阅读说明：本技术 使用曲司氯铵治疗膀胱过度活动症的方法 (Methods of treating overactive bladder using trospium chloride ) 是由 D·吉辛 于 2019-07-31 设计创作，主要内容包括：本申请提供了治疗膀胱过度活动症的方法以及训练或再训练膀胱、延长症状缓解、改善患有膀胱过度活动症的个体的生活质量和/或神经元重塑的方法,该方法通过以下方式来实现：向个体的膀胱局部施用有效量的曲司氯铵至少约24小时。(The present application provides methods of treating overactive bladder and methods of training or retraining the bladder, prolonging symptom relief, improving quality of life and/or neuronal remodeling in an individual with overactive bladder by: topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 24 hours.)

1. A method of training the bladder of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 24 hours.

2. A method of prolonging symptom relief in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein the individual experiences symptom relief for at least about 24 hours after completion of trospium chloride administration.

3. A method of improving the quality of life of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein the quality of life of the individual is improved upon treatment with trospium chloride.

4. The method of any one of claims 1-3, wherein the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days after completion of trospium chloride administration.

5. The method of any one of claims 1 to 4, wherein trospium chloride is administered topically to the bladder continuously for at least about 42 days.

6. The method of any one of claims 1 to 4, wherein the method further comprises topically administering an effective amount of trospium chloride to the bladder every 3 months or as needed (prn).

7. A method of treating overactive bladder, comprising continuously topically administering to the bladder of the individual an effective amount of trospium chloride for at least about 42 days.

8. The method according to claim 7, wherein trospium chloride is administered for about 56 days, about 84 days, or about 12 weeks continuously.

9. The method according to claim 6, wherein trospium chloride is administered continuously for at least about 12 weeks.

10. A method for maintenance therapy of overactive bladder in an individual, the method comprising continuously and locally administering trospium chloride to the bladder for at least about 24 hours, wherein the individual has received prior therapy for overactive bladder.

11. The method of claim 10, wherein the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours every 3 months.

12. The method of claim 10, wherein the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder in need (prn) for at least about 24 hours.

13. The method of claim 10, wherein the maintenance therapy comprises locally administering an effective amount of trospium chloride to the bladder at the time of symptom recurrence for at least about 24 hours.

14. The method of claim 10, wherein the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours when the individual experiences at least 50% relapse of baseline symptoms.

15. The method of claim 10, wherein the prior therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, at least about 42 days, at least about 56 days, at least about 84 days, or at least about 12 weeks.

16. The method according to any one of claims 1 to 15, wherein during administration of trospium chloride, the concentration of trospium chloride in the bladder is between 0.1 μ g/ml and 100 μ g/ml.

17. The method according to any one of claims 1 to 16, wherein the concentration of trospium chloride in the plasma of the subject is less than 2ng/ml during administration of trospium chloride.

18. The method of any one of claims 1-17, wherein the individual has idiopathic overactive bladder.

19. The method of any one of claims 1-18, wherein the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

20. The method of any one of claims 1-17, wherein the subject has failed a previous treatment for overactive bladder.

21. The method of any one of claims 1-19, wherein the subject has not received prior treatment for overactive bladder.

22. The method of any one of claims 1 to 18, wherein the subject has failed or is otherwise not eligible to oral therapy.

23. The method of any one of claims 1-22, wherein the individual has urinary incontinence or urge urinary incontinence.

24. The method of any one of claims 1-23, wherein the method results in neuronal remodeling or remodeling of a neural network.

25. The method of any one of claims 1 to 24, wherein symptomatic relief of urgency, frequency or incontinence is achieved.

26. The method of any one of claims 1 to 25, wherein the individual's quality of life score is improved.

27. The method of any one of claims 1-26, wherein the subject's micturition distress score is reduced.

28. The method of any one of claims 1 to 27, wherein the method reduces abnormal urge to urinate.

29. The method of any one of claims 1 to 28, wherein trospium chloride is administered to the bladder by use of an intravesical device.

Technical Field

The present application relates to methods of treating overactive bladder, training or retraining the bladder, prolonging symptom relief, improving quality of life and/or neuronal remodeling in individuals with overactive bladder by local delivery of trospium chloride to the bladder.

Background

Lower urinary tract disorders, including overactive bladder, detrusor instability, and urinary incontinence can be caused by a variety of pathologies. These pathologies are generally classified as neurological, myogenic or idiopathic. Due to the lack of observable etiologies of the disease, most patients often manifest themselves as idiopathic.

Recent studies have shown that the sensory system of the urothelium may play a significant role in afferent signals and detrusor activity. See de Groat and Yoshimura, handbb Exp Pharmacol.2009; (194) 91-138; daly et al, Current Opinion in Urology 2011,21: 268-; birder and Andersson, Physiol Rev 93: 653-. The pathology of this system is thought to play an important role in many patients with idiopathic lower urinary tract diseases.

The standard drug therapy for patients with idiopathic lower urinary tract disorders is systemic treatment, usually administered orally or transdermally. These therapies often lack sufficient efficacy due to dose-limiting side effects, low potency, or both.

There are currently only two alternatives for patients who fail systemic drug therapy. The first alternative is to inject Botox directly into the bladder wall, which may provide symptomatic relief, but also undesirably may produce long-term urinary retention requiring self-catheterization. A second alternative is to do so byThe nerve capsules produced by a device that was surgically implanted and shown to provide symptomatic relief. However, the equipment and surgical procedures are expensive, invasive, and require correctionThe incidence of adverse events from surgery or removal was 30%.

Overactive bladder is a chronic condition characterized by symptoms of lower urinary tract urgency, with or without urge incontinence, usually with frequency and nocturia. Overactive bladder is the most common cause of adult urinary incontinence or loss of bladder control and affects about 3300 million or about 17% of adults in the united states. Although the prevalence of U.S. men and women is similar (16.0% and 16.9%, respectively), the severity and nature of the symptoms expressed do differ, with women exhibiting a higher incidence of urge incontinence. With age, prevalence increases dramatically. Overactive bladder has a significant impact on the health-related quality of life, mental health and sleep quality of the affected individual; whether or not they exhibit symptoms of urge incontinence. The economic burden of overactive bladder is also severe, estimated to be about $ 120 billion per year in the united states alone. Overactive bladder is distinguished from stress incontinence, but when they occur simultaneously they are often referred to as mixed incontinence.

The urothelial sensory system is composed of many receptors and signal pathways, many of which exhibit significant "crosstalk". Due to the complexity of the urothelial sensory system, selective agents, such as darifenacin, may not adequately modulate urothelial sensory activation following non-specific noxious stimulation. Similarly, non-specific agents that exhibit antimuscarinic and calcium channel activity, such as oxybutynin, do not inhibit the urothelial response measured by the interphrinkage period, but may cause urinary retention.

Thus, there remains a need for more and better treatment options for lower urinary tract disorders, including overactive bladder. Advantageously, such treatment would address one or more of the problems associated with systemic administration of drugs and highly invasive and expensive surgical procedures. Advantageously, the treatment will also avoid or reduce the need for painful injections and repeated self-catheterization. Advantageously, the treatment will produce a sustainable response.

The disclosures of all publications, patents, patent applications, and published patent applications cited herein are hereby incorporated by reference in their entirety.

Disclosure of Invention

In some embodiments, provided herein is a method of training the bladder of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 24 hours.

In some embodiments, provided herein is a method of prolonging symptom relief in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein upon completion of trospium chloride administration, the individual experiences symptom relief for at least about 24 hours.

In some embodiments, provided herein is a method of improving the quality of life of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein the quality of life of the individual is improved upon treatment with trospium chloride.

In some embodiments according to any of the methods above, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days after completion of trospium chloride administration.

In some embodiments according to any of the above methods, the trospium chloride is administered topically to the bladder for at least about 42 consecutive days.

In some embodiments according to any of the above methods, the method further comprises topically administering an effective amount of trospium chloride to the bladder about every 3 months or on demand (prn).

In some embodiments, provided herein are methods of treating overactive bladder comprising continuously topically administering to the bladder of an individual an effective amount of trospium chloride for at least about 42 days.

In some embodiments according to any of the methods above, the trospium chloride is administered for about 56 days or about 12 weeks continuously. In some embodiments, the trospium chloride is administered continuously for at least about 12 weeks.

In some embodiments, also provided herein is a method for maintenance therapy of overactive bladder in an individual, the method comprising continuously and locally administering trospium chloride to the bladder for at least about 24 hours, wherein the individual has received prior therapy for overactive bladder. In some embodiments, the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours every 3 months. In some embodiments, the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours as needed (prn). In some embodiments, the maintenance therapy comprises locally administering an effective amount of trospium chloride to the bladder at least about 24 hours at the time of symptom recurrence. In some embodiments, the maintenance therapy comprises locally administering an effective amount of trospium chloride to the bladder for at least about 24 hours when the individual experiences at least 50% of a relapse of baseline symptoms. In some embodiments, the prior therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, at least about 42 days, at least about 56 days, or at least about 12 weeks.

In some embodiments according to any of the above methods, the concentration of trospium chloride in the bladder during administration of trospium chloride is between about 0.1 μ g/ml and 100 μ g/ml. In some embodiments, the concentration of trospium chloride in the plasma of the subject is less than about 2ng/ml during administration of trospium chloride.

In some embodiments according to any of the above methods, the subject has idiopathic overactive bladder.

In some embodiments according to any of the above methods, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In some embodiments according to any of the methods above, the subject has failed prior treatment for overactive bladder.

In some embodiments according to any of the methods above, the subject has not received prior treatment for overactive bladder.

In some embodiments according to any of the methods above, the subject has failed or is otherwise not eligible to receive oral therapy.

In some embodiments according to any of the above methods, the individual has urinary incontinence or urge urinary incontinence.

In some embodiments according to any of the methods above, the method results in neuronal remodeling or remodeling of a neural network. In some embodiments, symptomatic relief of urgency, frequency, or incontinence is achieved. In some embodiments, the quality of life score of an individual is improved. In some embodiments, the individual's urinary distress score is reduced. In some embodiments, the method reduces the urge to urinate abnormally.

In some embodiments according to any of the above methods, the trospium chloride is administered to the bladder by using an intravesical device.

Drawings

Referring now to the drawings, which are intended to be exemplary and not limiting, and wherein like elements are numbered alike. The detailed description set forth below refers to the accompanying drawings that illustrate examples of the present disclosure, and in which like reference numerals are used to refer to similar or identical items. Certain embodiments of the present disclosure may include elements, components, and/or configurations other than those shown in the figures, and some of the elements, components, and/or configurations shown in the figures may not be present in certain embodiments.

Fig. 1A is a cross-sectional side view of one embodiment of a device including a resilient portion that constrains an end plug.

Fig. 1B is a cross-sectional end view of the embodiment of fig. 1A.

Fig. 1C is a cross-sectional side view of the device of fig. 1A when the reservoir is not under osmotic pressure.

Fig. 1D is a cross-sectional side view of the device of fig. 1A when the reservoir is under osmotic pressure.

Figure 2 is a cross-sectional side view of one embodiment of a device having a pre-formed side wall aperture and two restraining end plugs.

Fig. 3A is a plan view of an embodiment of a device having pre-formed side wall apertures and two restraining end plugs.

Fig. 3B is an enlarged cross-sectional view of one of the end plugs of fig. 3A.

Fig. 3C is an exploded perspective view of the end plug of fig. 3B.

Fig. 4 is a cross-sectional end view of an embodiment of a drug delivery device.

Figure 5A is a plan view of one embodiment of a drug delivery device having a restraining plug and a pre-shaped release port.

Fig. 5B is an enlarged cross-sectional view of the device of fig. 5A.

Figure 6A is a plan view of one embodiment of a drug delivery device having a restraining plug and a pre-shaped release port.

Fig. 6B is an enlarged cross-sectional view of the device of fig. 6A.

Figures 7A-7C illustrate an intravesical device that may be used to provide local and continuous delivery of trospium chloride or another therapeutic agent. Fig. 12A is a plan view. Fig. 12B is a cross-sectional view taken along line 3-3 in fig. 12A. Fig. 12C is a view, shown in partial cross-section, of one end portion of a device disposed within a working channel of a deployment instrument.

Figure 8 shows the daily urinary trospium chloride recovery assessed on days 3, 7, 21, 35, 42, and 56 after TAR-302 insertion.

Fig. 9A and 9B show the study protocol (fig. 9A) and the average number of daily urinary incontinence assessed on days 0 (baseline), 42, and 84 after TAR-302 insertion (fig. 9B).

Fig. 10A and 10B show the efficacy of the treatment of overactive bladder. FIG. 10A shows the signal at TAR-302 orAfter treatment, the change in the number of daily urge incontinence in patients with refractory bladder overactivity by oral therapy at the end of the administration. Figure 10B shows the reduction in the number of daily urge incontinence in patients refractory to oral therapy after TAR-302 treatment,(solifenacin succinate) orReduction of the number of daily urge incontinence in overactive bladder patients untreated orally after LA (tolterodine tartrate) treatment.

FIG. 11 shows calculated micturition distress scores for individuals receiving TAR-302 treatment before TAR-302 treatment, at the end of TAR-302 dosing on day 42, and on day 84, i.e., day 42 after TAR-302 removal.

Figure 12 shows the calculated quality of life scores for individuals receiving TAR-302 treatment before TAR-302 treatment, at the end of TAR-302 dosing on day 42, and on day 84, i.e., day 42 after TAR-302 removal.

Fig. 13 shows an exemplary questionnaire for assessing distress scores.

Fig. 14 shows an exemplary questionnaire for assessing quality of life scores.

