urease inhibitors into granular formulations can limit bacterial growth. In addition, bacterial urease alkalizes urine, leading to supersaturation of calcium phosphate and struvite stones, followed by crystal formation, and possible urinary calculi.

[0237] Representative preservatives include antioxidants, antimicrobials and chelating agents. Antioxidant preservatives can be used to minimize the oxidation of pharmacologically active agents or any excipients within the shelf life of the preparation. Commonly used antioxidant preservatives that can be advantageously used herein include ascorbic acid, ascorbyl palmitate, sodium ascorbate, acetylcysteine, monothioglycerol and sulfites (bisulfite, metabisulfite and the like). Antimicrobial preservatives used to prevent microorganisms in the preparation from growing during storage and before use include agents such as benzalkonium chloride, benzyl alcohol, methylparaben, propylparaben and thimerosal. Chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and its salts (disodium EDTA, tetrasodium EDTA, sodium calcium edetate, etc.) can be used for the metal ions in the chelated preparation, otherwise these metal ions can promote undesirable enzymatic reactions or other reactions.

[0238] If the preparation is an emulsion, such as a mixture of hydrophobic particles in a hydrophilic vehicle, hydrophilic particles in a hydrophobic vehicle, hydrophilic particles and hydrophobic particles, or a mixture of a hydrophilic excipient and a hydrophobic excipient, it is recommended to use an emulsifier to promote the homogeneous dispersion of particles and / or excipients in a liquid vehicle. Emulsifiers as known in the art are surfactants that include polar or charged hydrophilic parts and non-polar lipophilic (hydrophobic) parts. Emulsifiers herein can also be used as dispersants, stabilizers and / or liquid vehicles. Suitable emulsifiers for incorporation into the preparation of the present invention include any emulsifiers commonly used for non-solid pharmaceutical products, such as poloxamer (including those determined above), polyoxyethylene ethers, polyethoxylated castor oils, polyoxyethylene fatty acid esters (polysorbates), polyoxyethylene stearates, propylene glycol alginate, sodium citrate, sorbitan fatty acid esters, lecithin and diethanolamine. See, e.g., Handbook of Pharmaceutical Excipients, 3rd ed., Kibbe, ed. (American Pharmaceutical Association, 2000).

[0239] E. Particle Combination

[0240] The intracapsular formulation may comprise two or more particle populations, wherein each population differs from each other population in at least one aspect. Thus, in another embodiment, the formulation additionally comprises a secondary particle population that is different from the primary particle population, for example, comprising a different pharmacologically active agent, a different amount of a pharmacologically active agent, a different controlled release carrier, or a different amount of a controlled release carrier, or having a different controlled release profile or specific gravity.

[0241] For example, a first or primary particle population may provide a first drug release profile (e.g., substantially immediate release of a bolus dose), and a second or secondary particle population may provide a second drug release profile (e.g., sustained release profile) that is different from the first drug release profile. As another example, one particle population may contain a first pharmacologically active agent, and a second particle population may contain a second pharmacologically active agent, and the two populations may or may not be formulated to have different drug release profiles. In some cases, it may be desirable that some fractions of the particles administered to the bladder sink into the trigone and exhibit the expected pharmacological activity there—e.g., destroying the biofilm at the trigone to deliver an anesthetic to the trigone, or administering an anti-infective agent to the trigone—an additional particle population may be made so as to be less buoyant than the first population. As mentioned earlier herein, this may be achieved by selecting different controlled release carriers, different carrier to active agent ratios, etc. Including less buoyant particles in the formulation can help deliver active agents to areas of the bladder that retain urine after contraction, such as a cystocele (also known as a prolapsed bladder, herniated bladder, sagging bladder, or dropped bladder). With a cystocele, the ligaments supporting the bladder and surrounding muscles stretch or weaken, allowing the bladder to sag, and it is a sagging region that can be treated by depositing less buoyant or non-buoyant particles in this area.

[0242] F. Representative Formulations and Dosage Considerations:

[0243] Representative granule formulations according to the present invention are as follows:

[0244] 5wt.% SSD, 95wt.% candelilla wax;

[0245] 10wt.% SSD, 90wt.% candelilla wax;

[0246] 15wt.% SSD, 85wt.% candelilla wax;

[0247] 25wt.% SSD, 75wt.% candelilla wax;

[0248] 40wt.% SSD, 60wt.% candelilla wax;

[0249] 5wt.% SSD, 95wt.% paraffin;

[0250] 10wt.% SSD, 90wt.% paraffin;

[0251] 15wt.% SSD, 85wt.% paraffin;

[0252] 25wt.% SSD, 75wt.% paraffin;

[0253] 15wt.% SSD, 85wt.% paraffin;

[0254] 25wt.% SSD, 75wt.% paraffin;

[0255] 40wt.% SSD, 60wt.% paraffin;

[0256] 5wt.% SSD, 95wt.% tripalmitin;

[0257] 10wt.% SSD, 90wt.% tripalmitin;

[0258] 15wt.% SSD, 85wt.% tripalmitin;

[0259] 25wt.% SSD, 75wt.% tripalmitin;

[0260] 40wt.% SSD, 60wt.% tripalmitin;

[0261] 5wt.% SSD, 95wt.% sodium carboxymethyl cellulose;

[0262] 10wt.% SSD, 90wt.% sodium carboxymethyl cellulose;

[0263] 15wt.% SSD, 85wt.% sodium carboxymethyl cellulose;

[0264] 25wt.% SSD, 75wt.% sodium carboxymethylcellulose;

[0265] 40wt.% SSD, 60wt.% sodium carboxymethyl cellulose;

[0266] 5wt.% SSD, 95wt.% stearyl alcohol;

[0267] 10wt.% SSD, 90wt.% stearyl alcohol;

[0268] 15wt.% SSD, 85wt.% stearyl alcohol;

[0269] 25wt.% SSD, 75wt.% stearyl alcohol;

[0270] 40wt.% SSD, 60wt.% stearyl alcohol;

[0271] 5wt.% SSD, 95wt.% cetyl alcohol;

[0272] 10wt.% SSD, 90wt.% cetyl alcohol;

[0273] 15wt.% SSD, 85wt.% cetyl alcohol;

[0274] 25wt.% SSD, 75wt.% cetyl alcohol;

[0275] 40wt.% SSD, 60wt.% cetyl alcohol;

[0276] 5wt.% SSD, 95wt.% polyvinyl alcohol;

[0277] 10wt.% SSD, 90wt.% polyvinyl alcohol;

[0278] 15wt.% SSD, 85wt.% polyvinyl alcohol;

[0279] 25wt.% SSD, 75wt.% polyvinyl alcohol;

[0280] 40wt.% SSD, 60wt.% polyvinyl alcohol;

[0281] 5wt.% SSD, 95wt.% 1,2-octanediol;

[0282] 10wt.% SSD, 90wt.% 1,2-octanediol;

[0283] 15wt.% SSD, 85wt.% 1,2-octanediol;

[0284] 25wt.% SSD, 75wt.% 1,2-octanediol;

[0285] 40wt.% SSD, 60wt.% 1,2-octanediol;

[0286] 10wt.% SSD, 45wt.% tristearin, 45wt.% hydroxypropyl methylcellulose (HPMC);

[0287] 20wt.% SSD, 40wt.% tristearin, 40wt.% HPMC;

[0288] 40wt.% SSD, 30wt.% tristearin, 30wt.% HPMC;

[0289] 15wt.% SSD, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0290] 20wt.% SSD, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0291] 15wt.% SSD, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0292] 20wt.% SSD, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0293] 15wt.% SSD, 5wt.% lidocaine, 80wt.% candelilla wax;

[0294] 20wt.% SSD, 5wt.% lidocaine, 75wt.% candelilla wax;

[0295] 15wt.% SSD, 5wt.% lidocaine, 80wt.% paraffin;

[0296] 20wt.% SSD, 5wt.% lidocaine, 75wt.% paraffin;

[0297] 15wt.% SSD, 5wt.% lidocaine, 80wt.% tripalmitin;

[0298] 20wt.% SSD, 5wt.% lidocaine, 75wt.% tripalmitin;

[0299] 15wt.% SSD, 5wt.% lidocaine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0300] 15wt.% SSD, 5wt.% lidocaine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0301] 15wt.% SSD, 85wt.% 378 triglyceride blend;

[0302] 25wt.% SSD, 75wt.% 378 triglyceride blend;

[0303] 40wt.% SSD, 60wt.% 378 triglyceride blend;

[0304] ·10wt.% SSD, 90wt.% Witepsol H15;

[0305] ·20wt.% SSD, 80wt.% Witepsol H15;

[0306] ·40wt.% SSD, 60wt.% Witepsol H15;

[0307] 5wt.% silver nitrate, 95wt.% candelilla wax;

[0308] 10wt.% silver nitrate, 90wt.% candelilla wax;

[0309] 15wt.% silver nitrate, 85wt.% candelilla wax;

[0310] 25wt.% silver nitrate, 75wt.% candelilla wax;

[0311] 40wt.% silver nitrate, 60wt.% candelilla wax;

[0312] 5wt.% silver nitrate, 95wt.% paraffin;

[0313] 10wt.% silver nitrate, 90wt.% paraffin;

[0314] 15wt.% silver nitrate, 85wt.% paraffin;

[0315] 25wt.% silver nitrate, 75wt.% paraffin;

[0316] 40wt.% silver nitrate, 60wt.% paraffin;

[0317] 5wt.% silver nitrate, 95wt.% tripalmitin;

[0318] 10wt.% silver nitrate, 90wt.% tripalmitin;

[0319] 15wt.% silver nitrate, 85wt.% tripalmitin;

[0320] 25wt.% silver nitrate, 75wt.% tripalmitin;

[0321] 40wt.% silver nitrate, 60wt.% tripalmitin;

[0322] 5wt.% silver nitrate, 95wt.% sodium carboxymethyl cellulose;

[0323] 10wt.% silver nitrate, 90wt.% sodium carboxymethyl cellulose;

[0324] 15wt.% silver nitrate, 85wt.% sodium carboxymethyl cellulose;

[0325] 25wt.% silver nitrate, 75wt.% sodium carboxymethyl cellulose;

[0326] 40wt.% silver nitrate, 60wt.% sodium carboxymethyl cellulose;

[0327] 5wt.% silver nitrate, 95wt.% stearyl alcohol;

[0328] 10wt.% silver nitrate, 90wt.% stearyl alcohol;

[0329] 15wt.% silver nitrate, 85wt.% stearyl alcohol;

[0330] 25wt.% silver nitrate, 75wt.% stearyl alcohol;

[0331] 40wt.% silver nitrate, 60wt.% stearyl alcohol;

[0332] 5wt.% silver nitrate, 95wt.% cetyl alcohol;

[0333] 10wt.% silver nitrate, 90wt.% cetyl alcohol;

[0334] 15wt.% silver nitrate, 85wt.% cetyl alcohol;

[0335] 25wt.% silver nitrate, 75wt.% cetyl alcohol;

[0336] 40wt.% silver nitrate, 60wt.% cetyl alcohol;

[0337] 5wt.% silver nitrate, 95wt.% polyvinyl alcohol;

[0338] 10wt.% silver nitrate, 90wt.% polyvinyl alcohol;

[0339] 15wt.% silver nitrate, 85wt.% polyvinyl alcohol;

[0340] 25wt.% silver nitrate, 75wt.% polyvinyl alcohol;

[0341] 40wt.% silver nitrate, 60wt.% polyvinyl alcohol;

[0342] 5wt.% silver nitrate, 95wt.% 1,2-octanediol;

[0343] 10wt.% silver nitrate, 90wt.% 1,2-octanediol;