Fig. 15A and 15B show the study protocol (fig. 15A) and the average number of daily urinary incontinence assessed on days 0 (baseline), 14, 56, and 84 after TAR-302 insertion (fig. 15B).

Detailed Description

The present application is based, at least in part, on the applicants' significant discovery that: prolonged symptomatic relief (e.g., reduced urinary incontinence) can be obtained by administering an effective amount of trospium chloride topically (e.g., intravesically) into the bladder of an individual suffering from overactive bladder. In phase I clinical trials, TAR-302 was a passive, non-absorbable trospium chloride-releasing intravesical system whose primary mode of action was the controlled release of trospium chloride into the bladder over a period of about 42 days, and the results showed that not only was the number of urinary incontinence reduced during the 42 days of trospium chloride administration to the bladder, but surprisingly also the number of urinary incontinence was significantly reduced within six weeks after termination of trospium chloride administration. The methods of the present invention have significant beneficial effects over previous methods of bladder treatment, including oral trospium chloride therapy, such as reduced side effects and higher concentrations of trospium chloride locally within the bladder. Thus, in some aspects, the invention is particularly applicable to individuals with idiopathic overactive bladder, failure of oral therapy, and/or with severe obstinate illness. In some aspects, the present application provides methods of training or retraining the bladder of an individual suffering from overactive bladder. In some aspects, the present application provides methods of prolonging symptom relief in an individual having overactive bladder. In some aspects, the present application provides methods of neuronal remodeling in an individual with overactive bladder. In some aspects, the present application provides methods of improving the quality of life of an individual having overactive bladder.

Definition of

As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, "a" or "an" means "at least one" or "one or more".

As used herein, the term "subject" refers to a mammal, including a human. Individuals include, but are not limited to, humans, cows, horses, cats, canines, rodents, or primates. In some embodiments, the subject is a human.

The term "effective amount" as used herein refers to an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, such as to ameliorate, alleviate, reduce, and/or delay one or more of its symptoms.

Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter per se. For example, "about 7 days" includes 7 days.

The term "about X-Y" as used herein has the same meaning as "about X to about Y". Similarly, "about X to Y" as used herein has the same meaning as "about X to about Y".

As used herein, "treatment" is a method for obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, lessening the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, reducing the dose of one or more other drugs required to treat the disease, delaying the progression of the disease, and/or improving the quality of life. The methods of the invention contemplate any one or more of these aspects of treatment.

Method

In one aspect, the present application provides a method of training (or retraining) the bladder of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 24 hours. In some embodiments, trospium chloride is administered for at least about 3 days, 5 days, or 7 days. In some embodiments, trospium chloride is administered for at least about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 to 100 mg/day, about 1 to 20 mg/day, about 2 to 10 mg/day, about 4 to 8 mg/day. In some embodiments, the concentration of trospium chloride in urine during trospium chloride administration is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

The present application also provides a method of training (or retraining) the bladder of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days). In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

The present application also provides a method of training (or retraining) the bladder of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder of the individual for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the individual has received a prior therapy, and wherein the individual is refractory to the prior therapy. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the present application provides a method of prolonging symptom relief in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein upon completion of trospium chloride administration, the individual experiences symptom relief for at least about 24 hours. In some embodiments, prolonged symptomatic relief of urgency, frequency or incontinence and/or urge incontinence is achieved. In some embodiments, upon completion of trospium chloride administration, the individual experiences remission for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, trospium chloride is administered for at least about 3 days, 5 days, or 7 days. In some embodiments, trospium chloride is administered for at least about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

The present application also provides a method of prolonging symptom relief in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the individual experiences symptom relief for at least about 24 hours after completion of the trospium chloride administration. In some embodiments, prolonged symptomatic relief of urgency, frequency or incontinence and/or urge incontinence is achieved. In some embodiments, upon completion of trospium chloride administration, the individual experiences remission for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

The present application also provides a method of prolonging symptom relief in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein after completion of the trospium chloride administration, the individual experiences symptom relief for at least about 24 hours (such as at least about 2 days, 5 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days after completion of the trospium chloride administration), wherein the individual has received prior therapy, and wherein the individual is refractory to the prior therapy. In some embodiments, prolonged symptomatic relief of urgency, frequency or incontinence and/or urge incontinence is achieved. In some embodiments, upon completion of trospium chloride administration, the individual experiences remission for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the application provides a method of neuronal remodeling in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, wherein neuronal remodeling continues for at least about 24 hours after the administration of trospium chloride is completed (such as for at least about 2 days, 5 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days after the administration of trospium chloride is completed). In some embodiments, trospium chloride is administered for at least about 3 days, 5 days, or 7 days. In some embodiments, trospium chloride is administered for at least about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the application provides a method of neuronal remodeling in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein neuronal remodeling continues for at least about 24 hours after the trospium chloride administration is completed (such as for at least about 2 days, 5 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days after the trospium chloride administration is completed). In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the application provides a method of neuronal remodeling in an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein neuronal remodeling continues for at least about 24 hours after the trospium chloride administration is completed (such as for at least about 2 days, 5 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days after the trospium chloride administration is completed), wherein the individual has received prior therapy, and wherein the individual is refractory to the prior therapy. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the present application provides a method of improving the quality of life of an individual having overactive bladder, the method comprising topically administering to the bladder an effective amount of trospium chloride for at least about 24 hours, wherein the quality of life of the individual improves for at least about 24 hours after the administration of trospium chloride is completed. In some embodiments, the individual has an improved quality of life score. In some embodiments, the subject has a decreased urinary distress score. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke. In some embodiments, the subject has had an intravesicular device.

In another aspect, the application provides a method of improving the quality of life of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the quality of life is improved for at least about 24 hours after the completion of the trospium chloride administration (such as for at least about 2 days, 5 days, 7 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days after the completion of the trospium chloride administration). In some embodiments, the individual has an improved quality of life score. In some embodiments, the subject has a decreased urinary distress score. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke. In some embodiments, the subject has had an intravesicular device.

In another aspect, the application provides a method of improving the quality of life of an individual having overactive bladder, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the quality of life is improved for at least about 24 hours after completion of the trospium chloride administration, wherein the individual has received a prior therapy, and wherein the individual is refractory to the prior therapy. In some embodiments, the individual has an improved quality of life score. In some embodiments, the subject has a decreased urinary distress score. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke. In some embodiments, the subject has had an intravesicular device.

Also provided herein is a method of increasing a quality of life score of an individual, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the quality of life is improved for at least about 24 hours after completion of the trospium chloride administration. In some embodiments, the improvement in quality of life is measured as an improved quality of life score. In some embodiments, the improvement in quality of life is measured as a decreased urinary distress score. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke. In some embodiments, the subject has had an intravesicular device.

Provided herein is a method of reducing a micturition distress score in an individual, the method comprising topically administering an effective amount of trospium chloride to the bladder for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the quality of life is improved for at least about 24 hours after completion of the trospium chloride administration. In some embodiments, the improvement in quality of life is measured as an improved quality of life score. In some embodiments, the improvement in quality of life is measured as a decreased urinary distress score. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke. In some embodiments, the subject has had an intravesicular device.

In another aspect, the application provides a method of treating overactive bladder, the method comprising continuously topically administering to the bladder of an individual an effective amount of trospium chloride for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days). In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is non-responsive or refractory to a prior therapy. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the application provides a method of treating overactive bladder, the method comprising continuously topically administering to the bladder of an individual an effective amount of trospium chloride for at least about 42 days (e.g., about 42 days, 56 days, 70 days, or 84 days), wherein the individual has received a prior therapy, and wherein the individual is refractory to the prior therapy. In some embodiments, trospium chloride is administered for at least about 56 days. In some embodiments, trospium chloride is administered for at least about 84 days. In some embodiments, trospium chloride is administered for at least about 100 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

In another aspect, the present application provides a method for maintenance therapy of overactive bladder in an individual, the method comprising continuously and topically administering trospium chloride to the bladder for at least about 24 hours, wherein the individual has received prior therapy for overactive bladder. In some embodiments, the maintenance therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours every 3 months. In some embodiments, the maintenance phase comprises topically administering an effective amount of trospium chloride to the bladder as needed (prn) for at least about 24 hours. In some embodiments, the maintenance therapy comprises locally administering an effective amount of trospium chloride to the bladder at least about 24 hours at the time of symptom recurrence. In some embodiments, the maintenance therapy comprises locally administering an effective amount of trospium chloride to the bladder for at least about 24 hours when the individual experiences at least 50% of a relapse of baseline symptoms. In some embodiments, the prior therapy comprises topically administering an effective amount of trospium chloride to the bladder for at least about 24 hours, at least about 42 days, at least about 56 days, or at least about 84 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, the subject is refractory to a prior therapy. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

Provided herein is a method for maintenance therapy of overactive bladder in an individual, the method comprising continuously and topically administering trospium chloride to the bladder for at least about 24 hours based on prn (as needed), wherein the individual has received prior therapy for overactive bladder. In some embodiments, the maintenance therapy comprises local administration of trospium chloride to the bladder for at least about 42 days, at least about 56 days, or at least about 84 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, the prior therapy comprises local administration of trospium chloride to the bladder. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

Also provided herein is a method for maintenance therapy of overactive bladder in an individual, the method comprising administering trospium chloride to the bladder continuously and topically for at least about 24 hours on a quarterly basis, wherein the individual has received prior therapy for overactive bladder. In some embodiments, the maintenance therapy comprises local administration of trospium chloride to the bladder for at least about 42 days, at least about 56 days, or at least about 84 days. In some embodiments, the prior therapy is oral therapy. In some embodiments, the prior therapy comprises local administration of trospium chloride to the bladder. In some embodiments, trospium chloride is administered by using an intravesical delivery device. In some embodiments, trospium chloride is administered at a dose of about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.1 to about 20, about 1 to about 10, about 2 to about 8, about 3 to about 7, or about 3 to about 5 μ g/mL. In some embodiments, trospium chloride is administered continuously or intermittently. In some embodiments, the individual having overactive bladder experiences at least about 50% baseline symptom relief for at least about 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks after completion of trospium chloride administration. In some embodiments, the subject is a human. In some embodiments, the individual has idiopathic overactive bladder. In some embodiments, the subject has multiple sclerosis, alzheimer's disease, parkinson's disease, or has previously suffered a stroke.

Trospium chloride

Trospium chloride is a muscarinic receptor antagonist. Trospium chloride is known to be useful in the treatment of overactive bladder, where trospium chloride is formulated for oral administration, e.g., santcura^TM(allergy). With other oral muscarinic receptor antagonistsAs such, patients often experience dose-limiting side effects or inadequate efficacy. In the present application, trospium chloride is formulated for topical delivery. Depending on the delivery mechanism employed, trospium chloride may be provided in solid or semi-solid form or liquid form, as described herein. In some embodiments, devices and systems described herein, the trospium chloride is provided in the form of a pharmaceutically acceptable salt of trospium chloride. In some embodiments, the pharmaceutically acceptable salt of trospium chloride is trospium chloride. In some embodiments, other suitable forms of trospium chloride are used, including but not limited to polymorphs, hydrates, and the like.

In some embodiments, trospium chloride is the compound 3- (2-hydroxy-2, 2-diphenylacetoxy) spiro [ bicyclo [3.2.1] octane-8, 1 '-pyrrolidine ] -1' -chloride and any pharmaceutically acceptable salts thereof. The chemical formula is given in formula I.

Dosing regimens

The following section describes various aspects (embodiments) of dosing and treatment regimens, any and all of which are applicable to the methods described herein.

In various embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder at a dose of about 0.075 mg/day to about 150 mg/day (such as about 0.15 mg/day to 150 mg/day, about 1 mg/day to 100 mg/day, about 1 mg/day to 20 mg/day, about 2 mg/day to 10 mg/day, about 4 mg/day to about 8 mg/day) during treatment. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder at a dose of no more than about 60 mg/day, 40 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, or 8 mg/day during the treatment period. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder at a dose of no less than about 0.1 mg/day, 0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day.

In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the subject for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 6 weeks or 42 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 8 weeks or 56 days. In some embodiments, trospium chloride is administered topically to the bladder for at least about 12 weeks or 84 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 16 weeks or 112 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 1,2, 3,4, 5, 6, 7,8, 9,10, 11, or 12 months. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, or 100 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for about 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or 112 days.

In some embodiments, the subject is administered trospium chloride topically (e.g., intravesically) to the bladder of the subject for at least about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days every week, two weeks, three weeks, four weeks, five weeks, or six weeks. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days per month, two months, three months, four months, five months, or six months. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about one week, two weeks, three weeks, or four weeks every month, two months, three months, four months, five months, or six months. In some embodiments, trospium chloride is administered locally (e.g., intravesically) to the bladder of the individual for at least about five weeks or six weeks every two months, three months, four months, five months, or six months.

In some embodiments, trospium chloride is administered locally (e.g., intravesically) into the bladder of an individual in an average amount of 1 mg/day to 100 mg/day, e.g., 1 mg/day to 20 mg/day, 2 mg/day to 10 mg/day, 4 mg/day to about 8 mg/day for up to about 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or 112 days. In some embodiments, trospium chloride is administered locally (e.g., intravesically) into the bladder of an individual for up to about 6, 7,8, 9,10, 11, or 12 months in an average amount of 1 to 100 mg/day, e.g., 1 to 20 mg/day, 2 to 10 mg/day, 4 to about 8 mg/day.

In some embodiments, trospium chloride is administered locally (e.g., intravesically) into the bladder of the individual in an average amount of about 10 mg/day for about 40 days to 45 days (such as about 42 days). In some embodiments, trospium chloride is administered locally (e.g., intravesically) into the bladder of the individual in an average amount of about 10 mg/day for about 80 to 87 days (such as about 84 days). In some embodiments, trospium chloride is administered only once.

In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is about or at least about 0.01, 0.05, 0.1, 0.5, 1,2, 3,4, 5, 6, 7, or 8 μ g/mL. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is about 2 μ g/mL to 3 μ g/mL, about 3 μ g/mL to 4 μ g/mL, about 4 μ g/mL to 5 μ g/mL, about 5 μ g/mL to 6 μ g/mL, or about 6 μ g/mL to 7 μ g/mL. In some embodiments, the concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.01 to about 100 μ g/mL, e.g., from about 0.1 to about 20 μ g/mL, from about 1 to about 10 μ g/mL, from about 2 to about 8 μ g/mL, from about 3 to about 7 μ g/mL, or from about 3 to about 5 μ g/mL. In some embodiments, the average concentration of trospium chloride in urine at the time of administration of trospium chloride is at least about 0.01, 0.1, 1,2, 3,4, 5, 6, 7,8, 9, or 10 μ g/mL. In some embodiments, the average concentration of trospium chloride in urine at the time of administration of trospium chloride is from about 0.01 to about 100, from about 0.1 to about 20, from about 1 to about 10, or from about 2 to about 8, from about 3 to about 7, or from about 3 to about 5 μ g/mL. In some embodiments, the plasma concentration of trospium chloride is less than about 2ng/ml, 1ng/ml, 0.9ng/ml, 0.8ng/ml, 0.7ng/ml, 0.6ng/ml, 0.5ng/ml, 0.4ng/ml, 0.3ng/ml, 0.2ng/ml, or 0.1 ng/ml. In some embodiments, the plasma concentration of trospium chloride is less than about 0.7 ng/ml. In some embodiments, the plasma concentration of trospium chloride is not detected.

In some embodiments, trospium chloride is administered to the bladder via an intravesical delivery device. In some embodiments, the device comprises trospium chloride in an amount of about 100mg to 2000mg (such as about 200mg to about 1600mg, about 400mg to about 1200mg, about 600mg to about 1000mg, about 700mg to about 900mg, or about 850mg of trospium chloride). In some embodiments, the device remains in the subject for at least about one, two, three, four, five, or six weeks. In some embodiments, the device remains in the subject for at least about 8 weeks, 10 weeks, or 12 weeks. In some embodiments, the device comprises trospium chloride in an amount of about 850mg and remains in the subject for about 42 days. In some embodiments, the device comprises trospium chloride in an amount of about 850mg and remains in the subject for about 84 days.

In some embodiments, the methods comprise a maintenance therapy comprising periodically administering an effective amount of trospium chloride locally (e.g., intravesically) into the bladder of the individual after a prior therapy. In some embodiments, the maintenance therapy comprises administering trospium chloride as needed. In some embodiments, the maintenance therapy comprises monthly, bimonthly, or quarterly administration of trospium chloride. In some embodiments, the maintenance therapy comprises no more than 1,2, 3,4, 5, 6, 7,8, 9,10, 11, or 12 administrations of trospium chloride per year. In some embodiments, maintenance therapy comprises administration of trospium chloride on a schedule agreed to by the individual and the physician. In some embodiments, the maintenance therapy comprises administering trospium chloride in anticipation of a recurrence of symptoms of overactive bladder. In some embodiments, maintenance therapy comprises administering trospium chloride at the time of a relapse of a symptom, e.g., at the time of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of baseline symptom relapse. In some embodiments, the maintenance phase comprises administering trospium chloride for at least about 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the maintenance phase comprises administration of trospium chloride for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks. In some embodiments, the maintenance therapy comprises administering trospium chloride for at least about 1,2, 3,4, 5, 6, 7,8, 9,10, 11, or 12 months. In some embodiments, the maintenance therapy comprises administering trospium chloride for at least about 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, or 100 days. In some embodiments, the maintenance therapy comprises administration of trospium chloride for about 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or 112 days.

In some embodiments, the prior therapy comprises administration of an antimuscarinic agent. In some embodiments, the antimuscarinic agent is administered locally (e.g., intravesically) into the bladder of the subject. In some embodiments, the antimuscarinic agent is administered orally to the subject for topical treatment. In some embodiments, the antimuscarinic agent is trospium chloride. In some embodiments, the prior therapy comprises administration of an anticholinergic agent. In some embodiments, the prior therapy comprises topical administration of trospium chloride to the bladder for about 42 days or about 56 days.

In some embodiments, the maintenance therapy is initiated immediately after or within 24 hours of completion of the prior therapy. In some embodiments, the maintenance therapy is initiated at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after the completion of the prior therapy. In some embodiments, the maintenance therapy is initiated at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after completion of the prior therapy. In some embodiments, maintenance therapy is initiated at least about 3,4, 5, 6, 7,8, 9,10, 11, or 12 months after completion of the prior therapy.

In some embodiments, the concentration of trospium chloride in urine during a prior therapy and/or maintenance therapy is at least about 0.01 μ g/mL, 0.05 μ g/mL, 0.1 μ g/mL, 0.5 μ g/mL, 1 μ g/mL, 2 μ g/mL, 3 μ g/mL, 4 μ g/mL, 5 μ g/mL, 6 μ g/mL, 7 μ g/mL, or 8 μ g/mL. In some embodiments, the concentration of trospium chloride in urine during a prior therapy and/or maintenance therapy is from about 0.01 μ g/mL to about 100 μ g/mL, e.g., from about 0.1 μ g/mL to about 20 μ g/mL, from about 1 μ g/mL to about 10 μ g/mL, from about 2 μ g/mL to about 8 μ g/mL, from about 3 μ g/mL to about 7 μ g/mL. In some embodiments, the average concentration of trospium chloride in urine during a prior therapy and/or maintenance therapy is at least about 0.01, 0.1, 1,2, 3,4, 5, 6, 7,8, 9, or 10 μ g/mL. In some embodiments, the average concentration of trospium chloride in urine during a prior therapy and/or maintenance therapy is about 0.01 to about 100, about 0.1 to about 20, about 1 to about 10, or about 3 to about 8 μ g/mL.

In some embodiments, the trospium chloride is administered continuously. In some embodiments, the trospium chloride is administered intermittently.

In some embodiments, trospium chloride is administered via the intravesical device, wherein the intravesical device is left in the bladder for a period of time, such as at least about 24 hours, for example, at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. In some embodiments, the intravesical device is indwelling in the bladder for at least about 1,2, 3,4, 5, or 6 months. In various embodiments, the intravesical device can continuously or intermittently release trospium chloride to achieve a concentration of trospium chloride in the bladder to produce a sustained therapeutically effective concentration of trospium chloride over a period of time from about 24 hours to about 6 months, such as from about 24 hours to 7 days, from about 24 hours to two weeks, from about 24 hours to four weeks, from about 24 hours to six weeks, from about 24 hours to eight weeks, from about 24 hours to ten weeks, from about 24 hours to twelve weeks, and the like. In some embodiments, trospium chloride is administered to the bladder for about 42 days. In some embodiments, trospium chloride is administered to the bladder for about 56 days or 112 days.

In some embodiments, the average total daily urinary trospium chloride recovery during the device residence time is at least about 0.1 mg/day, 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, or 3 mg/day. In some embodiments, the average total daily urinary trospium chloride recovery during the device residence time is no more than about 30 mg/day, 18 mg/day, 15 mg/day, 12 mg/day, 10 mg/day, 9 mg/day, or 8 mg/day. In some embodiments, the average total daily urine trospium chloride recovery during the device residence time is from about 0.1 mg/day to about 30 mg/day, from about 1 mg/day to about 25 mg/day, from about 2 mg/day to about 10 mg/day, from about 3 mg/day to about 9 mg/day.

Patient population

The subject treated by the methods described herein can be a mammal. In some embodiments, the subject is a human.

In some embodiments, the individual has idiopathic overactive bladder.

In some embodiments, the individual has received prior therapy for overactive bladder. In some embodiments, the subject is refractory to a prior therapy. In some embodiments, the subject has refractory overactive bladder. In some embodiments, the subject has severe overactive bladder. In some embodiments, the subject is non-responsive to a prior therapy. In some embodiments, the individual has progressed as a result of prior therapy. In some embodiments, the subject has experienced a baseline symptom recurrence upon completion of the prior therapy, e.g., wherein the subject has experienced at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the baseline symptom recurrence. In some embodiments, the prior therapy is oral therapy. In some embodiments, the prior therapy is a topical therapy. In some embodiments, the prior therapy comprises administration of an antimuscarinic agent. In some embodiments, the agent is selected from(solifenacin succinate) andLA (tolterodine tartrate). In some embodiments, the prior therapy comprises administration of an anticholinergic agent.

In some embodiments, the individual has not received prior therapy for overactive bladder.

In some embodiments, the subject is not suitable for oral therapy. For example, the individual cannot tolerate the side effects of the therapy. In some embodiments, the subject is elderly or infirm. In some embodiments, the oral therapy comprises an anticholinergic agent. In some embodiments, the oral therapy comprises an antimuscarinic agent. In some embodiments, the agent is selected from(solifenacin succinate) andLA (tolterodine tartrate).

In some embodiments, the subject has a neurological disorder. In some embodiments, the neurological disorder is multiple sclerosis. In some embodiments, the neurological disorder is parkinson's disease. In some embodiments, the neurological disorder is alzheimer's disease. In some embodiments, the individual has suffered a stroke.

In some embodiments, the individual has symptoms of overactive bladder with a major acute component, e.g., wherein more than 50% of the overactive bladder symptoms are associated with urgency (as opposed to frequency). In some embodiments, the individual has symptoms of overactive bladder with a major acute component for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. In some embodiments, the individual has symptoms of overactive bladder with a major acute component for at least about 3,4, 5, 6, 7,8, 9,10, 11, or 12 months. In some embodiments, the subject urinates about four, five, six, seven, eight, or more times per 24 hours. In some embodiments, the individual has at least about 2, 3,4, 5, or 6 occurrences of urinary incontinence associated with urgency in a 3 day diary. In some embodiments, the individual has at least one, two, or three episodes per 24 hours or day.

In some embodiments, the individual has urinary incontinence or urge incontinence.

In some embodiments, the individual has a post-urination residual urine volume (PVR) of less than about 300mL (such as less than about 300mL, 250mL, 200mL, 150mL, or 100 mL).

In some embodiments, the subject is a female. In some embodiments, the subject is a male.

In some embodiments, the subject is about 40 years to about 70 years old. In some embodiments, the individual is at least about 40, 45, 50, 55, 60, 65, or 70 years old. In some embodiments, the individual is no more than about 70, 65, 60, 55, 50, 45, or 40 years old.

Overactive bladder

In some embodiments, overactive bladder is associated with a neurological disorder. In some embodiments, the neurological disorder is multiple sclerosis. In some embodiments, the neurological disorder is parkinson's disease. In some embodiments, the neurological disorder is alzheimer's disease. In some embodiments, the neurological condition is a prior stroke.

In some embodiments, the overactive bladder is not associated with a neurological disorder.

Terminal point

In some embodiments, the methods provided herein extend symptom relief in an individual having overactive bladder, the methods comprising delivering trospium chloride locally to the bladder for at least about 24 hours. In some embodiments, the individual experiences at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% baseline symptom relief during or after completion of trospium chloride administration. In some embodiments, symptomatic relief comprises a reduction in urinary urgency and/or frequency. In some embodiments, symptom relief comprises a reduction in the urge to urinate abnormally. In some embodiments, the urinary urgency and/or frequency is reduced from baseline by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% during or after completion of trospium chloride administration. In some embodiments, symptom relief comprises a reduction in urinary incontinence and/or urge incontinence (e.g., number of daily urinary incontinence or number of urinary incontinence within 3 days). In some embodiments, urinary incontinence and/or urge incontinence (e.g., number of daily urinary incontinence or number of urinary incontinence within 3 days) is reduced from baseline symptoms by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% during or after the administration of trospium chloride is complete. In some embodiments, symptom relief is extended by at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after the completion of trospium chloride administration. In some embodiments, symptom relief is extended by at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after completion of trospium chloride administration. In some embodiments, symptom relief is extended by at least about 3,4, 5, 6, 7,8, 9,10, 11, or 12 months after completion of trospium chloride administration.

In some embodiments, the number of daily urination by the individual is reduced during or after the administration of trospium chloride is completed. In some embodiments, the number of daily urination is reduced by at least about 2.5%, 5%, 7.5%, or 10% relative to baseline symptoms during or after the administration of trospium chloride is complete. In some embodiments, the reduction is prolonged by at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after the completion of trospium chloride administration. In some embodiments, the reduction is extended by at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the completion of trospium chloride administration. In some embodiments, the reduction extends for at least about 3,4, 5, 6, 7,8, 9,10, 11, or 12 months after the administration of trospium chloride is complete.

In some embodiments, the amount of urine excreted per urine of the individual increases during or after completion of the administration of trospium chloride. In some embodiments, the urinary output per micturition is increased by at least about 2.5%, 5%, 7.5%, 10%, 20%, 25%, 30%, 35%, or 40% from baseline symptoms during or after the administration of trospium chloride is completed. In some embodiments, the increase is extended by at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after the completion of trospium chloride administration. In some embodiments, the increase is extended by at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks after the completion of trospium chloride administration. In some embodiments, the increase extends for at least about 3,4, 5, 6, 7,8, 9,10, 11, or 12 months after the administration of trospium chloride is complete.