[0344] 15wt.% silver nitrate, 85wt.% 1,2-octanediol;

[0345] 25wt.% silver nitrate, 75wt.% 1,2-octanediol;

[0346] 40wt.% silver nitrate, 60wt.% 1,2-octanediol;

[0347] 10wt.% SSD, 45wt.% tristearin, 45wt.% HPMC;

[0348] 20wt.% SSD, 40wt.% tristearin, 40wt.% HPMC;

[0349] 40wt.% SSD, 30wt.% tristearin, 30wt.% HPMC;

[0350] 15wt.% silver nitrate, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0351] 20wt.% silver nitrate, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0352] 15wt.% silver nitrate, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0353] 20wt.% silver nitrate, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0354] 15wt.% silver nitrate, 5wt.% lidocaine, 80wt.% candelilla wax;

[0355] 20wt.% silver nitrate, 5wt.% lidocaine, 75wt.% candelilla wax;

[0356] 15wt.% silver nitrate, 5wt.% lidocaine, 80wt.% paraffin;

[0357] 20wt.% silver nitrate, 5wt.% lidocaine, 75wt.% paraffin;

[0358] 15wt.% silver nitrate, 5wt.% lidocaine, 80wt.% tripalmitin;

[0359] 20wt.% silver nitrate, 5wt.% lidocaine, 75wt.% tripalmitin;

[0360] 15wt.% silver nitrate, 5wt.% lidocaine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0361] 15wt.% silver nitrate, 5wt.% lidocaine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0362] 15wt.% silver nitrate, 85wt.% 378 triglyceride blend;

[0363] 25wt.% silver nitrate, 75wt.% 378 triglyceride blend;

[0364] 40wt.% silver nitrate, 60wt.% 378 triglyceride blend;

[0365] 10wt.% silver nitrate, 90wt.% Witepsol H15;

[0366] 20wt.% silver nitrate, 80wt.% Witepsol H15;

[0367] 40wt.% silver nitrate, 60wt.% Witepsol H15;

[0368] 15wt.% fosfomycin, 85wt.% candelilla wax;

[0369] 25wt.% fosfomycin, 75wt.% candelilla wax;

[0370] 40wt.% fosfomycin, 60wt.% candelilla wax;

[0371] 15wt.% fosfomycin, 85wt.% paraffin;

[0372] 25wt.% fosfomycin, 75wt.% paraffin;

[0373] 40wt.% fosfomycin, 60wt.% paraffin;

[0374] 15wt.% fosfomycin, 85wt.% tripalmitin;

[0375] 25wt.% fosfomycin, 75wt.% tripalmitin;

[0376] 40wt.% fosfomycin, 60wt.% tripalmitin;

[0377] 15wt.% fosfomycin, 85wt.% sodium carboxymethylcellulose;

[0378] 25wt.% fosfomycin, 75wt.% sodium carboxymethylcellulose;

[0379] 40wt.% fosfomycin, 60wt.% sodium carboxymethylcellulose;

[0380] 15wt.% fosfomycin, 85wt.% stearyl alcohol;

[0381] 25wt.% fosfomycin, 75wt.% stearyl alcohol;

[0382] 40wt.% fosfomycin, 60wt.% stearyl alcohol;

[0383] 15wt.% fosfomycin, 85wt.% cetyl alcohol;

[0384] 25wt.% fosfomycin, 75wt.% cetyl alcohol;

[0385] 40wt.% fosfomycin, 60wt.% cetyl alcohol;

[0386] 15wt.% fosfomycin, 85wt.% polyvinyl alcohol;

[0387] 25wt.% fosfomycin, 75wt.% polyvinyl alcohol;

[0388] 40wt.% fosfomycin, 60wt.% polyvinyl alcohol;

[0389] 15wt.% fosfomycin, 85wt.% 1,2-octanediol;

[0390] 25wt.% fosfomycin, 75wt.% 1,2-octanediol;

[0391] 40wt.% fosfomycin, 60wt.% 1,2-octanediol;

[0392] 15wt.% fosfomycin, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0393] 20wt.% fosfomycin, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0394] 15wt.% fosfomycin, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0395] 20wt.% fosfomycin, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0396] 15wt.% fosfomycin, 5wt.% lidocaine, 80wt.% candelilla wax;

[0397] 20wt.% fosfomycin, 5wt.% lidocaine, 75wt.% candelilla wax;

[0398] 15wt.% fosfomycin, 5wt.% lidocaine, 80wt.% paraffin;

[0399] 20wt.% fosfomycin, 5wt.% lidocaine, 75wt.% paraffin;

[0400] 15wt.% fosfomycin, 5wt.% lidocaine, 80wt.% tripalmitin;

[0401] 20wt.% fosfomycin, 5wt.% lidocaine, 75wt.% tripalmitin;

[0402] 15wt.% fosfomycin, 5wt.% lidocaine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0403] 15wt.% fosfomycin, 5wt.% lidocaine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0404] 15wt.%Fosfomycin, 85wt.% 378 triglyceride blend;

[0405] ·25wt.%Fosfomycin, 75wt.% 378 triglyceride blend;

[0406] 40wt.% fosfomycin, 60wt.% 378 triglyceride blend;

[0407] 10wt.% fosfomycin, 90wt.% Witepsol H15;

[0408] 20wt.% fosfomycin, 80wt.% Witepsol H15;

[0409] 40wt.% fosfomycin, 60wt.% Witepsol H15;

[0410] 15wt.% lidocaine, 85wt.% candelilla wax;

[0411] 25wt.% lidocaine, 75wt.% candelilla wax;

[0412] 40wt.% lidocaine, 60wt.% candelilla wax;

[0413] 15wt.% lidocaine, 85wt.% paraffin;

[0414] 25wt.% lidocaine, 75wt.% paraffin;

[0415] 40wt.% lidocaine, 60wt.% paraffin;

[0416] 15wt.% lidocaine, 85wt.% tripalmitin;

[0417] 25wt.% lidocaine, 75wt.% tripalmitin;

[0418] 40wt.% lidocaine, 60wt.% tripalmitin;

[0419] 15wt.% lidocaine, 85wt.% sodium carboxymethylcellulose;

[0420] 25wt.% lidocaine, 75wt.% sodium carboxymethylcellulose;

[0421] 40wt.%lidocaine, 60wt.%sodium carboxymethylcellulose;

[0422] 15wt.% lidocaine, 85wt.% stearyl alcohol;

[0423] 25wt.% lidocaine, 75wt.% stearyl alcohol;

[0424] 40wt.%lidocaine, 60wt.%stearyl alcohol;

[0425] 15wt.% lidocaine, 85wt.% cetyl alcohol;

[0426] 25wt.% lidocaine, 75wt.% cetyl alcohol;

[0427] 40wt.%lidocaine, 60wt.%cetyl alcohol;

[0428] 15wt.% lidocaine, 85wt.% polyvinyl alcohol;

[0429] 25wt.% lidocaine, 75wt.% polyvinyl alcohol;

[0430] 40wt.% lidocaine, 60wt.% polyvinyl alcohol;

[0431] 15wt.%lidocaine, 85wt.%1,2-octanediol;

[0432] 25wt.%lidocaine, 75wt.%1,2-octanediol;

[0433] 40wt.%lidocaine, 60wt.%1,2-octanediol;

[0434] 15wt.% lidocaine, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0435] 20wt.%lidocaine, 70wt.%tristearate glyceryl, 10wt.%stearyl alcohol;

[0436] 15wt.% lidocaine, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0437] 20wt.%lidocaine, 70wt.%tripalmitin, 10wt.%stearyl alcohol;

[0438] 15wt.% lidocaine, 85wt.% 378 triglyceride blend;

[0439] ·25wt.%lidocaine, 75wt.% 378 triglyceride blend;

[0440] 40wt.%lidocaine, 60wt.% 378 triglyceride blend;

[0441] 10wt.% lidocaine, 90wt.% Witepsol H15;

[0442] 20wt.% lidocaine, 80wt.% Witepsol H15;

[0443] 40wt.%lidocaine, 60wt.%Witepsol H15;

[0444] 15wt.% mitomycin, 85wt.% candelilla wax;

[0445] 25wt.% mitomycin, 75wt.% candelilla wax;

[0446] 40wt.% mitomycin, 60wt.% candelilla wax;

[0447] 15wt.% mitomycin, 85wt.% paraffin;

[0448] 25wt.% mitomycin, 75wt.% paraffin;

[0449] 40wt.% mitomycin, 60wt.% paraffin;

[0450] 15wt.% mitomycin, 85wt.% tripalmitin;

[0451] 25wt.% mitomycin, 75wt.% tripalmitin;

[0452] 40wt.% mitomycin, 60wt.% tripalmitin;

[0453] 15wt.% mitomycin, 85wt.% sodium carboxymethylcellulose;

[0454] 25wt.% mitomycin, 75wt.% sodium carboxymethylcellulose;

[0455] 40wt.% mitomycin, 60wt.% sodium carboxymethylcellulose;

[0456] 15wt.% mitomycin, 85wt.% stearyl alcohol;

[0457] 25wt.% mitomycin, 75wt.% stearyl alcohol;

[0458] 40wt.% mitomycin, 60wt.% stearyl alcohol;

[0459] 15wt.% mitomycin, 85wt.% cetyl alcohol;

[0460] 25wt.% mitomycin, 75wt.% cetyl alcohol;

[0461] 40wt.% mitomycin, 60wt.% cetyl alcohol;

[0462] 15wt.% mitomycin, 85wt.% polyvinyl alcohol;

[0463] 25wt.% mitomycin, 75wt.% polyvinyl alcohol;

[0464] 40wt.% mitomycin, 60wt.% polyvinyl alcohol;

[0465] 15wt.% mitomycin, 85wt.% 1,2-octanediol;

[0466] 25wt.% mitomycin, 75wt.% 1,2-octanediol;

[0467] 40wt.% mitomycin, 60wt.% 1,2-octanediol;

[0468] 15wt.% mitomycin, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0469] 20wt.% mitomycin, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0470] 15wt.% mitomycin, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0471] 20wt.% mitomycin, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0472] 15wt.% mitomycin, 5wt.% lidocaine, 80wt.% candelilla wax;

[0473] 20wt.% mitomycin, 5wt.% lidocaine, 75wt.% candelilla wax;

[0474] 15wt.% mitomycin, 5wt.% lidocaine, 80wt.% paraffin;

[0475] 20wt.% mitomycin, 5wt.% lidocaine, 75wt.% paraffin;

[0476] 15wt.% mitomycin, 5wt.% lidocaine, 80wt.% tripalmitin;

[0477] 20wt.% mitomycin, 5wt.% lidocaine, 75wt.% tripalmitin;

[0478] 15wt.% mitomycin, 5wt.% lidocaine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0479] 15wt.% mitomycin, 5wt.% lidocaine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0480] ·15wt.% mitomycin, 85wt.% 378 triglyceride blend;

[0481] · 25wt.% Mitomycin, 75wt.% 378 triglyceride blend;

[0482] · 40wt.% mitomycin, 60wt.% 378 triglyceride blend;

[0483] 10wt.% mitomycin, 90wt.% Witepsol H15;

[0484] 20wt.% mitomycin, 80wt.% Witepsol H15;

[0485] 40wt.% mitomycin, 60wt.% Witepsol H15;

[0486] 15wt.% gemcitabine, 85wt.% candelilla wax;

[0487] 25wt.% gemcitabine, 75wt.% candelilla wax;

[0488] 40wt.% gemcitabine, 60wt.% candelilla wax;

[0489] 15wt.% gemcitabine, 85wt.% paraffin;

[0490] 25wt.% gemcitabine, 75wt.% paraffin;

[0491] 40wt.% gemcitabine, 60wt.% paraffin;