In some embodiments, provided herein is a method for improving the quality of life of an individual, comprising topically administering to the bladder an effective amount of trospium chloride for at least about 24 hours. In some embodiments, the quality of life score of an individual is increased. In some embodiments, the individual has an improved quality of life score for at least about 24 hours after completion of the topical administration of trospium chloride as compared to the previous quality of life score prior to topical treatment with trospium chloride. In some embodiments, the quality of life score comprises a score based on the frequency with which an individual has experienced one or more events over a period of time, e.g., never, rarely, sometimes, many times, most of the time, and every moment. In some embodiments, the event comprises being confounded by an abrupt urination urge with little or no warning. In some embodiments, the event comprises being plagued by an unexpected small leak of urine. In some embodiments, the event comprises being troubled by nocturnal voids. In some embodiments, the event comprises being bothered by the night because he/she must urinate. In some embodiments, the event comprises a disturbance by urine leakage associated with an urge to urinate. In some embodiments, the individual's quality of life score improves by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% upon topical administration of trospium chloride. In some embodiments, the quality of life score of the individual is improved for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks after the completion of the topical administration of trospium chloride.

In some embodiments, provided herein is a method for improving a quality of life score in an individual, comprising topically administering to the bladder an effective amount of trospium chloride for at least about 24 hours. In some embodiments, the individual has an improved quality of life score for at least about 24 hours after completion of the topical administration of trospium chloride as compared to the previous quality of life score prior to topical treatment with trospium chloride. In some embodiments, the quality of life score comprises a score based on the frequency with which an individual has experienced one or more events over a period of time, e.g., never, rarely, sometimes, many times, most of the time, and every moment. In some embodiments, the event comprises being confounded by an abrupt urination urge with little or no warning. In some embodiments, the event comprises being plagued by an unexpected small leak of urine. In some embodiments, the event comprises being troubled by nocturnal voids. In some embodiments, the event comprises being bothered by the night because he/she must urinate. In some embodiments, the event comprises a disturbance by urine leakage associated with an urge to urinate. In some embodiments, the individual's quality of life score improves by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% upon topical administration of trospium chloride. In some embodiments, the quality of life score of the individual is improved for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks after the completion of the topical administration of trospium chloride.

In some embodiments, provided herein is a method of reducing a disturbance associated with a bladder symptom in an individual, the method comprising delivering trospium chloride to the bladder of the individual for at least about 24 hours. In some embodiments, the distress score of the individual is reduced. In some embodiments, the reduction in distress score is at least about 24 hours after completion of the topical administration of trospium chloride compared to prior to topical treatment with trospium chloride. In some embodiments, the quality of life score may include a score based on the frequency with which an individual has experienced one or more events over a period of time, e.g., never, rarely, sometimes, many times, most of the time, and every moment. In some embodiments, the event comprises planning an escape route to a public place toilet. In some embodiments, the event comprises bladder symptoms that affect the frequency with which an individual feels problematic to him/herself. In some embodiments, the event comprises bladder symptoms that interfere with his/her ability to obtain good night rest. In some embodiments, the event comprises bladder symptoms that cause the individual to be depressed or irritated by the time he/she spends in the toilet. In some embodiments, the event comprises a bladder symptom that prevents the individual from activities away from the toilet (e.g., walking, running, hiking). In some embodiments, the event comprises a bladder symptom that awakens the individual from sleep. In some embodiments, the event comprises a bladder symptom that causes the individual to reduce his or her physical activity (exercise, etc.). In some embodiments, the event comprises a bladder symptom that causes the individual to have a problem with his/her partner or spouse. In some embodiments, the event comprises bladder symptoms that make the individual uncomfortable when the individual travels with other people due to the need to travel midway to the toilet. In some embodiments, the event comprises bladder symptoms affecting an individual's relationship to family and friends. In some embodiments, the event comprises embarrassment caused by bladder symptoms in the individual. In some embodiments, the event comprises a condition where a bladder symptom in the individual results in the individual locating the nearest toilet as soon as the individual arrives at the new location. In some embodiments, the individual's distress score improves by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% upon topical administration of trospium chloride. In some embodiments, the individual's distress score improves for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks after topical administration of trospium chloride is complete.

In some embodiments, a quality of life score [ i.e., a health-related quality of life (HRQL) converted score ] and a distress score (i.e., a symptom severity converted score) are calculated from the subject's self-assessment via a questionnaire. Exemplary questionnaires are shown in fig. 13-14. The assessment may be performed prior to administering trospium chloride (such as immediately prior to administering trospium chloride) to establish a baseline. The evaluation may also be performed at various time points during or after the administration of trospium chloride.

For example, a quality of life score may be calculated from the raw scores of fig. 14, where the raw scores are the total scores from the values of projects 1-13. Quality of life score ═ (highest possible score-actual raw score)/range of possible raw scores × 100, with the highest possible score being 78 and the range of possible raw scores being 65. Note that a higher quality of life score value indicates a better quality of life.

The distress score may be calculated as follows from the raw score of fig. 13, where the raw score is the total score from the values of items 1-6. The obsession score is (actual raw score-lowest possible raw score)/possible raw score range x 100, where the lowest possible raw score is 6 and the possible raw score range is 30. Note that a higher distress score indicates greater symptom severity or distress, and a lower score indicates minimal symptom severity.

In some embodiments, trospium chloride is delivered via the intravesical devices described herein. In some embodiments, the subject has a high tolerance for the device (e.g., less than about 30%, 20%, 15%, 10%, 5%, or 2% of the subjects need to remove the device prior to completion of the predetermined treatment.

In some embodiments, the method does not cause a significant degree of adverse events in the individual. Exemplary adverse events include Urinary Tract Infections (UTIs), bladder pain, hematuria, sinusitis, and bladder discomfort. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20% of the individuals develop UTI during treatment. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20% of individuals develop bladder pain during treatment. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20% of the individuals develop hematuria during treatment. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20% of individuals develop sinusitis during treatment. In some embodiments, less than about 50%, 40%, 30%, 25%, or 20% of individuals experience bladder discomfort during treatment.

In some embodiments, the residual urine volume (PVR) after urinary bladder voiding in an individual is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% following administration of trospium chloride. In some embodiments, the reduction is observed within about 7 days, 21 days, or 35 days after administration of trospium chloride.

Delivery of

I. Intravesical device

a. Device shape

In some embodiments, the methods provided herein comprise locally delivering to the bladder an effective amount of trospium chloride using an intravesical device. In some embodiments, the intravesical device has a deployed shape and a retention shape. For example, the device may be elastically deformable between a relatively straightened or uncoiled shape (deployed shape) suitable for insertion into the bladder of an individual through a lumen (e.g., urethra) and a retained shape suitable for retaining the device within the bladder. For purposes of this disclosure, terms such as "relatively expanded shape," "relatively higher profile shape," or "retention shape" generally refer to any shape suitable for retaining the device in an intended implantation location, including but not limited to a pretzel shape or other coiled shape (e.g., including double ovals or overlapping coils) suitable for retaining the device in the bladder. The shape is maintained so that the device is not entrained in the urine and expelled when the individual urinates. Similarly, terms such as "relatively low-profile shape" or "deployment shape" generally refer to any shape suitable for deploying a drug delivery device into a body (e.g., a bladder), including, but not limited to, linear or elongated shapes including working channel deployment devices suitable for passing through a catheter, cystoscope, or other deployment instrument positioned in the urethra or bladder, e.g., a suprapubic cystostomy or suprapubic catheter (also referred to as a cystostomy or a cystostomy) for draining urine from the bladder of an individual with impaired normal urine flow. In embodiments, the drug delivery device may naturally assume a relatively expanded shape and may be deformed into a relatively low-profile shape for insertion into the body, either manually or by means of an external device. For example, the external device may be an inserter configured for transurethral insertion. Once deployed, the intravesical device may spontaneously or naturally return to an original, relatively expanded shape to remain in the body. In some embodiments, the device behaves like a spring, deforming in response to a compressive load (e.g., deforming the device into a deployed shape), but spontaneously reverts to a retained shape once the load is removed.

In some embodiments, the shape-changing functionality of the intravesical devices described in the preceding paragraphs may be provided by including a shape-retaining frame (i.e., a "retaining frame") in the device, such as those disclosed in published applications US2012/0203203, US2013/0158675, US2015/0360012, US20150165177, US2015/0165178, US20160199544, WO2014/145638, WO2015200752, and WO2011/031855, which are incorporated herein by reference. In some embodiments, the device may include a retention frame lumen in which the retention frame is secured, which may be an elastic wire, for example, a superelastic alloy such as nitinol. The retention frame may be configured to spontaneously revert to a retention shape, such as a "pretzel" shape or another coiled shape, such as those disclosed in the previously incorporated applications. In particular, the retention frame may retain the device in the body, such as the bladder. The shape is maintained so that the device is not entrained in the urine and expelled when the individual urinates. For example, the retention frame can have an elastic limit and modulus that allows the device to be introduced into the body in a relatively low-profile shape, allows the device to return to a relatively expanded shape once inside the body, and prevents the device from assuming a relatively low-profile shape within the body in response to expected forces (such as hydrodynamic forces associated with contraction and urination of the detrusor muscle). Thus, once deployed, the device may remain in the bladder of the individual, thereby limiting or preventing accidental voiding.

In some other embodiments, the shape changing function of the intravesical device may be provided by forming the device housing at least in part with a heat-set elastomeric polymer, for example, as described in WO 2016/172704.

The material used to form the device body (i.e., housing) may be at least partially elastic or flexible to allow the device to move between the deployed and retained shapes. The retaining frame portion may tend to be located inside the drug reservoir portion when the device is in the retaining shape, but in other cases the retaining frame portion may be located inside, outside, above, or below the drug reservoir portion. The material used to form the device body may be water permeable such that once the device is deployed into the bladder, a solubilizing fluid (e.g., urine) may enter the drug reservoir portion to dissolve the non-liquid form of trospium chloride, chemotherapeutic agent, immunomodulatory agent, additional therapeutic agent, functional agent, or a combination thereof contained in the drug reservoir. For example, silicone or another biocompatible elastomeric material may be used. In other embodiments, the device body may be formed at least in part from a water impermeable material.

In some embodiments, the device body is made of a resilient biocompatible polymeric material. The material may be non-absorbable or absorbable. Exemplary non-absorbable materials include synthetic polymers selected from the group consisting of: poly (ethers), poly (acrylates), poly (methacrylates), poly (vinyl pyrrolidone), poly (vinyl acetate), poly (urethanes), cellulose acetate, poly (siloxanes), poly (ethylene), poly (tetrafluoroethylene), and other fluorinated polymers, as well as poly (siloxanes). Exemplary absorbable materials, in particular biodegradable or bioerodible polymers, include synthetic polymers selected from the group consisting of: poly (amides), poly (esters), poly (ester amides), poly (anhydrides), poly (orthoesters), polyphosphazenes, pseudopoly (amino acids), poly (glycerol-sebacate), poly (lactic acid), poly (glycolic acid), poly (lactic-co-glycolic acid), poly (caprolactone) (PC) derivatives, amino alcohol-based poly (ester amides) (PEA) and poly (octanediol citrate) (POC), and other curable bioabsorbable elastomers. PC-based polymers may require additional crosslinking agents, such as lysine diisocyanate or 2, 2-bis (e-caprolactone-4-yl) propane, to achieve elastomeric properties. Copolymers, mixtures and combinations of the above materials may also be employed.

In some embodiments, the device body comprises silicone, thermoplastic polyurethane, Ethylene Vinyl Acetate (EVA), or a combination thereof. In some embodiments, the device body comprises two different thermoplastic materials, one of which is a hydrophilic thermoplastic polyurethane and is permeable to the drug and the other of which is impermeable to the drug. The drug impermeable material may be selected from hydrophilic polyurethanes, hydrophilic polyesters and hydrophilic polyamides. The device body may comprise an annular tube formed by an extrusion or co-extrusion process using one or more of these materials, as described in U.S. publication 2016/0310715, which is incorporated herein by reference.

b. Drug core/payload

In embodiments in which trospium chloride is delivered from an intravesical drug delivery device, the component may be contained in the device in various forms, which may depend on the particular mechanism by which the device controllably releases the component into the fluid (e.g., urine) in the bladder. In some embodiments, the components are provided in solid, semi-solid, or other non-liquid form, which may advantageously facilitate stable storage of the components prior to use of the device, and may advantageously enable storage of the component payload of the device in a volume that is less than would be possible if the components were contained in liquid solution form. In some embodiments, the non-liquid form is selected from the group consisting of a tablet, a granule, a pellet, a powder, a semi-solid (e.g., an ointment, cream, paste, or gel), a capsule, and combinations thereof. In one embodiment, the composition is in the form of a plurality of tablets, such as mini-tablets as described in U.S. patent 9,757,546.

For example, trospium chloride may take such forms as suspensions, solutions, colloids, micelles, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

In one embodiment, trospium chloride is formulated with one or more excipients that include a viscosity enhancing agent to control the release of trospium chloride from the release orifice in the device housing. In another embodiment, the device reservoir includes both trospium chloride and a viscosity increasing agent, but they are not co-formulated, but are provided in discrete regions within the reservoir, for example as separate tablets. Suitable viscosity increasing agents, including but not limited to polyethylene oxide (PEO), are known in the pharmaceutical art. In some variations of this embodiment, the viscosifier may be provided (e.g., formulated) with urea or another osmotic agent.

In one embodiment, trospium chloride is delivered to the bladder of the subject along with a solubilizing agent. In one embodiment, the solubilizing agent is urea. In one embodiment, the urea is provided in a tablet or other solid form and is loaded in the drug reservoir of the intravesical drug delivery device along with trospium chloride. Depending on the device, urea may also be used as an osmotic agent to facilitate the development of osmotic pressure in the drug reservoir. In one particular embodiment, the trospium chloride and osmotic agent are configured as separate payloads (i.e., powders, tablets, or other solid forms) positioned within different regions of a drug reservoir, as described in PCT WO2015/026813(Lee et al), which is incorporated herein by reference.