[0492] 15wt.% gemcitabine, 85wt.% tripalmitin;

[0493] 25wt.% gemcitabine, 75wt.% tripalmitin;

[0494] 40wt.% gemcitabine, 60wt.% tripalmitin;

[0495] 15wt.% gemcitabine, 85wt.% sodium carboxymethylcellulose;

[0496] 25wt.% gemcitabine, 75wt.% sodium carboxymethylcellulose;

[0497] 40wt.% gemcitabine, 60wt.% sodium carboxymethylcellulose;

[0498] 15wt.% gemcitabine, 85wt.% stearyl alcohol;

[0499] 25wt.% gemcitabine, 75wt.% stearyl alcohol;

[0500] 40wt.% gemcitabine, 60wt.% stearyl alcohol;

[0501] 15wt.% gemcitabine, 85wt.% cetyl alcohol;

[0502] 25wt.% gemcitabine, 75wt.% cetyl alcohol;

[0503] 40wt.% gemcitabine, 60wt.% cetyl alcohol;

[0504] 15wt.% gemcitabine, 85wt.% polyvinyl alcohol;

[0505] 25wt.% gemcitabine, 75wt.% polyvinyl alcohol;

[0506] 40wt.% gemcitabine, 60wt.% polyvinyl alcohol;

[0507] 15wt.% gemcitabine, 85wt.% 1,2-octanediol;

[0508] 25wt.% gemcitabine, 75wt.% 1,2-octanediol;

[0509] 40wt.% gemcitabine, 60wt.% 1,2-octanediol;

[0510] 15wt.% gemcitabine, 65wt.% tristearin, 10wt.% stearyl alcohol;

[0511] 20wt.% gemcitabine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0512] 15wt.% gemcitabine, 65wt.% tripalmitin, 10wt.% stearyl alcohol;

[0513] 20wt.% gemcitabine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0514] 15wt.% gemcitabine, 5wt.% lidocaine, 80wt.% candelilla wax;

[0515] 20wt.% gemcitabine, 5wt.% lidocaine, 75wt.% candelilla wax;

[0516] 15wt.% gemcitabine, 5wt.% lidocaine, 80wt.% paraffin;

[0517] 20wt.% gemcitabine, 5wt.% lidocaine, 75wt.% paraffin;

[0518] 15wt.% gemcitabine, 5wt.% lidocaine, 80wt.% tripalmitin;

[0519] 20wt.% gemcitabine, 5wt.% lidocaine, 75wt.% tripalmitin;

[0520] 15wt.% gemcitabine, 5wt.% lidocaine, 70wt.% tristearin, 10wt.% stearyl alcohol;

[0521] 15wt.% gemcitabine, 5wt.% lidocaine, 70wt.% tripalmitin, 10wt.% stearyl alcohol;

[0522] 15wt.% gemcitabine, 85wt.% 378 triglyceride blend;

[0523] 25wt.% gemcitabine, 75wt.% 378 triglyceride blend;

[0524] 40wt.% gemcitabine, 60wt.% 378 triglyceride blend;

[0525] 10wt.% gemcitabine, 90wt.% Witepsol H15;

[0526] 20wt.% gemcitabine, 80wt.% Witepsol H15; and

[0527] 40 wt.% gemcitabine, 60 wt.% Witepsol H15.

[0528] It will be understood from the above and elsewhere in this application that the intracapsular formulations may contain additional components, including additional particle types (e.g., with different active agents, % loading and / or different controlled release vehicles), liquid carriers in which the particles are dispersed, and excipients such as pH adjusters, viscosity adjusters, dispersants, tonicity adjusters, preservatives and stabilizers, solubilizers and emulsifiers.

[0529] The target concentration of the pharmacologically active agent in the bladder is typically in the range of 10 ppm to 150 ppm in urine, i.e., 10 mg / L to 150 mg / L, such as 10 ppm, 16 ppm, 20 ppm, 35 ppm, 45 ppm, 50 ppm, 75 ppm, 100 ppm, 115 ppm, 125 ppm and 128 ppm (corresponding to 10 mg / L, 16 mg / L, 20 mg / L, 35 mg / L, 45 mg / L, 50 mg / L, 75 mg / L, 100 mg / L, 115 mg / L, 125 mg / L and 128 mg / L, respectively), etc., but this will of course depend on a variety of factors, including the active agent administered, the indication, the age, weight and condition of the subject, etc. A preferred subrange is 15 ppm to 130 ppm. The dosage can be calculated by extrapolating from the following examples. For a 90-day drug delivery period, about 100 L will pass through the bladder. Assuming that 100% of the active agent in the particles will be released into the bladder during a 90-day period, achieving a concentration of 20 mg / L requires the delivery of 2000 mg (2 g) of active agent or 2 g to treat 100 L of urine. For a population of particles containing 25% active agent and 75% controlled release carrier, 8 g of particles must be applied to deliver 2 g of active agent to the bladder. As another example, during a 180-day drug delivery period, about 200 L of urine will pass through the bladder. Similarly, assuming that 100% of the active agent in the particles is released into the bladder during a 180-day period, achieving a concentration of 50 mg / L requires the delivery of 10,000 mg (10 g) to treat 200 L of urine. For a population of particles that also contains 25 wt.% of active agent and 75 wt.% of controlled release carrier for illustration purposes, 40 g of particles must be applied to deliver 10 g of active agent to treat 200 L of urine. The calculations can be easily adjusted for different ratios of active agent to carrier, time periods of drug delivery, and target concentrations of active agent in the bladder. It should also be noted that as urine production varies throughout the day, the concentration of active agent in the bladder also varies throughout the day (and may peak during times of low urine production).

[0530] The extended drug delivery time period ranges from about one month to at least about three months, e.g., about two months to about four months, about three months, at least about three months, four months, five months, six months, etc., during which the active agent is released from the particles into the bladder, and preferably during which a therapeutically effective concentration of the active agent or a metabolite thereof is provided in the bladder.

[0531] G. Indications and Administration:

[0532] The granular formulations of the present invention can be administered to a subject to treat a disorder of the urinary system. The disorder can be a disease or other adverse condition of the bladder, kidney, ureter and / or urethra, and is not limited in any respect unless the disorder is responsive or expected to be responsive to intracapsular administration of a specific pharmacologically active agent or a specific type of pharmacologically active agent. Examples of urinary disorders that can be treated according to the present invention include urinary tract infections (commonly referred to as "UTIs" or urinary tract infections), such as bacterial infections, fungal infections, and viral infections; cancer or benign tumors of the urinary system; urinary incontinence (including urge incontinence or overactive bladder, "OAB") and urine retention; urinary tract inflammation, injury or scarring; and kidney stones, diabetic nephropathy or renal failure.

[0533] Examples of representative active agents for specific indications and therapeutic indications are as follows:

[0534] Cystitis (infection of the lower urinary tract), including acute cystitis, chronic cystitis, hemorrhagic cystitis, bacterial cystitis and emphysematous cystitis, any of which may be caused by bacterial infection, fungal infection or viral infection, and treated accordingly with appropriate anti-infective agents (for representative antibacterial, antifungal and antiviral agents, see Section 2.A);

[0535] Interstitial cystitis (also known as painful bladder syndrome, BPS), is usually treated with serotonin reuptake inhibitors (SRIs) such as tricyclic antidepressants (amitriptyline, imipramine, desipramine, etc.), serotonin-norepinephrine reuptake inhibitors (such as duloxetine or venlafaxine), anti-inflammatory agents (as described in Section 2.A; ibuprofen is typical), or pentosan polysulfate;

[0536] Neurogenic bladder dysfunction, which is usually treated with anticholinergics (e.g., oxybutynin or tolterodine) to reduce bladder contractions, or muscarinics (e.g., bethanechol or alpha-blockers such as phentolamine) to treat overflow incontinence;

[0537] Overactive bladder (OAB; also known as "urge incontinence") syndrome, which is usually treated with antimuscarinic drugs (e.g., darifenacin, scopolamine, oxybutynin, tolterodine, solifenacin, trospium chloride, or fesoterodine) or with β3-adrenergic receptor agonists (such as mirabegron or vibergolone);

[0538] Incontinence caused by OAB, which is typically treated with narcotics or analgesics such as those identified in Section 2.A.

[0539] Stress incontinence, also known as stress urinary incontinence (SUI), is caused by inadequate closure of the bladder outlet by the urethral sphincter;

[0540] Chlamydia (Chlamydia trachomatis) and gonorrhea (Neisseria gonorrhoeae), which are typically treated with antibiotics such as azithromycin, doxycycline, erythromycin, levofloxacin, ofloxacin, or tetracycline (see Section 2.A for additional representative active agents for the treatment of Chlamydia);

[0541] Gonococcal urethritis caused by infection with Neisseria gonorrhoeae, which is usually treated with ceftriaxone or a combination of ceftriaxone and azithromycin;

[0542] Nongonococcal urethritis, which is usually treated with antibiotics such as azithromycin, doxycycline, erythromycin, levofloxacin, or ofloxacin and is usually caused by Chlamydia trachomatis, Trichomonas vaginalis, adenoviridae, uropathogenic Escherichia coli, HSV1 or HSV-2, cytomegalovirus, Ureaplasma urealyticum, methicillin-resistant Staphylococcus aureus, or Group B Streptococcus, most commonly caused by Chlamydia;

[0543] Enzyme poisoning, which is usually treated with benzathine benzylpenicillin or ceftriaxone;

[0544] Pyelonephritis, which is usually treated with fluoroquinolone antibiotics (such as ciprofloxacin or levofloxacin), cephalosporin antibiotics (such as ceftriaxone), aminoglycoside antibiotics (such as gentamicin), or fosfomycin;

[0545] Kidney stones, which can be treated with, for example, allopurinol, alkalinizing agents, or thiazide diuretics, as explained in Section 2.A;

[0546] Pain associated with kidney stones, which is usually treated with NSAID anti-inflammatory / analgesics or with opioid analgesics;

[0547] Diabetic nephropathy (diabetic kidney disease) treated with renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, direct renin inhibitors or mineralocorticoid antagonists or with antidiabetic agents (see section 2.A);

[0548] Vesicoureteral reflux (VUR), a disorder that increases the likelihood of urinary tract infections, especially in children; and

[0549] Cancer or benign tumors of the urinary system treated with chemotherapeutic agents as described in Section 2.A, in particular apiquatone, fosfomycin, gemcitabine and BCG immunotherapy.

[0550] Application

[0551] The intravesical formulation is administered using any known or later developed device suitable for introducing the pharmaceutical formulation into the bladder. For example, the formulation can be administered by passing through a urethral syringe, a Toomey syringe or via a catheter.

[0552] Intracapsular administration of the formulations of the present invention is particularly useful for treating individuals for whom therapeutically effective doses of oral medications may be problematic, including the elderly and children, with the elderly accounting for the majority of individuals with recurrent and / or severe urinary disorders. In addition, the present invention also finds application in treating individuals with any of a wide range of conditions and diseases that increase the likelihood of urinary disorders, particularly complicated urinary tract infections. Such individuals include subjects with lupus and other systemic autoimmune diseases; subjects receiving immunosuppressive therapy; subjects with neurological disorders; subjects with sexually transmitted diseases; diabetic patients; cancer patients; patients with functional or anatomical abnormalities of the urinary tract; patients who experienced UTIs as children; patients who have received extensive antimicrobial therapy; patients with nosocomial infections; and many other individuals.