In some embodiments, the device may include a drug reservoir lumen. In some of these embodiments, each drug reservoir lumen may contain one or more drug tablets or other solid drug units. In one embodiment, the device contains about 10 to 100 cylindrical drug tablets, such as mini-tablets, in a plurality of discrete drug reservoir lumens. In certain embodiments, the mini-tablets may each have a diameter of about 1.0mm to about 3.3mm (such as about 1.5mm to about 3.1mm) and a length of about 1.5mm to about 4.7mm (such as about 2.0mm to about 4.5 mm). In some other embodiments, the drug reservoir lumen contains trospium chloride in powder or granular form.

In some embodiments, the intravesical device houses and releases a functional agent in conjunction with trospium chloride. The functional agent may facilitate release of the drug from the device and/or may facilitate stabilization (i.e., delay in degradation) of trospium chloride in the urine of the bladder. For example, if proteolytic degradation of trospium chloride in urine is of concern, the functional agent may comprise an anti-protease.

c. Medicine shell

The release of trospium chloride from the intravesical devices described herein can be driven and controlled by different mechanisms of action. In various embodiments, the drug may be released from the intravesical drug delivery device by diffusion through the wall of the drug housing, by diffusion through one or more defined pores in the wall of the drug housing, by osmotic pressure through pores in the drug housing, by osmotic pressure through one or more transiently formed microchannels, by erosion of the drug formulation in contact with urine in the bladder, or by a combination thereof. In some embodiments, drug release is controlled by drug diffusion through or from a drug permeable polymer or matrix component defining a portion of the device housing. In one embodiment, the device comprises a drug permeable polymer component.

The dimensions of the shell (including the thickness of the walls) can be selected based on, among other factors, the volume of the drug (and functional agent, if any) formulation to be contained, the desired rate of delivery of the drug from the device body/shell, the intended site of implantation of the device within the body, the desired mechanical integrity of the device, the desired rate of release or permeability to water and urine, the desired induction time before initial release begins, and the desired method or route of insertion into the body. In embodiments where the housing is a tube, the tube wall thickness may be determined based on the mechanical properties and water permeability of the tube material, as too thin a tube wall may not have sufficient mechanical integrity, while too thick a tube wall may experience an undesirably long induction time for initial drug release from the device and/or may not have sufficient flexibility to allow delivery through the urethra or other narrow body lumen.

In some embodiments, the housing may comprise an elongated annular tube having an inner diameter of about 2mm to about 5 mm. The drug and functional agent (if any) may be solid tablets having a diameter substantially the same as the inner diameter of the elongated annular tube. In some embodiments, the housing contains one or more first units (e.g., tablets) comprising a drug and one or more second units (e.g., tablets) comprising a functional agent that facilitates the release of the drug and/or facilitates the stabilization of trospium chloride in the urine of the bladder. One or more of the first unit of tablets may fill the lumen of the tube for a length of about 1cm to about 3cm, and one or more of the second unit of tablets may fill the lumen of the tube for a length of about 10cm to about 15 cm. In one embodiment, the ratio of the volume of the first unit to the volume of the second unit is from about 0.05 to about 0.5. Other lengths and ratios of tablet payloads are contemplated.

In some embodiments, the housing may be an elongated annular tube having a wall thickness of 0.1mm to 0.4mm (such as a wall thickness of 0.2 mm). The shell material may comprise one or more biocompatible elastomers. The shell material may be selected such that the shell has a hardness of 25A to 80A, such as 25A, 50A, 65A, 70A, or 80A.

In various embodiments, the intravesical device can continuously or intermittently release the drug to achieve a concentration of the drug in the bladder to produce a sustained therapeutically effective concentration of the drug in the urine in the bladder, as described in the methods provided herein. In certain embodiments, the intravesical device can release trospium chloride in an amount ranging from 1 mg/day to 1000 mg/day, such as from 20 mg/day to 300 mg/day or from 25 mg/day to 300 mg/day. In certain embodiments, these release rates are provided over a treatment period, as described herein. In certain embodiments, these release rates are provided over a treatment period of 14 days to 21 days.

d. Osmotic and diffusion system

After in vivo deployment, the device releases trospium chloride. As described above, drug release may occur through one or more orifices or through-holes in the device under the force of osmotic pressure due to the osmotic pressure gradient between the interior and exterior of the device. Release may also occur by diffusion, whereby the drug passes through one or more apertures or through holes in the device and/or through a drug permeable wall of the device due to a drug concentration gradient between the interior and exterior of the device. Combinations of these release patterns within a single device are possible, and in some embodiments preferred, in order to achieve an overall drug release profile that is not easily achieved from either pattern alone.

In some embodiments where the device comprises a drug in solid form, elution of the drug from the device occurs after dissolution of the drug within the device. Body fluids enter the device, contact and dissolve the drug, and thereafter the dissolved drug diffuses from or flows out of the device under osmotic pressure or via diffusion. The "dissolved drug" may include micro-and nano-sized particles of the drug in suspension that remain unchanged after the solid form of the drug is substantially dissolved, and that can also be released from the device, for example, through an aperture in the device housing. For example, the drug may dissolve upon contact with urine in the bladder. In certain embodiments, the water-permeable wall portion of the housing is permeable to the drug in the aqueous solution such that the dissolved drug is released via the wall portion, also referred to herein as "transmural diffusion". After deployment of the device in the bladder of an individual, urine permeates through the wall, enters the reservoir, and dissolves trospium chloride and the functional agent (if present). In some embodiments, the drug then diffuses directly through the wall at a controlled rate due to the drug concentration gradient between the interior and exterior of the device. For example, the shell and/or any water or drug permeable wall portion may be silicone, thermoplastic polyurethane, ethylene vinyl acetate copolymer (EVA), or a combination thereof.

In some embodiments, an intravesical device includes (i) a body including a wall bounding a reservoir defined within the body, wherein the wall has a pre-formed through-hole and includes a water permeable portion, and the body includes an elastic portion; (ii) a pharmaceutical formulation comprising trospium chloride disposed within the reservoir; and (iii) a restraining plug closing the opening of the body and contacting the resilient portion of the body, wherein the opening is in fluid communication with the reservoir, wherein the water permeable portion of the wall is configured to allow water to enter the device and contact the drug formulation in the reservoir, and wherein release of trospium chloride from the device is controlled by: (a) releasing trospium chloride through the preformed through-holes in the wall, and (b) releasing trospium chloride by transiently forming one or more microchannels extending to the opening between the resilient portion of the body and the restraining plug upon generation of hydrostatic pressure within the reservoir effective to form the one or more microchannels. The pharmaceutical formulation may be in the form of a plurality of tablets, and the body may be in the form of a silicone tube. These embodiments are further described in PCT/US18/16463, which is incorporated herein by reference.

In a first aspect, as shown in fig. 1A-1D, a drug delivery device 50 described herein includes one or more restraining plugs 56 that contact a resilient portion 54 of a device body 52 to allow release of a drug through a distal opening of the device body, as described in U.S. patent application publication 2016/0008271 to Lee, the relevant portions of which are incorporated herein by reference. However, in certain embodiments, as opposed to being orifice-free (i.e., without a predefined hole system) as in U.S. patent application publication 2016/0008271 to Lee, the device includes at least one pre-formed through-hole (i.e., orifice) 66 disposed in the wall of the device body 52, as shown in fig. 2 and 3A.

Thus, in certain embodiments, as shown in fig. 1-4, drug delivery device 50 comprises: a body 52 having a wall bounding a reservoir 60 defined within the body 52, the wall having at least one pre-formed through-hole 66 disposed therein and including a water permeable portion 64, the body 52 including an elastic portion 54; a drug formulation 58 comprising a drug, the drug formulation 58 disposed within the reservoir 60; and at least one restraining plug 56 closing an opening of the body 52 in fluid communication with the reservoir 60 and contacting the resilient portion 54 of the body 52. The water permeable portion 64 of the wall is configured to allow water to enter the drug delivery device 50 and contact the drug formulation 58 located in the reservoir 60, and control the release of the drug 58 from the device 50 by at least one of: (i) releasing the drug 58 through the at least one pre-formed through-hole 66 (i.e., hole, orifice), and (ii) releasing the drug by momentarily forming one or more micro-channels 62 extending to the opening between the resilient portion 54 of the body 52 and the at least one restraining plug 56 upon generation of hydrostatic pressure effective to form the one or more micro-channels 62. In these embodiments, the restraining plug 56 may be partially or completely unsealed at the distal end opening of the device 50. Such systems have been found to provide consistent and reproducible drug release profiles while providing a safety valve system that advantageously provides for the release of drug when the through-hole is partially or completely blocked. Thus, the device is operable to release the medicament via the pre-shaped orifice and until hydrostatic pressure within the medicament reservoir reaches a threshold pressure of the restraining plug, at which point release occurs via the restraining plug. For example, drug delivery through at least one preformed through-hole may be osmotically driven.

In a second aspect, as shown in fig. 5-6, a drug delivery device 50 as described herein includes a sealed distal end (shown sealed with an adhesive 70) with one or more of the constraining plugs 56 in contact with the resilient portion 54 of the device body 52 to allow release of the drug via pre-shaped release ports 68 in the device body 52 (e.g., the sidewall) adjacent the constraining plugs 56. The elastic portion 54 may be located at or near the end of the device 50 (as shown in fig. 9-10), or may be otherwise disposed along the length of the device, such as at or near the center of the device. The restraining plug 56 may be positioned adjacent to one or more pre-shaped release ports 68 in the device body 52 such that the restraining plug 56 covers and effectively closes the pre-shaped release ports 68 when a threshold hydrostatic pressure has not been reached within the drug reservoir 60. In such embodiments, the restraining plug 56 and resilient portion 54 of the device may be similar to those described above and in U.S. patent application publication 2016/0008271 to Lee, except that one or more microchannels 62 formed instantaneously when the drug reservoir 60 reaches a threshold hydrostatic pressure extend from the drug reservoir 60 to the pre-shaped release port 68.

Thus, in certain embodiments, as shown in fig. 5-6, a drug delivery device 50 comprises: a tubular body 52 comprising a wall bounding a reservoir 60 defined within the body, the wall having a water permeable portion 64 and an elastic portion 54 having at least one pre-formed relief port 68 (e.g., through hole, aperture, orifice, slit) disposed therein; a drug formulation 58 comprising a drug, the drug formulation 58 disposed within the reservoir 60, wherein the water permeable portion 64 of the wall allows water to enter the drug delivery device and contact the drug formulation 58 located in the reservoir 60; and at least one restraining plug 56 secured within the reservoir 60 in contact with the resilient portion 54 of the body 52 and adjacent to the at least one pre-formed release port 68 such that upon generation of hydrostatic pressure within the reservoir 60 effective to form the one or more microchannels 62, the at least one restraining plug 56 controls release of the drug from the device via the at least one pre-formed release port 68 by momentarily forming the one or more microchannels 62 extending to the at least one pre-formed release port 68 between the resilient portion 54 of the body and the at least one restraining plug 56. In certain of these embodiments, the at least one pre-formed relief port 68 is a through hole or slit provided in the wall of the body 52.

Any suitable number and location of the restraining plugs 56 and pre-shaped release ports 68 may be used to achieve the desired drug release profile. For example, as shown in fig. 5B, the device 50 may include two preformed ports 68 (shown here as holes) spaced 180 degrees apart from each other in the tubular device body 52 such that a single constraining plug 56 is positioned adjacent to both holes. As shown in fig. 5B, a pair of holes 68 and corresponding restraining plugs 56 may be provided at or near each distal end of the device. For example, as shown in fig. 6B, a single pre-formed port 68 (shown here as a slit) may be provided adjacent each of the restriction plugs 56. As shown in fig. 6B, a pre-shaped port 68 and corresponding constraining plug 56 may be provided at or near each distal end of the device.

In some embodiments, the drug delivery device includes an osmotic system as described in WO2014/145638 and U.S. publication 2016/0310715, both of which are incorporated herein by reference in their entirety. In some embodiments, a drug delivery device includes a housing having an enclosed drug reservoir lumen bounded by a first wall structure and a hydrophilic second wall structure; and a drug formulation comprising trospium chloride contained within the drug reservoir lumen, wherein the first wall structure is permeable or impermeable to water and impermeable to the drug, and the second wall structure is permeable to trospium chloride.

In some embodiments, the device housing has walls bounding and defining a drug reservoir of the device, the walls being made of a first material that functions as a first wall structure and a second material that functions as a second wall structure, such that drug release occurs substantially only through the second material. In one embodiment, the device does not comprise a well; drug release occurs only by diffusion through the second wall structure. As used herein, the terms "impermeable to the drug" and "impermeable to water" refer to a wall structure that is substantially impermeable to the drug or water such that substantially no drug or water is released through the wall structure during a therapeutic release period. For use in the bladder, it is desirable that the device be compliant (i.e., readily bendable, soft feeling) during detrusor contraction in order to avoid or reduce discomfort and irritation to the patient. Thus, the stiffness of the first and second materials of construction is a design consideration, and the proportion of high stiffness material may be limited in constructing a device shell of a given size while maintaining proper compliance in the bladder. For example, the shore hardness of tecophilic thermoplastic polyurethane (Lubrizol Corp.) may be greater than 70A, such as 80A to 65D, while the shore hardness of silicone tubing may be 50A to 70A. Thus, it may be advantageous to utilize a combination of these two different polymeric materials rather than having the device made entirely of a second material that is permeable to the water-swellable hydrophilic drug.