[0553] Other Uses

[0554] Although the formulation / particles are described for treating diseases of the urinary tract (e.g., UTI), the skilled person will appreciate other uses of the invention. For example, the particles can be coated with agents such as tissue plasminogen activator or streptokinase. They can be instilled into anatomical spaces such as the pleural cavity of the chest for the purpose of dissolving adhesions and cavities in sterile or infected pleural effusions. The particles can be inserted surgically or through a thoracostomy tube in the chest. The particles will float to the top of the cavity, selectively delivering therapy to break up abscesses / cavities and connect them to adjacent spaces, which more effectively empties the chest cavity and allows the lungs to expand better into the thorax.

[0555] The platform can be used with drugs whose targets are preferentially in the apical portion of the anatomical space, potential space, surgical space, or pathological space that would benefit from floating drug delivery particles. For example, in an apical bleb causing a pneumothorax, it is desirable to deliver a targeted stimulus to the apex of the bladder to induce scarring apically to the pleural wall. The loaded particles can be preferentially delivered to this target in the following manner:

[0556] a) inserting the drug delivery rod into the chest cavity;

[0557] b) The thoracic cavity receives a fluid instillation, allowing the particles to travel to the top of the space using buoyancy;

[0558] c) The fluid is then rapidly evacuated from the space, leaving the floating particles at their target to deliver a high and focused drug concentration or mechanical stimulation.

[0559] In a similar manner, the particles could be injected through peritoneal dialysis catheters to disrupt adhesions and lumens that render the catheter nonfunctional, saving the patient a repeat procedure.

[0560] The pellets can be inserted via a catheter into abscess cavities located in sensitive areas that make surgical removal undesirable (such as the face, breasts, genital tissue, CNS). The pellets can be used in other fluid-filled areas:

[0561] a) CSF (spinal column or skull)

[0562] b) Sinus venosus of the skull (valveless)

[0563] c) Pleural space

[0564] d) Peritoneal space

[0565] e) Pericardial space

[0566] The buoyancy of the particles can be used to preferentially target therapy into the vascular tree. Specifically, if the aorta has multiple terminal vessels, there is no way to deliver targeted therapy other than blanket coverage of the entire downstream region (shotgun approach) or selective catheter delivery (technically difficult). Buoyancy allows the patient to be positioned so that the particles will preferentially enter the least dependent vascular branches (or specifically avoid the most dependent branches). Example

[0567] The following non-limiting examples are provided for illustrative purposes only, so as to contribute to a more complete understanding of the representative embodiments now contemplated. These embodiments are intended to be only a subset of all possible situations in which the components of the preparation can be combined. Therefore, these embodiments should not be construed as limiting any embodiment described in this specification, including those of the type and amount of the components of the preparation and / or its method and use.

[0568] Example 1

[0569] Antimicrobial efficacy of SSD in artificial urine

[0570] The antimicrobial efficacy of SSD in artificial urine against a variety of test microorganisms was evaluated by determining the reduction in planktonic logarithms after specific contact times. The test was designed to measure the % kill and log reduction of planktonic cultures of several microorganisms after six different exposure times. SSD was tested at four different dilutions to demonstrate the kill rate of silver ions.

[0571] The challenge time, dilution range of silver ions and dilution range of SSD are provided in Table 1:

[0572] Table 1

[0573] sample Excitation time (hours) <![CDATA[Dilution (Ag + ), mg / L]]> Dilution(SSD),mg / L SSD 0,1,2,4,6 3,5,10,20 9.93,16.55,33.11,66.22 Negative control 0,1,2,4,6 - -

[0574] Artificial urine was prepared as described by Brooks et al. (1997), "A simple artificial urine for growth of urinary pathogens," Lett Appl Microbiol 24(3):203-6, sterilized by filtration through a 0.2 mm filter unit, and stored at 4° C. The microorganisms, growth media, and conditions are set forth in Table 2:

[0575] Table 2

[0576]

[0577]

[0578] The organisms in Table 2 were tested over time using exposure time points of 1 h, 2 h, 4 h and 6 h (as indicated in Table 1) from the same plate. Three plates were required for each strain, for a total of 27 challenge plates. Three replicates were used, with sterile controls and growth controls used for each experiment. The working solution consisted of the test composition or control composition according to Table 1, and 4.8 mL of the working solution was added to the appropriate wells of the challenge plate.

[0579] Inoculum preparation

[0580] Using cryogenic stocks (at -70°C), a first subculture of the microorganisms was punched out on appropriate media (TSA plates for bacterial isolates or SDA plates for Candida albicans as indicated in Table 2).

[0581] Incubate the plates at 37°C ± 2°C for 24 hours and store at 4°C ± 1°C until needed. From the first subculture, a second subculture is removed on an appropriate medium (again, TSA for bacterial isolates, or SDB / SDA for Candida albicans). From the first subculture, a second subculture is removed on an appropriate medium (TSA for bacterial isolates, or SDB / SDA for Candida albicans). Approximately 4-5 large, well-defined colonies or 5-10 small, well-defined colonies from the second subculture plate are emulsified in distilled, deionized water and adjusted to achieve a turbidity equivalent to a 0.5 McFarland standard.

[0582] Bacteria were emulsified in 6 mL of water, while Candida albicans was emulsified in 12 ml of distilled water. The cell suspension was centrifuged (3000 × g for 10 min), and the pellet was washed twice by decanting the supernatant and resuspending the cell pellet in an equal volume of distilled deionized water. After washing, the cell pellet was resuspended in distilled deionized water, bacteria were resuspended in 20 mL of water, and Candida albicans was resuspended in 4 ml of distilled water.

[0583] The cell density of the inoculum was confirmed by serial dilution and spot plating. Purity was checked by checking the spot plates for abnormal-looking colonies after 16-20 hours of incubation. All strains were determined to be pure cultures.

[0584] Inoculation of the stimulation plate

[0585] 200 μL of inoculum was added to each well of the challenge plate, except for the sterile control (SC) well. 200 μL of sterile water was added to the SC well. The inoculated plates were incubated at 37°C ± 2°C in a non-CO2 incubator, and samples were obtained at 0 hours, 1 hour, 2 hours, 4 hours, and 6 hours.

[0586] Recovery rate

[0587] After each challenge time point, in the most concentrated serial dilution plate, mix 100 μL with 100 μL of modified D / E Neutralizer composition (D / E Neutralizing Broth, 5 g / L L-cysteine ​​and 5 g / L glutathione, 2x strength). Place 180 μL of sterile 0.9% saline in the remaining dilutions. Prepare 1 to 10 7 Serial dilutions of . Then 10 μL is taken from each well and spot plated onto the prepared TSA plate or SDA plate. The plate is incubated at 37°C ± 2°C and the number of resulting colonies is counted after about 16-24 hours of incubation. The data are evaluated as log10 CFU / mL.

[0588] Neutralization Verification

[0589] Each inoculum of 200 μL per strain was placed into triplicate wells containing 2 mL of modified D / E neutralizer composition and 1.8 mL of 20 ppm Ag+ test solution. After 5 min, 100 μL from each well of the neutralization efficacy plate was pipetted into the first row of a 96-well microtiter plate. 180 μL of sterile 0.9% saline was placed in the remaining rows. Serial dilutions were prepared, 10 μL were taken out from each well and spot plated, the plate was incubated, and the data were evaluated as described in "recovery".

[0590] Computing and Statistics

[0591] ·Point CFU / mL=(CFU / 10μL) / 0.010

[0592] ·Log10(CFU / mL)=Log10(CFU / mL+1)

[0593] Log10 reduction = Log10 (CFU / mL) (growth control) - Log10 (CFU / mL) (test condition)

[0594] % Killing = ((antilog mean (growth control) - antilog mean (test condition)) / antilog mean (growth control)) x 100

[0595] P values ​​compared to growth controls are one-way ANOVA with Tukey's multiple comparison post hoc test.

[0596] result

[0597] After 4 hours, a Log10 reduction of >4 was observed for E. coli, K. pneumoniae, P. mirabilis, and C. albicans at all four SSD concentrations tested. After 6 hours, a Log10 reduction of >3 was observed for S. saprophyticus at all four SSD concentrations tested. There were no detectable differences in the amount or rate of killing between the four different concentrations of SSD tested.

[0598] Example 2

[0599] Antimicrobial efficacy of SSD and cefpodoxime against UTI bacterial isolates

[0600] According to SSD for Table 2 (in Figure 2The antimicrobial efficacy of SSD and cefpodoxime was evaluated against the organisms listed in Table 1 (detailed in Table 1 ) and against two multidrug resistant (MDR) clinical isolates of Escherichia coli. Cefpodoxime, a commonly prescribed antibiotic, was used as a control. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined. These define the potency of the drug in terms of the concentration at which the drug will inhibit (MIC) the growth of the challenged microorganism or completely kill (MBC) 1 × 10 6 The MIC values ​​for SSD and cefpodoxime against each of the 10 isolates were generated according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) using reference frozen form broth microdilution susceptibility plates and 50% pooled human urine. Fifteen doubling dilutions (1:2 serial dilutions) of both SSD and cefpodoxime were tested, and bacterial colony counts were performed for each isolate tested to determine the starting inoculum concentration (target 5×105 CFU / mL). The results are Figure 2 (Table 3)

[0601] Example 3

[0602] Pellet Manufacturing:

[0603] Granules were prepared using a melt spray congealing (MSC) process, in which tristearate ( 118, from IOI Oleochemicals GmbH, hereinafter "Dynasan") as a controlled release carrier, and silver sulfadiazine (SSD), an antibiotic, as the pharmacologically active agent. The process involves dispersing the SSD in a Dynasan melt, and then atomizing the composition so provided using a rotary atomizer. The atomized droplets are allowed to condense, resulting in the SSD being entrapped in the Dynasan matrix. The MSC manufacturing process is Figure 1 The particle size of the MSC particles can be adjusted by controlling the feed material viscosity, rotation speed and feed rate as well as the disc design and disc size. Reducing the feed material viscosity, rotation speed and / or feed rate will provide larger particles.

[0604] MSC protocol for preparation of particles with 25% silver sulfadiazine and 75% Dynasan: see Figure 1Dynasan (40 g) was melted at 90°C in a kettle 1. After melting was complete, SSD (13.3 g) was added to the kettle containing the molten Dynasan and dispersed therein using homogenization up to 20,000 rpm for about 3 minutes. The SSD suspension so prepared was then fed into a feed line 3 at a rate of 75 g / min to 100 g / min and fed through a feed pump 5 to a 4"-disc rotary atomizer 7 heated to about 90°C to 100°C and rotating at about 2400 rpm. The SSD suspension formed a thin film across the surface of the disk and was atomized into distinct droplets at its periphery. The atomized droplets condensed in flight and were collected (40 g, 75% yield) on a tray 9, but could also be collected in a plastic housing, or by using a cyclone separator, or using other suitable means. To ensure a narrow particle size distribution, a sieve may be used to screen out particles outside the desired size range.

[0605] Example 4

[0606] Particle density assessment:

[0607] Controlled release particles were prepared with different ratios of SSD and controlled release carrier (CRC), and the particle density was evaluated. The density of various materials is provided in Table 4, while the CRC in the particles, SSD:CRC weight ratio, CRC wt.%, CRC density and (theoretical) particle density are described in Table 5:

[0608] Table 4

[0609] Material <![CDATA[Density (g / cm 3 )]]> SSD 1.496 Trimyristin 0.885 Tripalmitin 0.8752 Glyceryl Tristearate 0.862 Stearyl Alcohol 0.812 Glyceryl Behenate 0.942 Poloxamer P407 1.05 Urine 1.027 0.9% Saline 1.0046

[0610] Table 5

[0611]

[0612]

[0613] Example 5

[0614] SSD particle release profile:

[0615] Contains 25wt.% SSD and 75wt.% Particles of 118 were prepared as described in Example 3 and dispersed in PBS buffered to a pH of 7.4. The concentration of the particles in PBS was 10 mg / mL, with a corresponding concentration of 2.5 mg / mL of the active agent in the formulation. The average particle size (i.e., d(0.5)) was found to be 174 mm.

[0616] The amount of drug released over time was evaluated using a dissolution test performed at 37°C under constant stirring. The results are presented in Table 6, which shows the amount of SSD released, the percentage of total SSD released, and the SSD release rate (% SSD released per hour) at different time points during the evaluation period:

[0617] Table 6

[0618] Time (hours) Released SSD mg Freed SSD % Freed SSD % / hour 3 0.027 1.175 0.392 5 0.038 1.654 0.631 23 0.051 2.202 0.662 96 0.092 3.962 0.686 120 0.117 5.059 0.732 143 0.139 6.010 0.773

[0619] The percentage of SSD released over time is plotted. Figure 3 The results shown in indicate that zero-order release kinetics were achieved, i.e., SSD was released from the particles at an approximately constant rate. At the calculated release rates, the particle formulation would provide controlled release drug delivery in the bladder for up to three months.

[0620] Example 6

[0621] SSD particle release profile:

[0622] Two SSD particle formulations were prepared, both with 20% SSD loading and 75% GTS, one of which was prepared in phosphate buffered saline (PBS) and the other in artificial urine medium (AUM). The particle size was 545 μm, the pH of the formulation was 7.5, and the concentration of the particles in the liquid carrier was 50 mg / mL in both formulations (where the corresponding SSD concentration was 10 mg / mL).

[0623] The amount of drug released over time was assessed using USP dissolution apparatus I at 37°C with constant stirring. To simulate bladder function, 90% of the dilution was removed and replaced at each sampling interval. Figure 4 and Figure 5 Presented in.

[0624] Example 7

[0625] Assessment of particle degradation:

[0626] Figure 6 and Figure 7The results of the degradation assay for evaluating the degradation of tristearin (GTS) / silver sulfadiazine (SSD) particles in artificial urine medium (AUM) are shown. The assay detects the presence or absence of stearic acid produced by the hydrolytic cleavage of the GTS carrier over time. The GTS / SSD microspheres were immersed in AUM with and without lipase for 7 days (168 hours), incubated at 37°C and mixed at 100rpm. Since lipase is an esterase that catalyzes the hydrolytic cleavage of esters, tristearin is hydrolyzed by lipase to produce glycerol and stearic acid; lipase is not present in urine or AUM. Therefore, the microsphere group immersed in AUM with lipase serves as a positive control group. After 7 days, culture medium was collected from both groups, and an ELISA assay (abcam, "Free Fatty Acid Assay Kit-Quantitative", ab65341) for the detection of long-chain free fatty acids (FFA) group was run. In the FFA assay protocol, fatty acids are converted to their CoA derivatives (coenzyme A), which are subsequently oxidized, resulting in the formation of color / fluorescence. Fatty acids are then quantified by colorimetry (λ=570nm) or fluorescence (Ex / Em=535 / 587nm). Palmitic acid is used to generate a standard curve.

[0627] Free fatty acid assay (FFA) protocol:

[0628] • Add media samples and standards from both groups (AUM with and without lipase) to a 96-well plate;

[0629] Mix and incubate at 37°C for 30 min; and

[0630] • Use a spectrophotometric microplate reader to quantify and analyze FFA.

[0631] Figure 6 The results shown in the middle graph show that after 7 days, there was no detectable degradation of the microspheres in the AUM without lipase. This behavior is expected to occur in the human bladder environment, as healthy human urine does not contain lipase. This suggests that the microspheres will persist and maintain their shape and form in the bladder for a long period of time.

[0632] Particle surface dissolution:

[0633] Scanning electron microscope image ( Figure 7 ) confirmed that no surface erosion occurred in the group of microspheres exposed to AUM without lipase, pH 7.5 for 7 days. That is, the images of the microspheres after 7 days were not significantly different from the images taken after 1 hour.

[0634] Example 8

[0635] Vector evaluation:

[0636] Figure 8 A list of carriers and vehicles that have been tested to improve the deliverability of microspheres via foley catheters is outlined. Figure 8 30 mL of each carrier solution listed in was mixed with 5 grams of microspheres and loaded into a Toomey syringe. The Toomey syringe with drug product and carrier was then used to inject through a 12Fr foley catheter. The product output through the foley catheter was rinsed with DI water, dried and weighed to determine the amount that could be delivered and the product lost in the Toomey syringe and catheter.

[0637] Fig. 9 The results of our investigation into whether any carrier or vehicle to which the microspheres were exposed affected their mucoadhesive properties were presented. To test this, the microspheres were immersed in Figure 8 The microspheres were placed in different carrier solutions and then placed on the mucosal surface of a circular tissue section from a bovine bladder. After the microspheres were placed on the tissue section, the tissue section was lifted and immersed in DI water. Fig. 9 The images obtained are provided. With some carriers, such as 0.05% Tween (Tween 20 or Tween 80) and methylcellulose, the microspheres continued to adhere to the tissue.

[0638] An ideal floating carrier is one that exhibits good mucoadhesion and a slow degradation rate, which in turn provides long-term particle retention and sustained drug release in the bladder. Fig.10 The graph shows the results for particles prepared with the carriers indicated in the graph, with mucoadhesion shown as the percentage retained over time, and degradation rates shown over a time period of less than 24 hours to more than 7 days. The materials in the upper left quadrant are both mucoadhesive and slowly degrade, while the materials in the upper right quadrant are excipients that degrade at a faster rate and can be used to accelerate drug release. Fig.10 Placebo microspheres (without any API) were formed using the combinations of materials shown.

[0639] This result was then used to prepare particles using the following as a controlled release vehicle:

[0640] 1) Tristearate only (control)

[0641] 2) 90% tristearate glyceryl: 10% stearyl alcohol

[0642] 3) 90% tristearate glyceryl: 10% hydroxypropyl methylcellulose

[0643] 4) 90% paraffin: 10% stearyl alcohol

[0644] 5) 90% paraffin: 10% hydroxypropyl methylcellulose (HPMC)

[0645] 6) 90% paraffin: 10% poloxamer 407

[0646] 7) 90% paraffin: 10% Softisan 378

[0647] 8) 90% paraffin: 10% Witespol S58

[0648] 9) 90% Tripalmitin: 10% Stearyl Alcohol

[0649] 10) 90% Tripalmitin: 10% NoveonAA (polyacrylic acid polymer)

[0650] 11) 90% Tripalmitin: 10% Witepsol S58

[0651] 12) 90% Tripalmitin: 10% HPMC

[0652] 13) 90% Tripalmitin: 10% Poloxamer 407

[0653] The mucoadhesive ability of the particles prepared with the controlled release carrier described above was tested by slathering 2 grams of microspheres on the mucosal surface of a circular tissue section from a bovine bladder and then immersing the tissue section in DI water and measuring the microspheres that remained adhered to the tissue section. The percentage of microspheres retained was calculated by dividing the microspheres that remained adhered to the tissue section by the original amount slathered on the tissue section. The results of this experiment are given in Fig.11 Shown in.

[0654] Fig.12 Indicates that it is possible to incorporate Fig.10 One of the materials listed in the table above can be used to accelerate drug release. Fig.12 In the experiment, the drug (SSD) was released from two batches of granules with different amounts of stearyl alcohol as carrier (10% and 30% by weight). Stearyl alcohol (StOH) is an excipient that degrades faster than tristearin alone. Fig.12 As shown in Figure 3, the formulation with a higher amount of StOH (30 wt.%) released SSD at a faster rate than the formulation with 10 wt.% StOH. Drug release was evaluated in artificial urine medium at pH 7.5, in which the microspheres were immersed in the medium. 90 mL of diluent was removed at each sampling interval. Samples were evaluated using LC-MS to detect the release of SSD over time.

[0655] The particles formulated with the controlled release carriers listed above were then evaluated for their ability to exhibit buoyancy over 24 hours in artificial urine medium. 500 mg of each of the formulations above were placed in a tube with 10 mL of LAUM. The tubes were then placed in an incubator at 37°C and mixed at 100 rpm for 24 hours. Images of each sample were then taken to evaluate whether the particles formulated with different combinations of controlled release carriers were buoyant after 24 hours. The results are shown in Fig.13 Shown in.

[0656] Fig.14 The retention rate in a single excretion is simulated. For example, assuming a person excretes 5 times a day and the retention rate is 99%, the amount of product left after one day is 1*0.99^(5 excretions x 1 day) = 95%. After 30 days, the amount of product left will be 1*0.99(5 excretions x 30 days) = 22%. This is a chart drawn for different retention rates (99%-99.8%).

[0657] Example 9

[0658] Effect of shape on drug release

[0659] In this example, various shapes of carrier particles were compared. The molecules were prepared by a variety of methods including direct compression, solid lipid extrusion and melt techniques. In order to formulate different shapes and geometries, techniques such as injection molding, melt spray congealing, compression, solid lipid extrusion via hot melt extrusion and casting techniques using 3D printed molds were used.

[0660] The particles tested included cylindrical rods with diameters ranging from 2 mm to 5 mm and heights of 5 mm to 15 mm, which were formulated with molten polymer with drug and injected into silicone tube molds of desired dimensions. Spheres with diameters ranging from 100 μm to 1 mm were formulated using melt spray congealing using an atomizer. Spheres with diameters greater than 1 mm were formulated by casting a hot melt mixture of polymer and drug in a 3D printed mold.

[0661] Product retention and tolerance in the bladder depends on buoyancy. To maintain buoyancy, the density of the drug product must be within the specific gravity range of water or urine, where the density of water is 0.997 g / mL and the density of urine is in the range of 1.005 g / mL-1.030 g / mL.

[0662] Buoyancy and retention in the bladder are influenced by several factors:

[0663] 1) Density - a function of the buoyancy of the dosage form which depends on the density of the surrounding medium,

[0664] 2) Size - Dosage units with a diameter greater than 2 mm are reported to have a 90%-95% retention rate in the bladder.

[0665] 3) Shape of dosage form - single geometry (cylinder, sphere, hemisphere, ellipsoid, torus (ring with bending modulus, cube, hexagonal prism, truncated pyramid, dodecahedron, etc.), multiple units (mixed geometries, same geometry in different sizes), swellable forms (shape change or size expansion upon contact with surroundings triggered by pH, temperature, wettability such as with swellable material, or manual mechanical expansion such as when inflating a balloon) facilitates retention in the bladder. Multiple unit formulations allow for co-administration of units with different release profiles or containing incompatible materials and allow for greater safety margins against dosage form failure compared to single unit dosage forms.

[0666] 4) Coagulation of multiple forms - a single geometry or multiple different geometrical forms of the formulation adhere and coagulate in the presence of water / urine to form a single bulk formulation of a size larger than the urethra diameter, thereby enhancing its retention. This can occur if the formulation is coated with an adhesive or swellable polymer chains that have an affinity for each other when they are wetted.

[0667] The formulation can be designed to float in several ways:

[0668] 1) Microporous compartment system - the drug is encapsulated within a microporous polymer matrix to form a drug delivery vehicle or formulation. The peripheral wall of the formulation is completely sealed by dip coating in a polymer melt to prevent any direct contact with the surrounding medium.

[0669] 2) Hollow cores or pores, where the hollow core consists of a drug reservoir protected by a polymer matrix, or the hollow core is filled with air surrounded by a drug embedded in a polymer matrix. Variations include more than one hollow core at different locations, orientations, and sizes. The core can be filled with vacuum, air, or an inert gas.