The arrangement of the first wall structure and the second wall structure may take a variety of forms. In certain embodiments, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at least one end of the cylindrical tube, or the first and second wall structures are adjacent to each other and together form the cylindrical tube. That is, drug release is controlled by drug diffusion through drug permeable components defining a portion of the closure housing. The drug permeable wall structure may be positioned, sized and have material properties to provide a controlled desired rate of diffusion of the drug from the device. In some embodiments, the drug permeable wall may comprise a disc stabilized in the lumen of the tube at or near the end of the tube, the disc optionally being sandwiched between an inner and outer gasket. In some embodiments, the drug permeable wall is part of a side wall of the tubular housing, or is part of an end plug located at an end of the tubular housing.

The length and width of the wall portion formed of water permeable material can be selected to provide a desired water flux rate into the reservoir defined by the device housing. In one embodiment, the width of the water-permeable wall portion, when viewed in cross-section perpendicular to the lumen axis, can be quantified by defining the arc angle of the wall. The water permeable region of the device housing may be controlled to give a selected area of permeate water uptake and hence rate of permeate water uptake, and also advantageously maintain a suitable overall size and elasticity of the device formed of a suitable biocompatible elastomer. Advantageously, by forming the device housing through a co-extrusion process, structural variations of the water-permeable regions can be created with conventional co-extrusion equipment by selecting processing parameters, thereby advantageously providing the ability to economically and efficiently manufacture a variety of structural device configurations. In some embodiments, the length of the water permeable region extends along only a portion of the overall length of the device. In such embodiments, a larger arc angle of the water permeable region may thus be employed while maintaining the drug release rate at a desired level over an extended period of time. Such intravesical device housings are described, for example, in US 2016/0310715.

In some embodiments, the wall may have a varying thickness over the circumference of the wall, e.g., the thickness of the drug-permeable portion may be less than the thickness of the drug-impermeable portion. Further, the thinner drug-permeable wall structure may be disposed at various locations relative to the adjacent, thicker drug-impermeable wall structure. In some embodiments, drug release is controlled by drug diffusion through drug permeable components defining a portion of the enclosure housing. The drug permeable wall structure may be positioned, sized and have material properties to provide a controlled desired rate of diffusion of the drug from the device.

In some embodiments, a drug delivery device includes a housing including a first wall structure and a second wall structure adjacent to one another and together forming a tube defining a drug reservoir lumen; and a medicament contained in the medicament reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures being permeable to water; (ii) the first wall structure being impermeable to the drug and the second wall structure being permeable to the drug, such that the drug can be released in vivo by diffusion through the second wall structure; (iii) the second wall structure comprises less than 90% of the cross-sectional area of the tube in a cross-section perpendicular to the longitudinal axis of the tube; and (iv) the first wall structure comprises a first polyurethane composition.

In some embodiments, the device includes an elongated elastomeric housing having a drug reservoir lumen extending between a first closed end and a second closed end; and a medicament contained in the medicament reservoir lumen, wherein: (i) the housing includes a tubular wall structure comprising: a first annular segment formed entirely of a first material that is impermeable to the drug and a second annular segment formed at least partially of a second material that is permeable to the drug, and the second annular segment is configured to release the drug in vivo by diffusion through the second material in the second annular segment; and (ii) the first annular segment has a first end integrally formed and connected with a first end of the second annular segment.

In some embodiments, the walls defining the drug reservoir lumen may have varying thicknesses. A housing with walls of different thicknesses may improve the flexibility, compressibility, or both of the housing. The different wall thicknesses may also help secure the solid drug unit within the drug reservoir lumen.

In some embodiments, the intravesical device body or housing may include openings (e.g., at opposite ends of the annular tube) that need to be sealed after the drug reservoir is loaded with the drug payload during the assembly process. Any of these defined openings or ends of the housing (including the unitary housing and the modular housing unit) may be sealed to close the opening, if desired. The seal may be achieved with a sealing substance or structure. The sealing structure may be formed of a biocompatible material, including a metal such as stainless steel, a polymer (such as silicone, ceramic, or sapphire), or an adhesive, or the like, or combinations thereof. The sealing substance or structure may be biodegradable or bioerodible. In one embodiment, a medical grade silicone adhesive or other adhesive is loaded into the opening in a fluid or processable form and then cured within the housing opening to seal it. In some embodiments, the housing comprises one or more predetermined apertures for releasing the drug from the device. These drug release apertures are not defined openings that are sealed. In other embodiments, the housing does not include a predetermined drug release aperture.

In some embodiments, the device releases the drug without a predetermined drug release aperture (i.e., orifice). The release of drug from a device without a predetermined drug release orifice may be driven by diffusion or osmotic pressure. Examples of such suitable "non-porous" delivery systems are described in PCT patent application publication WO 2014/144066(TB 130) and U.S. patent application publication 2014/0276636(TB 134), which are incorporated herein by reference.

In some embodiments, the drug delivery device comprises an osmotic system, as described in U.S. publication 2016/0199544, U.S. patent 8,679,094, and U.S. publication 2016/0008271, which are incorporated herein by reference.

In some embodiments, the drug delivery device includes an osmotic system as described in U.S. publication 2016/0279399(TB137), which is incorporated herein by reference. In some embodiments using such systems, trospium chloride may be loaded into the device housing in liquid form prior to insertion of the device into the bladder of an individual.

In some embodiments, a device includes a housing defining a reservoir; a first unit contained within the reservoir, the first unit comprising a drug; and a second unit housed within the reservoir at a location different from the first unit, wherein the second unit includes a functional agent that facilitates release of trospium chloride from the housing in vivo. In some embodiments, a device includes a housing defining a reservoir; a first unit contained within the reservoir, the first unit comprising a drug; and a second unit contained within the reservoir at a location different from the first unit, wherein the second unit comprises a functional agent (i.e., an anti-protease agent) that facilitates stabilization of trospium chloride in the bladder urine. In some embodiments, the first unit comprises one or more solid tablets or powders comprising at least one drug (e.g., trospium chloride, such as gemcitabine), and the second unit comprises one or more solid tablets or powders (e.g., comprising an osmotic agent such as urea). In some embodiments, the housing is in the form of an elongated elastomeric tube having an interior cavity (i.e., reservoir) in which all of the solid tablets of the first and second units are aligned and contained. The diameter of the solid tablet may be substantially the same as the diameter of the lumen.

When osmotic release is the desired mode of drug release, the functional agent in the second unit may include an osmotic agent that facilitates osmotic release of the drug. For example, the osmotic agent may have a higher solubility than the drug, such that the osmotic agent accelerates the dissolution and/or subsequent release of the drug. This advantageously allows for the delivery of low solubility drugs or other drugs, typically delivered via diffusion only, from osmotic delivery based devices. The device may exhibit an induction period while dissolving a sufficient volume of the functional agent and/or drug to achieve an osmotic pressure gradient.

Subsequently, the device may exhibit a zero order release rate over an extended period and then a reduced non-zero order release rate over an attenuation period. The desired delivery rate can be achieved by controlling/selecting various parameters of the device including, but not limited to, the surface area and thickness of the water-permeable wall; permeability to water of the material used to form the wall; the shape, size, number and placement of the holes; and dissolution profiles of drugs and functional agents.

The devices described herein can also be configured to release drugs either alone via diffusion or via a combination of diffusion and osmotic release. The device may be configured to allow the dissolved drug to pass through a portion of the housing or one or more apertures therein.

Alternatively, or in combination with the water permeable wall portion, the housing may comprise at least one aperture configured to allow fluid to enter the reservoir in vivo. The housing may also include one or more holes or through-holes configured to allow the dissolved drug to pass therethrough.

In some embodiments of the osmotic system, the device housing comprises a first elastomeric material that is water-permeable and a second elastomeric material that is water-impermeable, wherein both materials are selected to be impermeable to the drug contained in the housing.

Figures 7A-7C illustrate one embodiment of an intravesical device that may be used in the methods described herein. The device 100 includes a drug reservoir portion 102 and a retention frame portion 104. In fig. 7A, the device 100 is shown in a relatively expanded shape adapted to be retained within the bladder of an individual. In fig. 7C, the device 100 is shown in a relatively low-profile shape for deployment through a working channel 202 of a deployment instrument 200 (such as a cystoscope or other catheter), e.g., for insertion through and through the urethra and into the bladder of a patient. After deployment (release of the device) of the drug delivery device into the bladder, the device 100 may assume a relatively expanded shape to retain the drug delivery device in the bladder. In the exemplified embodiment, the drug reservoir portion 102 and the retention frame portion 104 of the drug delivery device 100 are longitudinally aligned and integrally formed or otherwise coupled to each other along their lengths.

The drug delivery device 100 includes a resilient or flexible device body 106 defining a drug reservoir lumen 108 and a retention frame lumen 110. The drug reservoir lumen 108 is configured to contain a drug (e.g., trospium chloride) in the form of a plurality of solid drug units 112 to form the drug reservoir portion 102. The voids 116 or breaks formed between adjacent drug units 112 allow the drug units 112 to move relative to each other such that the device 100 is flexible despite being loaded with a solid form of drug. The retention frame interior 110 is configured to receive a retention frame 114 to form the retention frame portion 104.

As shown in the cross-sectional view of fig. 7B, the device body 106 includes a tube or wall 122 defining the drug reservoir lumen 108 and a tube or wall 124 defining the retention frame lumen 110. The tubes 122, 124 and lumens 108, 110 may be substantially cylindrical, with the drug reservoir lumen 108 having a relatively larger diameter than the retention frame lumen 110, although other configurations may be selected based on, for example, the amount of drug to be delivered, the diameter of the retention frame, and deployment considerations (such as the inner diameter of the deployment instrument). The device body 106 may be integrally formed, such as via molding or extrusion, although the tubes 122, 124 may also be separately constructed and assembled. The wall 124 defining the retention frame lumen 110 may extend along the entire length of the wall 122 defining the drug reservoir lumen 108 such that the retention frame lumen 110 has the same length as the drug reservoir lumen 108 as shown, but in other embodiments, one wall may be shorter than the other. Additionally, in the illustrated embodiment, the two walls 122, 124 are attached along the entire length of the device, although intermittent attachment may also be employed.

As shown in fig. 7A, the drug reservoir lumen 108 is loaded with a plurality of drug units 112 arranged in series. For example, between about 10 and about 100 drug units 112 may be loaded, such as between about 20 and about 80 drug units 112. The pharmaceutical unit may be, for example, a tablet, bead or capsule. Substantially any number of drug units may be used depending on the size of the reservoir and the drug units. The drug reservoir lumen 108 includes open ends 130 and 132, which are shown as relatively circular openings at opposite ends of the drug reservoir lumen 108. At least one of these openings provides access to a drug unit 112 to be placed into the drug reservoir lumen 108 during device loading and assembly.

After loading the drug units 112, the end plugs 120 block the openings 130 and 132. The end plug 120 may be cylindrical and may be secured in the drug reservoir lumen 108 by frictional engagement and/or adhesive or other fastening means. As shown, each end plug 120 includes a hole 118 to provide a passage for releasing drug from the drug reservoir lumen 108. In some alternative embodiments, only one of the end plugs comprises a hole. In some other alternative embodiments, none of the end plugs include a hole, and in some of those embodiments, tube wall 122 includes a defined hole to release the drug therethrough.

The retention frame lumen 110 carries a retention frame 114, which may be an elastic wire, such as a nitinol wire, that is (heat) shaped into the overlapping coiled shape shown in fig. 7A. The retention frame 114 may have an elastic limit and modulus that allows the device 100 to be introduced into the body in a relatively low-profile shape, allows the device 100 to return to a relatively expanded shape once inside the body, and prevents the device from assuming a relatively low-profile shape within the body in response to expected forces, such as hydrodynamic forces associated with contraction and urination of the detrusor muscle.

e. Erosion-based system

In some embodiments that may be used with tablets containing low solubility drugs, the drug is provided in the form of a tablet that is fixed in a device having an exposed tablet face such that release of the drug from the device occurs by controlled erosion/dissolution, as described in U.S. patent 9,107,816. In some embodiments, the device may include a modular housing. The modular housing is typically formed of at least two separate housing units, each unit containing at least one solid drug unit. The material forming each housing unit defines at least one drug reservoir lumen capable of containing a solid drug unit. The drug reservoir lumen may have one or more defined openings. For example, the drug reservoir lumen may have two opposing openings that correspondingly expose opposing end faces of at least one solid drug unit contained therein. In certain embodiments, at least two individual housing units in the modular housing are connected directly or indirectly by a holding frame. In some embodiments, the modular housing units may be placed on a holding frame to form a "bracelet" design. The device may have one housing unit or a plurality of housing units. The number of housing units may be limited only by the size of the holding frame to which they are connected.