[0670] Four carrier particles were tested, e.g. Fig. 15B As shown in:

[0671] Small sphere (2mm)

[0672] Large sphere (4mm)

[0673] Small cylinder (2mm×4mm)

[0674] Large cylinder (2mm×10mm)

[0675] As described below, silver sulfadiazine (SSD) was used for further studies of cylindrical carrier particles.

[0676] Solid core vs. hollow core

[0677] The next study involved comparing the release of SSD from cylindrical particles (solid and hollow) over time. Briefly, SSD was conjugated to the particles and incubated in solution. The concentration of SSD in solution was measured at regular intervals from t0 to 430 hours.

[0678] Fig. 15B The concentration of SSD over time is shown. The rods were loaded with either 18% SSD (top) or 25% SSD (hollow). For both types of particles, the concentration of SSD remained relatively constant throughout the test duration (i.e., to 420 hours). Similarly, Fig. 15C The concentration percentage release over time is shown. The straight line indicates a steady release of the active agent (ie SSD).

[0679] Example 10

[0680] Effect of amikacin solubility on release kinetics

[0681] Several antimicrobial agents were considered for use as the active agent with the carrier particles.

[0682] Table 7

[0683]

[0684]

[0685] Tested against both MDR and non-MDR E. coli isolates

[0686] (Others are tested only for non-MDR E. coli isolates)

[0687] Amikacin is an aminoglycoside used to treat infections caused by more tolerant strains of Gram-negative and some Gram-positive bacteria. It is highly soluble in water at 50 mg / ml. Formulations with free amikacin resulted in 100% release in less than 4 hours. In this example, amikacin was conjugated with pamoic acid via the following steps.

[0688] 1) preparing an amikacin solution in water in the presence of an acid;

[0689] 2) preparing a solution of pamoic acid in water in the presence of a base;

[0690] 3) Mixing the solution until solids precipitate;

[0691] 4) The final step requires filtration and drying of the solid via freeze drying or vacuum oven drying.

[0692] The structure of amikacin is Fig.16AAmikacin conjugated with pamoic acid ( Fig. 16B ) slows its release by reducing its reaction time in urine.

[0693] Next, the conjugate was attached to carrier particles (4 mm x 10 mm rods). The release rate of amikacin in solution (i.e., free amikacin) was measured over time. Fig. 16B Depicted graphically.

[0694] Embodiment 11

[0695] Effect of shape on drug release

[0696] In this example, the release properties of different shapes were investigated. Fig.17A Four shapes used in this embodiment are shown:

[0697] Small sphere (2mm)

[0698] Large sphere (4mm)

[0699] ·Small stick (2mm×4mm)

[0700] Large stick (2mm×10mm)

[0701] An ideal controlled-release particle maintains drug levels at a relatively constant (and pharmaceutically effective) level over a specified period of time. Fig. 17B The percentage of drug released over time for the four carriers tested is shown. The large rods exhibit the most preferred drug release rate. The percentage of drug released increases gradually until 336 hours. The small rods and small spheres have lower drug release rates. The large spheres appear to be the least effective.

[0702] Similarly, Fig. 17C The drug concentration (ppm) over time for the four carriers tested is shown. As mentioned above, the large rods exhibited the most preferred drug release rate. The drug concentration (ppm) remained relatively constant from t0 to 336 hours.

[0703] Example 12

[0704] Effects of different excipients on drug release

[0705] In this example, the effects of different excipients are compared. Materials that degrade faster and / or are more hydrophilic will show faster drug release. Five carrier particles were compared using the same shape (sphere):

[0706] 75% GTP + 5% Stearyl Alcohol

[0707] 80% GTS

[0708] 75% GTP, 5% HPMC

[0709] 80% GTP

[0710] Fig.18A The percentage of drug released over time for the four carrier particles tested is shown. The first carrier (75% GTP + 5% stearyl alcohol) degraded at the highest rate and exhibited the most preferred drug release rate.

[0711] Similarly, Fig.18B The drug concentration (ppm) over time is shown for the four carriers tested. As mentioned above, the first carrier (75% GTP + 5% stearyl alcohol) exhibited the most preferred drug release rate. The drug concentration (ppm) remained relatively constant from t0 to 336 hours.

[0712] The study was repeated using rod-shaped particles (2 mm x 4 mm). The following carrier particles were studied:

[0713] 75% GTP + 5% PAA

[0714] 75% GTP + 5% HPMC

[0715] The results are Fig.19A and Fig.19B The carrier with PAA degraded at the highest rate and exhibited the most favorable drug release rate. In contrast, the carrier with HPMC remained relatively stable with minimal drug release.

[0716] The following preparations were further studied

[0717] 75% GTP + 5% PAA

[0718] 75% GTP + 5% StOH

[0719] The results are Fig. 20A The carrier with PAA showed the most preferred drug release rate. In contrast, the carrier with StOH showed the minimum drug release.

[0720] Based on the above results, rods with different amounts of PAA were compared. Specifically, the following formulations were further studied:

[0721] 75% GTP + 5% PAA

[0722] 75% GTP + 2.5% PAA

[0723] 75% GTP + 1% PAA

[0724] The results are Fig. 20BThe carrier with 5% PAA exhibited the most preferred drug release rate. In contrast, the carrier with a smaller amount of PAA exhibited a lower level of drug release.

[0725] Embodiment 13

[0726] Silver sulfadiazine drug release formulations - different amounts of PAA

[0727] In order to identify the preferred concentration of PAA, rods with higher amounts of PAA were compared. Specifically, the following formulations were further investigated for rods (4 mm x 10 mm) loaded with 18% SSD:

[0728] 75% GTP + 5% PAA

[0729] 75% GTP + 7.5% PAA

[0730] 75% GTP + 10% PAA

[0731] The results are Fig.21A and Fig. 21B The carriers with 5% PAA and 7.5% PAA showed similar concentrations of SSD. The higher PAA (10%) showed the fastest drug release rate.

[0732] Based on the above results, rods prepared by different methods were investigated. The rods (4 mm x 10 mm) contained 85% GTP and 15% amikacin. The following rod preparations were compared:

[0733] Stirring (stirring at 100 rpm)

[0734] Homogenization (homogenization at 5,000 rpm)

[0735] The results are Fig.22A and Fig. 22B The stirred carrier exhibited a fast drug release rate. In contrast, the homogenized carrier exhibited a slower drug release level.

[0736] The characteristics of each type of rod are Fig. 22C The stirred carrier exhibited a zero order release profile, with 100% released in 17.5 days. In contrast, the homogenized carrier exhibited a first order release profile, with 100% released in 69.5 days.

[0737] Embodiment 14

[0738] Topcoatings to modify drug release

[0739] Dipping or spraying the final form of the formulation in solvents such as acetone and ethanol or polymer / excipients can slow drug release by providing an additional barrier around and outside the formulation to allow drug release to occur. The viscosity of the polymer melt, the polymer / excipient mixture, the duration of the dip, the percentage of solvent in the solution (v / v) all affect the thickness of the coating and how tightly the barrier packs into the final form (e.g., like a knitted sweater).

[0740] Dipping can occur partially, where some portions of the formulation are coated while the remainder are not, or the entire rod / formulation can be dipped and thus coated.

[0741] Materials with tunable degradation could be used for controlled drug release

[0742] Materials in the bladder that have been tested by the present inventors for drug delivery in the bladder include the following classes, known exclusively as These materials differ according to their melting point and hydroxyl value. Materials with lower melting points closer to body temperature (e.g., 30°C-39°C) will degrade faster than materials with higher melting points. Hydroxyl value is defined as the milligrams of potassium hydroxide (KOH) required to neutralize the acetic acid absorbed by the acetylation of one gram of chemical substances containing free hydroxyl groups. Hydroxyl is a common hydrophilic group and can be used to modify the surface and change the wettability of the excipient due to its ability to form hydrogen bonds with surrounding water. The density of hydrogen bonds formed between hydroxyl and water molecules in the adsorption layer contributes to the overall wettability of the excipient. The increase in wettability can increase the degradation of the excipient via hydrolysis, and thereby achieve drug release. Consider the two properties of the material to select the basis, main excipient or a combination of several excipients for the formulation to achieve ideal degradation and drug release probability and drug release rate. The base polymer material may include a hydrophobic material with a high melting point, such as tripalmitin (also known as glyceryl tripalmitate) in the range of 50%-95% (w / w), mixed with an excipient in the relative range of 1%-50% (w / w) to enhance degradation and drug release. 116) or tristearin (e.g. 118) or glyceryl monostearate (e.g. 114). The mixed polymer can be melted and then mixed with the drug (or API) in the range of 1%-25% (w / v).

[0743] Several rapidly degrading materials were tested as rapid release formulations, as summarized in Table 8 below.

[0744] Table 8

[0745]

[0746] Based on the above results, rods were prepared by using Witepsol S58 and Witepsol H19 as fast release formulations. Fig.23 The particles with Witepsol S58 released amikacin rapidly (ie, reached a peak concentration of 5000 μg / ml in about one hour). In contrast, the particles with Witepsol H19 released amikacin slowly (reached a peak concentration of 150 μg / ml in about two hours).

[0747] Embodiment 15

[0748] Adjusting crystallinity

[0749] Polymorphs occur when a polymer solidifies with different chemically identical lattice structures, thus having different tertiary and quaternary structures. Adjusting the crystallinity of a product or making different polymorphs enables the adjustment of drug release, buoyancy, density, material properties such as hardness, stability, packing, and appearance. In this example, an alpha (a) crystal structure and a beta (β) crystal structure were produced and compared.

[0750] Alpha (a): Based on a theoretical polymer lattice, this will appear "shiny" because the lattice is highly ordered and the carbon chains are laid in parallel so there is a smooth surface in the quaternary structure. To create alpha, the energy of the system must be lowered to reduce motion along the monomer degrees of freedom and reduce intramolecular hindrance.

[0751] Beta (β): will appear more randomly packed and "chalky" because the monomer has a bent glycerol carbon chain. If beta was more randomly packed then energy must be stored between the polymer units during the polymerization process.

[0752] The properties of each type of crystal structure are Fig.24 Factors that can be adjusted to achieve a beta structure or an alpha structure include:

[0753] Cooling rate and temperature: Slow cooling at room temperature (e.g., 25°C) produces the b crystal structure. Fast cooling at 4°C produces the a crystal structure.

[0754] • Cure Rate: Curing the bars in an oven at 115°F / 55°C for 14 hours produced the b crystal structure.

[0755] • Melt cycles: The polymer is melted, allowed to resolidify, and melted again to produce the b crystal structure.

[0756] • Surface area and size of the rod: Larger rods take longer to cool, and the b-crystal structure is more likely to form with a 5 mm x 15 mm rod than with a 4 mm x 5 mm rod.

[0757] Effect of drugs or excipients on polymorphism: The addition of polar drugs or excipients will favor the b crystal structure. Different carbon end groups such as tristearate and tripalmitate affect crystallinity.

[0758] Example 16

[0759] Coating

[0760] Extended circulation is a prerequisite for effective drug delivery and therapeutic effect. Coatings of different polymers and excipients around the rod can enhance the buoyancy of the rod by covering air pockets / pores. Without the coating, the pores or air pockets are replaced by the surrounding medium / urine and thereby cause the rod to sink. In aspects, the coating helps to exclude water, keep the particles floating and / or extend / control the drug delivery rate. In aspects, the coating changes the rate at which the particles degrade.

[0761] A variety of factors can be fine-tuned to achieve the ideal coating thickness - exposure time, curing temperature, solvent type, solvent concentration, solvent-polymer (v / v) ratio, synthetic polymers and natural polymers (i.e., poly(ethylene glycol) PEG, tripalmitin, tristearin, poly(lactic-co-glycolic acid), poly(caprolactone), etc.) so that their addition to the rod as a coating does not increase the overall density above that of urine.

[0762] The above findings also enable increased drug loading without compromising buoyancy. The coating can be made by a variety of processes - dipping the rod directly into a hot melt of a polymer and solvent mixture or spraying. The coating can slow drug release and burst release by acting as a barrier for drug diffusion out. This can be adjusted by the thickness of the coating or by coating portions of the rod (half rod vs. full rod) or different polymers / excipients that differ in hydrophobicity.

[0763] For example, increasing the drug loading from 15% to 20% and 25% does not compromise buoyancy and thereby allows for an increase in the drug loading per rod. Fig.25 .

[0764] Embodiment 17

[0765] Treatment of chronic UTI

[0766] In this example, an elderly female patient visits a healthcare provider due to signs / symptoms of a UTI. The provider notes that the patient has had three UTIs over a six-month period. Previously, she had been prescribed oral antibiotics (i.e., amoxicillin or nitrofurantoin). Although prophylactic antibiotics are an option, the patient wishes to avoid them. In addition, the healthcare provider acknowledges the risk of antibiotic resistance.

[0767] The provider proposes the option of using intracapsular controlled release particles. Conventional drug delivery systems (e.g., tablets, capsules, etc.) may suffer from poor bioavailability and fluctuations in plasma drug levels. The use of intracapsular particles allows the drug to be delivered at a specified controlled rate and at the target site for greater efficacy and safety.

[0768] The particles were prepared as described herein. Specifically, the rod-shaped particles contained 85% GTP and 15% amikacin. Relatively large particles were used (i.e., rods with a length of 2.0 mm to 2.5 mm). The provider administered the particles using a 5 mm syringe (i.e., transurethra). Thereafter, presence / location was observed via ultrasound.

[0769] The Provider states that most of the particles are retained in the bladder because (a) during the first half of the voiding cycle, when the urethral opening is at its largest, they tend to remain away from the urethral opening; (b) as the bladder is drained and the urethral opening gradually narrows, in the second half of the voiding cycle and as voiding nears completion, the particle diameter is wider than the narrowing urethral opening; and (c) at the end of the voiding 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 and prevent outflow of the particle formulation until the active agent is substantially completely released.

[0770] The particles deliver the drug to specifically increase drug concentration in the bladder / urethra. Benefits include:

[0771] No need to take antibiotics (tablets, capsules, etc.) on a regular basis

[0772] Antibiotics are effective at lower doses (lower doses are needed for topical rather than systemic use)

[0773] Lower likelihood of adverse / unwanted side effects

[0774] Low likelihood of antibiotic resistance

[0775] Avoid first-pass metabolism

[0776] Improved therapeutic window

[0777] The patient reported symptom relief within six hours of the procedure. The patient had no discomfort nor any sense that the particles were present. The patient was evaluated one week later and had no signs / symptoms of infection. Additionally, the provider noted that there was no detectable circulating amikacin, although amikacin was present in the bladder at effective concentrations. An ultrasound was performed, and approximately 90% of the particles were still present in the bladder. A second ultrasound was performed four weeks later, and approximately 10% of the particles were present. Thereafter, the patient was advised to maintain regular visits to her healthcare provider and report any signs / symptoms of a possible UTI.

[0778] Embodiment 18

[0779] Treatment of overactive bladder

[0780] Overactive bladder can result when the bladder muscles begin to contract on their own, even when the amount of urine in your bladder is low. These "involuntary contractions" create an urgent need to urinate. Several conditions may cause signs and symptoms of overactive bladder, including: neurological disorders (such as stroke and multiple sclerosis), diabetes, UTIs that can cause symptoms similar to overactive bladder, hormonal changes during menopause, tumors, bladder stones, an enlarged prostate, constipation, or previous surgery to treat incontinence.

[0781] In this example, an elderly male patient visits a healthcare provider due to signs / symptoms of overactive bladder. He complains of frequent and sudden urges to urinate that are difficult to control. He describes the sensation of needing to urinate multiple times during the day and night. He also has frequent accidental urine leakage (i.e., urge incontinence). Behavioral therapy (i.e., pelvic floor muscle exercises, exercise, and dietary changes) has no effect.

[0782] Oxybutynin is an antispasmodic that can help reduce bladder muscle spasms and the frequent urge to urinate caused by these spasms. Oxybutynin is indicated for patients with symptoms of overactive bladder or detrusor overactivity, including frequent urination and urgency. The provider proposes the option of using intracapsular controlled release particles with oxybutynin to help relax the bladder muscles. The particles are prepared as described herein. Specifically, rod-shaped particle rods (4 mm×10 mm) contain 85% GTP and 15% oxybutynin. The particles are administered to the patient using a 5 mm syringe.

[0783] The patient reported symptom relief within two hours of the procedure. The patient had no discomfort nor any perception of the presence of the pellets. The patient was evaluated one week later and reported an 80%-90% reduction in signs / symptoms of overactive bladder. In addition, the provider noted that there was no detectable circulating (i.e., systemic) oxybutynin. The patient was advised to maintain regular visits to his healthcare provider and report any symptoms of overactive bladder. If symptoms recur, the healthcare provider will discuss the possibility of repeating the treatment.

[0784] Embodiment 19

[0785] Treatment of interstitial cystitis

[0786] Interstitial cystitis is a chronic condition that causes bladder pressure, bladder pain, and sometimes pelvic pain. The pain ranges from mild discomfort to severe pain. This condition is part of a spectrum of diseases known as painful bladder syndrome. Interstitial cystitis most often affects women and can have a long-term impact on quality of life.

[0787] In this example, a 65-year-old female patient visits a healthcare provider due to signs / symptoms of interstitial cystitis. Previously, she had used antihistamines along with nonsteroidal anti-inflammatory drugs with little or no improvement in symptoms.

[0788] Pentosan Polysulfate Sodium It is a weak blood thinner used to treat discomfort or bladder pain associated with interstitial cystitis. The most common side effects of Elmiron are hair loss, diarrhea, and nausea.

[0789] The provider suggests the option of using intracapsular controlled release particles with pentosan polysulfate sodium.Conventional drug delivery systems (eg, tablets, capsules, etc.) can suffer from poor bioavailability and fluctuations in plasma drug and side effects.

[0790] The particles were prepared as described herein. Specifically, rod-shaped particle rods (4 mm x 10 mm) contained 85% GTP and 15% sodium pentosan polysulfate. The particles were administered to the patient using a 5 mm syringe.

[0791] The patient reported symptom relief within 24 hours of the procedure. The patient had no discomfort nor any sense of the presence of the pellet. The patient was evaluated one week later and reported approximately 80% reduction in signs / symptoms of interstitial cystitis. The patient is advised to maintain regular visits to her healthcare provider and report any discomfort. If symptoms recur, the healthcare provider will discuss the possibility of repeating the treatment at regular intervals.

[0792] Embodiment 20

[0793] Bladder cancer treatment

[0794] Types of bladder cancer include urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma. In this example, a 75-year-old male patient visits a healthcare provider complaining of frequent and painful urination. He also reports the presence of blood in his urine. The healthcare provider evaluates the patient and ultimately sends a tissue biopsy for diagnosis.

[0795] The patient was diagnosed with urothelial carcinoma. This type of cancer develops in the cells that line the inside of the bladder. Urothelial cells swell when the bladder is full and contract when the bladder is empty. These same cells line the inside of the ureters and urethra, and cancer can form in those places, too. Urothelial carcinoma is the most common type of bladder cancer in the United States.

[0796] The specialist recommended surgery, followed by chemotherapy. Chemotherapy after surgery (called adjuvant chemotherapy) can kill remaining cancer cells and reduce the chances of these cancer cells forming new tumors. For adjuvant chemotherapy, the specialist recommended intravesical chemotherapy to target cancers that are confined to the lining of the bladder but have a high risk of recurrence or progression to a higher stage. The patient agreed to the recommended course of treatment. The adjuvant therapy will be intravesical chemotherapy with gemcitabine.

[0797] The patient undergoes surgery and is allowed recovery time. Thereafter, the patient receives adjuvant therapy using particles as described herein. Specifically, rod-shaped particle rods (4 mm x 10 mm) contain 85% GTP and 15% gemcitabine The particles are administered directly into the patient's bladder through the urethra using a 5 mm syringe.

[0798] An ultrasound was performed one week after the procedure, and approximately 90% of the particles were still present in the bladder. This method allows effective levels of the agent to remain in the bladder for extended periods of time (i.e., greater than one month). Thereafter, the patient is advised to maintain regular visits to his healthcare provider and report any discomfort.

[0799] Certain embodiments of the present invention are described herein, including the best modes known to the inventor for carrying out the present invention. Of course, after reading the foregoing description, the changes to the embodiments described will become apparent to those of ordinary skill in the art. The inventor anticipates that the technician will adopt such changes as appropriate, and the inventor contemplates that the present invention is implemented in a manner different from that clearly described herein in addition. Therefore, the present invention includes all modifications and equivalents of the subject matter set forth in the appended claims hereof permitted by applicable law. In addition, the above-mentioned embodiments are encompassed by the present invention in any combination of all possible variations thereof, unless otherwise noted herein or otherwise clearly contradictory to the context.

[0800] Then, in one embodiment, a controlled release pharmaceutical formulation is provided for intravesicular administration to a subject, the formulation may include a particle population having an average diameter greater than 2.0 mm, and may include about 2.5 wt.% to about 95 wt.% of a pharmacologically active agent and about 5 wt.% to about 97.5 wt.% of a controlled release carrier, the controlled release carrier effectively floats the particles in the urine, and provides sustained release of the active agent in the bladder over a period of time of about one month to at least about three months, for example, about one month to about four months, throughout the extended drug delivery period. According to some embodiments, the drug delivery period is in the range of about two months to about four months, such as about three months. In some embodiments, the average diameter of the particles is in the range of 2.0 mm to about 12.0 mm, 2.0 mm to about 6.5 mm, 2.0 mm to about 6.0 mm, about 2.5 mm to about 5.5 mm, about 2.5 mm to about 5.0 mm, about 2.5 mm to about 4.5 mm, about 2.5 mm to about 3.5 mm, or 2.0 mm to about 3.0 mm.

[0801] In one aspect, the controlled release particles described herein are cylindrically-shaped (ie, barrel-shaped or cylindrical) or substantially cylindrical. In one aspect, they have a diameter of about 10 mm. 3 Up to 50mm 3 In one aspect, the particles have a volume of about 1 mm 3 , about 2mm 3 , about 3mm 3 , about 5mm 3 , about 7mm 3 , about 10mm 3 , about 15mm 3 , about 20mm 3 , about 25mm 3 , about 30mm 3 、Approx. 35mm 3 、Approx. 40mm 3 、Approx. 45mm 3 , about 50mm 3 、Approx. 60mm 3 、Approx. 70mm 3 、Approx. 80mm 3 、Approx. 90mm 3 , about 100mm 3 In one aspect, the particle has a hollow core.

[0802] In one aspect, the particles have a size of about 2 mm 2 , about 3mm 2 , about 5mm 2 , about 7mm2 , about 10mm 2 , about 15mm 2 , about 20mm 2 , about 25mm 2 , about 30mm 2 、Approx. 35mm 2 、Approx. 40mm 2 、Approx. 45mm 2 , about 50mm 2 、Approx. 60mm 2 、Approx. 70mm 2 、Approx. 80mm 2 、Approx. 90mm 2 , about 100mm 2 or larger surface area.