In some embodiments, one or more of the individual housing units includes a retention frame lumen through which a common retention frame extends. In certain embodiments, the retention frame lumen and the drug reservoir lumen of each housing unit are arranged parallel to each other. In a particular embodiment, the retention frame lumen and the drug reservoir lumen of each housing unit are arranged perpendicular to each other. In further embodiments, the retention frame lumen and the drug reservoir lumen of each housing unit are arranged at an angle other than 0 ° (parallel) and 90 ° (perpendicular), such as 5 °,10 °, 30 °, 45 °, 60 °, or 85 °. In further embodiments, the devices described herein comprise two or more housing units having at least two of the following configurations: (1) the retention frame lumen and the drug reservoir lumen are arranged substantially parallel to each other, (2) the retention frame lumen and the drug reservoir lumen are arranged substantially perpendicular to each other, and (3) the retention frame lumen and the drug reservoir lumen are arranged at angles other than 0 ° (parallel) and 90 ° (perpendicular).

f. Integrated silicone-drug delivery system

In some embodiments, the device may comprise an elastic polymer-drug matrix, as described in WO2015/200752, which is incorporated herein by reference in its entirety.

g. Device with multiple release portions

In some embodiments, the device comprises at least two drug releasing portions, at least one releasing portion releasing drug at a different rate than the other releasing portion, as described in WO2011/031855, which is incorporated herein by reference in its entirety. The release portions may achieve different release rates by having different configurations, by accommodating different drug formulations, or by employing different release mechanisms, the like, or combinations thereof. The release portions may be combined to achieve a desired release profile. For example, the device may include release portions that exhibit different induction or lag times before the initial release begins, release the drug at different rates or according to different release profiles after the release begins, or release the drug over different time periods before the drug load is substantially depleted, etc., or combinations thereof. The different release portions may be combined to achieve a desired release profile from the drug delivery device as a whole, such as a release profile that exhibits a relatively short initial lag time and thereafter continues to release at a relatively constant rate over an extended period.

In some embodiments, the device is loaded with a plurality of solid drug tablets that may be smaller in size than conventional drug tablets. Because the device controls the release of the drug into the body, the drug itself may contain little or no excipients to control the release of the drug. Conversely, excipients present in a pharmaceutical tablet can be present primarily or entirely to facilitate the tableting process or in vivo dissolution. Thus, the device may provide a high drug payload based on volume or weight, yet the device may be small enough for deployment in vivo in a minimally invasive manner.

The drug housing also allows the drug to flow out in a liquid or semi-solid form upon implantation or after dissolution in vivo. The wall may be formed of a drug permeable material that allows the drug to flow out through the drug housing along its entire length. The wall may also be formed at least in part from a material that is semi-permeable to the drug, depending on the form of the drug. For example, the wall may be permeable to one form, such as a charged form, of the drug, but not another form, such as an uncharged form (e.g., a base form versus a salt form). The wall may also include one or more openings or channels formed completely therethrough to allow the medicament to exit the medicament housing.

The drug moiety may have any combination of the properties or configurations described herein, meaning that a hole may be provided, omitted, replaced with a through hole, or reinforced with additional or through holes; the shell may have a porous wall with an open or closed cell structure; one or more degradable timing structures or release modifying structures may be associated with the shell; or any combination thereof.

The drug tablets may be arranged in any arrangement other than a serial arrangement, depending on the configuration of the drug housing. The drug tablet may fill any portion of the drug housing except the entire drug housing, as illustrated. A filling material such as a silicone adhesive may be used to fill any portion of the drug housing not loaded with drug tablets, or air may be used, thereby increasing the buoyancy of the device. The composition of the drug tablets may be the same or may vary along the device. The drug may also be in a form other than a drug tablet, such as other liquid, semi-solid, or solid forms (e.g., granules).

In some embodiments, the drug delivery device comprises at least two discrete or separate drug portions associated with a single retention portion. The drug portions may be separate drug housings each associated with a retention portion, or the drug portions may be separate regions within a single drug housing associated with a retention portion.

Each drug portion may be defined by a portion of a drug housing wall and at least one separation structure separating the drug portion from a second drug portion. The separation structure may be a plug (such as a cylinder, sphere, or disc, etc.) inserted into the housing, the plug being held in place by its size or held in place with an adhesive. The partition structure may also be part of the housing formed directly therein (such as by molding).

The device having at least two discrete portions may be adapted to controllably release at least two drug payloads from a corresponding number of drug reservoirs. The two discrete portions may have the same configuration or different configurations as described herein. The two pharmaceutical payloads may be the same as each other or may be different from each other depending on the content (such as active ingredient content or excipient content), form (such as salt form or base form), state (such as liquid, semi-solid or solid state), and the like or combinations thereof. Thus, the two discrete portions may release the two drug payloads at the same or different times, at the same or different rates, via the same or different release mechanisms, or any combination thereof.

For example, one drug portion may be configured to release its payload relatively quickly after implantation, and another drug portion may be configured to experience an induction time before release begins, or a combination thereof. The initiation of release of the two payloads in the different drug moieties may be staged. Examples of fast-release drug portions include drug portions that function as relatively fast-acting osmotic pumps (such as silicone tubing with relatively thin walls), drug portions loaded with a drug in a fast-release form (such as a liquid form or a specially formulated solid form), drug portions associated with relatively fast-acting degradable timing structures, or combinations thereof. Thus, the device may release the drug during the initial acute phase and during the maintenance phase.

As another example, one drug portion may be configured to release its drug payload at a relatively faster rate than the other drug payloads. For example, one drug portion may contain a drug payload with low water solubility for diffusional release beginning shortly after implantation and another drug portion may contain a drug payload with high water solubility for osmotic release after an induction period. As another example, one drug portion may contain a drug payload in a liquid state for rapid release through the pores of a degradable timing membrane with a rapid action, and another drug portion may contain another drug payload of a solid tablet for slow release after dissolution in vivo. As another example, one drug portion may have a relatively solid wall, while another drug portion may have a plurality of pores or orifices formed through its wall (which may increase the release rate due to diffusion) or a closed-cell porous wall (which may increase the release rate due to increased permeation of water or drug through the wall).

The release portions may be combined to achieve a desired release profile. For example, the device may include release portions that exhibit different induction or lag times before the initial release begins, release the drug at different rates or according to different release profiles after the release begins, or release the drug over different time periods before the drug load is substantially depleted, etc., or combinations thereof. The different release portions may be combined to achieve a desired release profile from the drug delivery device as a whole, such as a release profile that exhibits a relatively short initial lag time and thereafter continues to release at a relatively constant rate over an extended period.

By combining multiple different drug moieties in a single device, the device can exhibit a desired trospium chloride release profile. The release profile from the device may generally be the sum of the release profiles of the discrete portions, e.g., where the first portion exhibits a minimum lag time before release begins, the second portion exhibits a shorter induction period as the osmotic pressure gradient acts, and the third portion exhibits a longer delay as the degradable structure dissolves or degrades before beginning. Once released from either fraction, the release rate may be relatively zero-order for an extended period, followed by a decay period. It should be noted that three discrete portions are examples, and any number or combination of discrete portions may be used to achieve a desired release profile.

Because the different drug moieties may be only discrete regions within a single tubular housing, it may be advantageous that the construction and deployment of the device may be relatively simple, but the different drug moieties exhibit different release profiles due to different drug payloads, pore placements, and degradable timing structures. In other embodiments where the drug portion uses walls of, for example, different materials, thicknesses, or porous cell structures, the shell may vary along its length or a separate drug shell may be used. Thus, controlled release can be achieved in a series of ways.

II. gels

In another embodiment, the coating substance may be administered intravesically to the bladder wall (e.g., to the urothelial region inside the bladder), wherein the coating substance comprises trospium chloride and one or more excipient materials that promote adhesion of the coating substance to the bladder wall and provide continuous controlled release of trospium chloride over the treatment period. The coating substance may be a mucoadhesive formulation, such as a gel, an ointment, a cream, a paste, a film, an emulsion gel, a tablet, a polymer, or a combination thereof. The mucoadhesive formulation polymer may include a hydrogel or hydrophilic polymer, polycarbophil (e.g., carbomer, etc.), chitosan, polyvinylpyrrolidone (PVP), lectin, pegylated polymer, cellulose, or combinations thereof. Suitable celluloses include Methylcellulose (MC), carboxymethylcellulose (CMC), Hydroxypropylcellulose (HPC), or combinations thereof. The coating substance may include a penetration enhancer. Non-limiting examples of permeation enhancers include dimethyl sulfoxide (DMSO), sodium carboxymethyl cellulose (NaCMC), lipids, surfactants, or combinations thereof. The coating substance may be deployed in the bladder such that the coating substance engages the bladder wall.

The coating substance may be deployed in the bladder using a deployment instrument. The deployment instrument may be any device designed to navigate through a natural lumen of the body to reach the intended implantation site. For deployment in the bladder, the deployment instrument may be sized and shaped to be able to pass through the urethra or a suprapubic cystostomy or suprapubic catheter of an individual to the bladder of the individual. The deployment instrument may be a known device such as a catheter or cystoscope, or a specially designed device. The deployment instrument is used to deploy the coated substance into the body and subsequently removed from the body, thereby allowing the coated substance to be fully implanted into the body. Once so implanted, the coating material can release the drug into the body for an extended period of time. Similar procedures may be used to deploy any of the devices or drugs described herein into other parts of the body through other natural lumens. For example, a deployment instrument may be used to deploy a liquid drug or drug formulation into the bladder by passing the deployment instrument through the urethra or a suprapubic cystostomy.

Examples

Example 1: intravesical trospium chloride delivery for the treatment of overactive bladder

The objective of this study was to confirm sustained local delivery of trospium chloride with the trospium chloride releasing intravesical system (TAR-302). TAR-302 is a passive, non-absorbable trospium chloride-releasing intravesical system whose primary mode of action is the controlled release of trospium chloride into the bladder over a period of time (e.g., 42 days).

Part I.A。

The study included ten subjects. These subjects were idiopathic overactive bladder patients who failed to receive oral drug therapy. TAR-302 was placed into the bladder by inserter on study day 0 and TAR-302 was removed on study day 42. During the 42 day dwell time, TAR-302 gradually released trospium chloride in the bladder at a dose of about 4 mg/day to 8 mg/day. See fig. 3A.

Daily urine trospium chloride recovery was evaluated on days 3, 7, 21, 35, 42, and 56. On the PK sampling day, the average daily total trospium chloride recovery was about 6.28 mg/day, ranging from 3.03 mg/day to 8.31 mg/day. Dotted grey lines indicate passage of QDs at about 20mg twice daily or 60mg¹Is administered orally to estimate daily trospium chloride recovery. See fig. 8.

TAR-302 therapy produces a distribution of benign adverse events. No evidence of typical antimuscarinic systemic side effects, retention or encrustation was observed. At the end of dosing (i.e., day 42), the average daily number of urinary incontinence decreased from baseline of 5.42 to 1.28. See fig. 9B. The therapeutic effect of TAR-302 is superior to that of patients refractory to oral therapyThe latter reduced the average daily number of urinary incontinence relative to baseline by 2.7. See fig. 10A. The curative effect of TAR-302 is also superior to that of TAR-302(solifenacin succinate) andoral treatment with LA (tolterodine tartrate), the latter two reduced the average number of daily urinary incontinence relative to baseline by 1.4 and 0.8, respectively. See fig. 10B. More significantly, a persistent response was observed after removing TAR-302. On day 84 (six weeks after TAR-302 removal), subjects averaged 2.44 urinary incontinence per day, which was a 55% reduction from baseline of 5.42. See fig. 9B.

TAR-302 also significantly improved the micturition distress score and the quality of life score, as shown in fig. 11-12. A 40.3% reduction in the distress score was observed after 42 days of treatment with TAR-302. Six weeks after removal of TAR-302, the distress score decreased by 19.1 points, which is a clinically significant improvement. FIG. 12: similarly, a significant 42.2 point increase in quality of life score was observed at the end of the 42 day TAR-302 treatment period. A significant improvement in quality of life score of 17.9 points was observed on day 84 even six weeks after TAR-302 removal.

a. Result index

Primary outcome indicators included report-based Adverse Events (AE), trial drug events (IPE), Physical Examination (PE), vital signs, clinical laboratory examinations, plans throughout the studyCystoscopy, bladder ultrasonography, residual urine volume after bladder voiding (PVR), and use of concomitant medication to assess the safety of TAR-302.

Secondary outcome indicators include the following.

1. Tolerance to TAR-302 is assessed throughout the study based on, for example, the percentage of subjects who are tolerant to indwelling TAR-302 for a specified period of time and who do not need to remove TAR-302 before a predetermined removal date (due to satisfaction of any subject stopping criteria or other drug or device composition related adverse events).

2. Pharmacokinetic analysis of plasma and urine from day 0 to day 56 was evaluated. For example, plasma and urine trospium chloride exposures are examined and analyzed.

3. A reduction in urinary incontinence from day 0 to day 84 relative to baseline was assessed. For example, negative changes in the number of daily urinary incontinence relative to baseline, where urinary incontinence is defined as an involuntary urine leakage event, are assessed and analyzed.

4. The reduction in the number of daily urination from day 0 to day 56 was evaluated. For example, negative changes in the number of toilet discharges from a subject relative to baseline are assessed and analyzed.

5. The increase in the urine output per urination from day 0 to day 56 was evaluated. For example, the increase in measured (urine output) over a separate 24 hour period relative to baseline is assessed and analyzed.