[0803] In one aspect, the controlled release particles described herein are spherical (ie, round) or substantially spherical. In one aspect, they have a diameter of about 10 mm. 3 Up to 50mm 3 In one aspect, the particles have a volume of about 1 mm 3 , about 2mm 3 , about 3mm 3 , about 5mm 3 , about 7mm 3 , about 10mm 3 , about 15mm 3 , about 20mm 3 , about 25mm 3 , about 30mm 3 、Approx. 35mm 3 、Approx. 40mm 3 、Approx. 45mm 3 , about 50mm 3 、Approx. 60mm 3 、Approx. 70mm 3 、Approx. 80mm 3 、Approx. 90mm 3 , about 100mm 3 In one aspect, the particle has a hollow core.

[0804] In one aspect, the particles have a size of about 2 mm 2 , about 3mm 2 , about 5mm 2 、About 7mm 2 , about 10mm 2 , about 15mm 2 , about 20mm 2 , about 25mm 2 , about 30mm 2 、Approx. 35mm 2、Approx. 40mm 2 、Approx. 45mm 2 , about 50mm 2 、Approx. 60mm 2 、Approx. 70mm 2 、Approx. 80mm 2 、Approx. 90mm 2 , about 100mm 2 or larger surface area.

[0805] In aspects, the particles have a surface area to volume ratio (SA / V) of about 1.2, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.4, about 2.6, about 2.8, about 3.0, or more.

[0806] In aspects, the intravesical drug delivery formulations disclosed herein are capable of reducing signs / symptoms associated with a disease (e.g., a urinary tract disorder) in individuals with the disease by, for example, 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%, or at least 95%, compared to patients not receiving the same treatment.

[0807] In other aspects, the intravesical drug delivery formulations are capable of reducing the number of bacteria in the bladder / urethra in individuals with bladder / urethra infections by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 10% to about 90%, about 20% to about 9 ...50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 50% to about 100%, about 5 About 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 70% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, or about 60% to about 70%.

[0808] In other aspects, the intravesical drug delivery formulations disclosed herein are capable of reducing recovery time associated with a disease (e.g., a urinary tract disorder) in individuals with the disease by, for example, 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%, or at least 95%, compared to patients not receiving the same treatment.

[0809] In other aspects, the intravesical drug delivery formulations disclosed herein are capable of reducing the effective amount of a pharmaceutically active agent required to treat a disease (e.g., a urinary tract disorder) in an individual suffering from the disease by, for example, 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%, or at least 95% as compared to conventional oral administration / systemic use of the active agent.

[0810] In aspects, the particles of the intravesical drug delivery formulation have a density of less than 1.030 g / ml. In aspects, they have a density of about 0.9 g / ml, about 1.000 g / ml, about 1.010 g / ml, about 1.020 g / ml, about 1.030 g / ml, about 1.040 g / ml, about 1.050 g / ml, about 1.060 g / ml, about 1.070 g / ml or more.

[0811] All patents, patent publications and other publications cited and identified in this specification are individually and clearly incorporated herein by reference in their entirety, for the purpose of describing and disclosing the compositions and methods that can be used in combination with the present invention, such as described in such publications. These publications are provided only for the disclosures prior to the filing date of the present application. In this regard, any content should not be interpreted as the inventor being unqualified by prior invention or for any other reason prior to the recognition of such disclosures. About date or statement, all representations about the content of these files are based on information available to the applicant, and do not constitute any recognition about the date of these files or the correctness of the content.

Claims

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

2. The intravesical drug delivery system according to claim 1, wherein the particles are substantially cylindrical.

3. The intravesical drug delivery system of claim 1, wherein the particles are substantially spherical. The intravesical drug delivery system according to claim 1 , wherein the particles have a hollow core. The intravesical drug delivery system according to claim 1 , wherein the particles have a solid core. The intravesical drug delivery system according to claim 1 , wherein the excipient portion comprises a degradable material.

7. The intravesical drug delivery system according to claim 1, wherein the active agent is a drug for treating disorders of the urinary system.

8. The intravesical drug delivery system of claim 1, wherein the active agent is one or more of 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, and a contrast agent for diagnosis and monitoring.

9. The intravesical drug delivery system according to claim 8, wherein the anti-infective agent is an antibacterial agent.

10. The intravesical drug delivery system according to claim 8, wherein the anti-infective agent is an antifungal agent.

11. The intravesical drug delivery system according to claim 8, wherein the anti-infective agent is an anti-viral agent.

12. The intravesical drug delivery system of claim 8, wherein the anti-infective agent comprises elemental silver, silver ions, silver salts, or silver coordination compounds.

13. The intravesical drug delivery system of claim 8, wherein the anti-infective agent comprises silver bromide, silver chloride, silver iodate, silver iodide, fosfomycin, silver oxide, silver perchlorate, silver tetrafluoroborate, silver acetate, silver benzoate, silver carbonate, silver lactate, silver laurate, silver palmitate, silver sulfadiazine (fosfomycin) or a fosfomycin degradation product generated in situ.

14. The intravesical drug delivery system of claim 1, wherein the particles have an average diameter of 2.0 mm to about 8.0 mm.

15. The intravesical drug delivery system of claim 1, wherein the particles have an average diameter of 2.0 mm to about 6.0 mm.

16. The intravesical drug delivery system of claim 1, wherein the particles have an average diameter of 2.0 mm to about 4.5 mm.

17. The intravesical drug delivery system of claim 1, wherein the particles comprise about 2.5 wt.% to about 25 wt.% of the active agent and about 5 wt.% to about 97.5 wt.% of the excipient.

18. The intravesical drug delivery system of claim 1, wherein the particles comprise about 5 wt.% to 50 wt.% of the active agent.

19. The intravesical drug delivery system of claim 1, wherein the particles comprise a mucoadhesive material.

20. The intravesical drug delivery system of claim 19, wherein the mucoadhesive material is selected from wax; derived from monovalent C2-C6 alcohol, divalent C2-C6 alcohol or polyvalent C2-C6 alcohol and C8-C 24 Fatty acid esters of fatty acids; C8-C 24 Fatty acids; C8-C 24 Fatty alcohol; hydroxylated C8-C 12 Alkanes; polymers and copolymers of hydroxylated vinyl monomers; polymers and copolymers of carboxylated vinyl monomers; cellulosic polymers and basic addition salts thereof; and combinations of any of the foregoing.

21. The intravesical drug delivery system of claim 19, wherein the mucoadhesive material is selected from C8-C 22 Saturated fatty acid monoglycerides, diglycerides and triglycerides; saturated C8-C 22 Fatty acids; saturated C8-C 22 Fatty alcohol; dihydroxylated C8-C 12 alkanes; acrylic acid and methacrylic acid polymers and copolymers; cross-linked acrylic acid and methacrylic acid polymers and copolymers; poly(vinyl alcohol); sodium carboxymethylcellulose; hydroxypropyl methylcellulose; and combinations of any of the foregoing.

22. The intravesical drug delivery system of claim 19, wherein the mucoadhesive material is selected from C8-C 22 A blend of triglycerides of saturated fatty acids; C8-C 22 Saturated fatty acid triglycerides and C8-C 22 A blend of monoglycerides of fatty acids; two or more C8-C 22 A blend of mono- and di-glycerides of saturated fatty acids; C8-C 22 Saturated fatty acid monoglyceride; saturated C 12 -C 22 Fatty alcohol; saturated C 12 -C 22 Fatty acids; and combinations thereof.

23. The intravesical drug delivery system of claim 19, wherein the mucoadhesive material is selected from the group consisting of candelilla wax, paraffin wax, sodium carboxymethylcellulose, poly(vinyl alcohol), stearyl alcohol, and combinations thereof.

24. The intravesical drug delivery system of claim 1, wherein the particles have an average specific gravity of less than 1.

03.

25. The intravesical drug delivery system of claim 1, wherein the particles have an average specific gravity of less than 1.

005.

26. The intravesical drug delivery system of claim 1, wherein the particles comprise a first subset of particles and a second subset of particles, Wherein the first subset of particles and the second subset of particles differ in one or more of average diameter, shape, buoyancy and deformability.

27. The intravesical drug delivery system of claim 1, wherein the particles comprise a first subset of particles and a second subset of particles, Wherein the first subset of particles and the second subset of particles differ in one or more of a pharmacologically active agent, a different amount of a pharmacologically active agent, a different controlled release carrier, or a different amount of a controlled release carrier or a different controlled release profile.

28. The intravesical drug delivery system of claim 1, wherein the particles comprise a matrix and the pharmacologically active agent is dispersed in the matrix.

29. The intravesical drug delivery system of claim 1, wherein the particles comprise a coating on a core comprising the pharmacologically active agent dispersed therein.

30. The intravesical drug delivery system of claim 1, further comprising a liquid vehicle in which the particles are dispersed.

31. The formulation of claim 30, wherein the liquid vehicle further comprises at least one of a viscosity modifier, a tonicity modifier, a buffer, and a dispersant.

32. A controlled release pharmaceutical formulation for intravesicular administration of a pharmacologically active agent to a subject, the formulation comprising: A population of particles having an average diameter greater than 2.0 mm and comprising from about 2.5 wt.% to about 95 wt.% of an active agent and from about 5 wt.% to about 97.5 wt.% of a controlled release carrier effective to float the particles in the urine and provide sustained release of the active agent in the bladder over an extended drug delivery period.

33. The formulation of claim 32, wherein the extended drug delivery period is between about one month to about three months.

34. The formulation of claim 32, wherein the controlled release carrier is selected such that the active agent is released into the bladder at a substantially constant release rate.

35. The formulation of claim 32, wherein the particles are reversibly deformable.

36. The intravesical drug delivery system of claim 1, wherein the particles comprise a first subset of particles and a second subset of particles, Wherein the first subset of particles and the second subset of particles differ in one or more of average diameter, shape, buoyancy and deformability.

37. The formulation of claim 36, wherein the first subset of particles, the second subset of particles, or both the first subset of particles and the second subset of particles are deformable to an extent that allows passage within a chute having an inner diameter in the range of 6 mm to 8 mm.

38. The formulation of claim 36, wherein the second subset of particles comprises a different pharmacologically active agent, a different amount of a pharmacologically active agent, a different controlled release carrier, or a different amount of a controlled release carrier, or has a different controlled release profile relative to the first subset of particles.

39. The formulation of claim 32, wherein the controlled release carrier comprises a mucoadhesive material.

40. The formulation of claim 39, wherein the mucoadhesive material is selected to promote retention of the particles within the bladder over a prolonged drug delivery period.

41. The formulation of claim 32, wherein the particles are substantially cylindrical.

42. The formulation of claim 32, wherein the particles are substantially spherical.

43. The formulation of claim 32, wherein the particles have a hollow core.

44. The formulation of claim 32, wherein the particles have a solid core.

45. The formulation of claim 32, wherein the pharmacologically active agent is a drug used to treat disorders of the urinary system.

46. ​​A controlled release pharmaceutical formulation for intravesicular administration to a subject to treat a bacterial infection of the bladder, the formulation comprising: A population of particles having an average diameter in the range of 2.5 mm to about 4.0 mm and an average specific gravity less than 1.005, wherein the particles comprise: 50 wt.% to 95 wt.% of a controlled release carrier effective to float the particles in urine and provide sustained release of the active agent in the bladder over a drug delivery period of at least about one month, wherein the controlled release carrier comprises a mucoadhesive material to facilitate retention of the particles by the bladder wall; and 5wt.% to 50wt.% of silver sulfadiazine, wherein the silver sulfadiazine is dispersed in the carrier.

47. A method for preparing the formulation according to claim 32, comprising the steps of: a) melting the carrier; b) adding the pharmacologically active agent to the molten carrier to provide an active agent-carrier mixture; c) homogenizing the mixture to provide a suspension of the active agent in the molten carrier; d) atomizing the suspension to provide particles comprising the active agent and the carrier as condensed droplets; as well as e) collecting the particles to provide the formulation.

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