Other outcome metrics include assessing quality of life (QoL) from day 0 to day 84. For example, evidence of QoL improvement is assessed by having the subject answer any one or a combination of the following questions: during the past four weeks, a. the extent to which the subject suffers from an uncomfortable urge to urinate; b. the extent to which the subject is troubled by an abrupt urination rush with little or no warning; c. the extent to which the subject is troubled by an unexpectedly small amount of leakage urine; e. the extent to which the subject is troubled by nocturnal voids; f. the degree to which the subject is troubled at night because he/she must urinate; g. the extent to which a subject is afflicted with urine leakage associated with an urge to urinate; h. the frequency with which a subject's bladder symptoms cause the subject to plan an "escape route" to a public place toilet; i. the frequency with which bladder symptoms in a subject cause the subject to perceive himself/herself as having problems; j. the frequency with which bladder symptoms in a subject interfere with his/her ability to obtain good night rest; k. the frequency with which a subject's bladder symptoms cause him/her to become depressed or irritated from the time he/she spends in the toilet; the frequency with which the subject's bladder symptoms prevent him/her from activities away from the toilet (e.g., walking, running, hiking); frequency of bladder symptoms in the subject waking the subject from sleep; n. bladder symptoms in a subject cause the subject to reduce the frequency of his or her physical activity (exercise, etc.); frequency with which bladder symptoms of a subject cause the subject to have problems with his/her partner or spouse; p. the frequency with which bladder symptoms of a subject cause discomfort to the subject when the subject travels with others due to the need to travel midway to the toilet; q. the frequency with which a subject's bladder symptoms affect his/her relationships with family and friends; r. frequency of bladder symptoms in the subject causing his/her embarrassment; s. the frequency with which a subject's bladder symptoms result in locating the nearest toilet as soon as he/she reaches a location that he/she never reached.

b. Qualification standard

Inclusion criteria include the following. 1. The subject had symptoms of overactive bladder (OAB) (urinary frequency/urgency) with urge incontinence or mixed incontinence with major urge components for at least 6 months. For example, according to the diary entry, the subject urinates eight or more times per 24 hours, or the subject is recorded in a 3-day diary as at least 4 urinary incontinence associated with urgency (the subject must have at least one episode per 24 hours or day). 2. When receiving anticholinergic agents to treat OAB, the subject has inadequate response or limited side effects.

Exclusion criteria included the following. 1. The subject is less than 18 years of age. OAB is caused by a neurological disorder. 3. Screening revealed the presence of significant renal dysfunction (glomerular filtration rate <30 mL/min). 4. Screening found there was significant polyuria (urine volume >4,000 mL/day) for any reason. 5. History of pelvic radiotherapy exists. 6. There is a history of bladder cancer or bladder pathology that the investigator deems inappropriate for inclusion in the study. Active malignancies were present within 7.12 months, except for subjects with negligible risk of metastasis or death and who received treatment with the expected cure outcome. 8. The subject has any bladder or urethra anatomical features that may interfere with the safe placement, indwelling use, or removal of TAR-302. 9. Researchers believe that subjects have a history of significant stress urinary incontinence. 10. Subjects had active bladder stones or had a history of bladder stones <6 months prior to study enrollment. 11. The subject had a history (>4 times/1 year) of recurrent symptomatic Urinary Tract Infection (UTI). 12. The subject suffers from urinary or gastric retention or uncontrolled narrow angle glaucoma. 13. The subject had a post-micturition residual urine volume (PVR) of 300mL or greater. 14. The subject has a known hypersensitivity reaction to trospium chloride, a chemically related drug or component excipient. 15. The subject has a known hypersensitivity reaction to the device materials, including silicone and nitinol. 16. The subjects took trospium chloride voluntarily. 17. New drugs or modified doses of current drugs used to treat OAB (i.e., anticholinergics, beta-3 adrenergic receptor agonists, spasmolytics, antidepressants, or hormones) were added or modified within 30 days prior to the sign of the Informed Consent Form (ICF). The stable dose must be continued until the last study visit. If previously used and discontinued, these drugs must have been discontinued for >2 weeks before day 0. 18. Intravesical botulinum toxin was used within 9 months prior to screening visits. 19. Intravesical anticholinergic drugs were used within 30 days prior to the screening visit. 20. The subject has a history of non-drug therapy for treatment of OAB (i.e., InterStim therapy). A history of non-invasive neuromodulation (i.e., transcutaneous tibial nerve stimulation (PTNS)) was allowed if discontinued at least 8 weeks prior to study day 0. 21. Pregnant (confirmed by urinalysis at screening) or lactating or female subjects with fertility potential and who have not used an acceptable method of contraception. 22. The subject has a medical condition that may lead to non-compliance with the study protocol. 23. Subjects had participated in another drug, device, or behavioral study within 60 days prior to the screening visit. 24. The subject has a history of or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immune, dermatological, neurological or psychiatric disease or disorder that the investigator deems prohibited from participating in the study. 25. Any one of the following medical histories occurred within 3 months prior to the screening visit. Major illness/major surgery (requiring hospitalization), including pelvic, lower back surgery, or procedures unrelated to bladder cancer; most outpatient procedures are not excluded; renal or ureteral stone disease or apparatus; and (5) delivering.

Part II.B。

This open label phase 1b study evaluated the safety, tolerability, and primary efficacy of TAR-302 in patients with refractory or intolerant oral therapy of idiopathic overactive bladder (iOAB). At study enrollment, study subjects were asked to develop at least 4 urinary incontinence within 3 days. The subject received a single administration of TAR-302 with an intravesical residence time of 42 days. The TAR-302 is placed with an insertion catheter and removed via cystoscopy. Pharmacokinetic (PK) analyses were performed in blood and urine. Response to TAR-302 was assessed using a 3-day urinary incontinence log, and quality of life was assessed using an OAB-q profile (OAB-q SF).

Results

Eleven subjects successfully completed the study. The baseline characteristics are presented in table 1. Throughout the study, TAR-302 was well tolerated: AEs potentially associated with TAR-302 were all mild and included hematuria (n-4), bladder discomfort (n-2), and bladder pain (n-2). Only 1 example of a typical antimuscarinic exposure AE was observed: a single progressive dry mouth was reported on day 36, followed by spontaneous regression. 2 subjects experienced UTI, which was considered likely to be relevant to the insertion procedure.

PK analysis showed that the mean trospium chloride levels in urine throughout the study were 3.27 μ g/mL, well above the predicted urine levels achieved with oral trospium chloride (0.5 μ g/mL to 1 μ g/mL) (see santcura FDA drug insert, obtained 3 months 2019). These intravesical concentrations produced negligible systemic exposure (mean: 0.22 ng/mL).

Table 1: demographic data

The subjects experienced a 75% reduction in the number of daily Urge Incontinence (UI) from 5.57/day at baseline to 1.4/day on day 42 (P < 0.01). 3 of 11 subjects were fully self-controlled on day 42. Subjects also experienced a clinically and statistically significant improvement in both symptom distress and health-related quality of life as measured by OAB-q SF: the mean score for the symptom affliction sub-scale decreased by 41 points (74 points at baseline, 33 points at day 42, P <0.01), and the mean score for the HRQOL sub-scale increased by 45 points (32 points at baseline, 77 points at day 42, P < 0.001).

Surprisingly, the subject also appeared to experience a persistent symptomatic benefit following removal of TAR-302 on day 42, despite no further therapeutic intervention during this segment. The average number of UIs remained significantly below baseline, 2.67 UIs/day at day 84, -52%, p < 0.05); additional indicators of UI improvement are recorded in table 2. In addition, clinical (but not statistically significant) improvement was also observed on both OABq-SF subscales at day 84: symptoms were less troubled by 19 points (baseline 74 points versus day 84, 55 points) and HRQOL increased by 18 points (baseline 32 points versus day 84, 50 points; minimum clinically significant change of 10 points).

Table 2: UI responder analysis

TAR-302 shows encouraging safety, tolerability, and primary efficacy in the management of symptoms in urge incontinence patients with poor control of oral therapy.

Example 2

In this study, TAR-302 was placed into the bladder of a subject with overactive bladder by an inserter on study day 0, and the TAR-302 was removed on study day 56, followed immediately by placement of another TAR-302 inserter, which was removed on day 112. Based on prn (as needed), subjects further received TAR-302 treatment.

I. Result index

The primary outcome indicators included assessing the safety of TAR-302 based on reported Adverse Events (AE), trial drug events (IPE), Physical Examination (PE), vital signs, clinical laboratory examinations, planned cystoscopy, bladder ultrasound examination, residual urine volume after bladder voiding (PVR), and use of concomitant medications throughout the study.

Secondary outcome indicators include the following.

1. Tolerance to TAR-302 is assessed throughout the study based on, for example, the percentage of subjects who are tolerant to indwelling TAR-302 for a specified period of time and who do not need to remove TAR-302 before a predetermined removal date (due to satisfaction of any subject stopping criteria or other drug or device composition related adverse events).

2. Pharmacokinetic analysis of plasma and urine from day 0 to day 112 was evaluated. For example, plasma and urine trospium chloride exposures are examined and analyzed.

3. The reduction in urinary incontinence relative to baseline over the duration of participation in the study was assessed. For example, negative changes in the number of daily urinary incontinence relative to baseline, where urinary incontinence is defined as an involuntary urine leakage event, are assessed and analyzed.

4. The reduction in the number of daily urination from day 0 to day 112 was evaluated. For example, negative changes in the number of toilet discharges from a subject relative to baseline are assessed and analyzed.

5. The increase in the urine output per urination from day 0 to day 112 was evaluated. For example, the increase in measured (urine output) over a separate 24 hour period relative to baseline is assessed and analyzed.

Other outcome metrics include assessing quality of life (QoL) from day 0 to day 112. For example, evidence of QoL improvement is assessed by having the subject answer any one or a combination of the following questions: during the past four weeks, a. the extent to which the subject suffers from an uncomfortable urge to urinate; b. the extent to which the subject is troubled by an abrupt urination rush with little or no warning; c. the extent to which the subject is troubled by an unexpectedly small amount of leakage urine; e. the extent to which the subject is troubled by nocturnal voids; f. the degree to which the subject is troubled at night because he/she must urinate; g. the extent to which a subject is afflicted with urine leakage associated with an urge to urinate; h. the frequency with which a subject's bladder symptoms cause the subject to plan an "escape route" to a public place toilet; i. the frequency with which bladder symptoms in a subject cause the subject to perceive himself/herself as having problems; j. the frequency with which bladder symptoms in a subject interfere with his/her ability to obtain good night rest; k. the frequency with which a subject's bladder symptoms cause him/her to become depressed or irritated from the time he/she spends in the toilet; the frequency with which the subject's bladder symptoms prevent him/her from activities away from the toilet (e.g., walking, running, hiking); frequency of bladder symptoms in the subject waking the subject from sleep; n. bladder symptoms in a subject cause the subject to reduce the frequency of his or her physical activity (exercise, etc.); frequency with which bladder symptoms of a subject cause the subject to have problems with his/her partner or spouse; p. the frequency with which bladder symptoms of a subject cause discomfort to the subject when the subject travels with others due to the need to travel midway to the toilet; q. the frequency with which a subject's bladder symptoms affect his/her relationships with family and friends; r. frequency of bladder symptoms in the subject causing his/her embarrassment; s. the frequency with which a subject's bladder symptoms result in locating the nearest toilet as soon as he/she reaches a location that he/she never reached.

Example 3: exposure to idiopathic overactive bladder (iOAB) and urinary incontinence by TAR-302-5018 Prospective multicenter open label study of intravesical delivery of trospium chloride in subjects-part 1。

TAR-302-5018 contained 850mg of trospium chloride and in vitro studies have shown an average release of 10 mg/day over a 42 day retention period. Assuming a urine production rate of 1500 mL/day, this average daily release rate is estimated to produce a urine concentration of 7 μ g/mL in humans.

I. Target

The objectives of this study included assessing the safety and tolerability of TAR-302-.

Process II

Subjects with urob associated with urge incontinence who were refractory or intolerant to oral anticholinergic therapy were screened for inclusion in the study. On day 0, eligible subjects received TAR-302-5018 transurethrally via a TARIS inserter. On day 42, TAR-302 and 5018 were removed by flexible or rigid cystoscopy. Following removal of TAR-302-. In addition, PK assessments were performed at visits day 0, day 3(± 1 day), day 7 (± 1 day), day 21 (± 1 day), day 35 (± 2 days), day 42 and day 56 (± 2 days). Subjects were contacted by phone between visits on days 13 (+ 1), 27 (+ 1), 38 (+ 1), and 49 (+ 1) for safety assessment and reminder of the study procedure.

Approximately 10 subjects were included in this study. Twelve subjects were enrolled and received TAR-302-5018 insertion; these 12 subjects were included in the intent-to-treat (ITT) population and the safety population. Eleven subjects completed the study and were included in the protocol (PP) compliant population.

Diagnosis and Primary inclusion criteria

To be eligible for participation in the present study, subjects must have met all of the following inclusion criteria when enrolled: 1. overactive bladder (OAB) (urinary frequency/urgency) with urge incontinence or mixed incontinence with symptoms of the major urge component for at least 6 months. This means that the subject urinated 8 or more times per 24 hours according to the diary record, and/or the subject had at least 4 urinary incontinence associated with urgency (or had to have at least 1 episode per 24 hours) recorded in a 3-day diary. 2. Inadequate response or limited side effects are seen with the acceptance of anticholinergic agents for OAB.

Subjects were not eligible for inclusion in the study if they met any of the following exclusion criteria: 1. age <18 years. 2.OAB caused by neurological disorders. 3. Screening revealed the presence of significant renal dysfunction (glomerular filtration rate <30 mL/min). 4. Screening found there was significant polyuria (urine volume >4,000 mL/day) for any reason. 5. There is history of radiotherapy of pelvic cavity. 6. There is a history of bladder cancer or bladder lesions that the investigator considered unsuitable for inclusion in the study. Active malignancies were present within 7.12 months, except for subjects with negligible risk of metastasis or death and who received treatment with the expected cure outcome. 8. The subject has any bladder or urethra anatomical features that may interfere with the safe placement, indwelling use, or removal of TAR-302 and 5018. 9. Researchers believe that subjects have a history of significant stress urinary incontinence. 10. Subjects had active bladder stones or had a history of bladder stones <6 months prior to study enrollment. 11. There was a history (>4 times/1 year) of recurrent symptomatic Urinary Tract Infection (UTI). 12. The subject suffers from urinary or gastric retention or uncontrolled narrow angle glaucoma. 13. The residual urine volume after urination (PVR) was 300mL or more. 14. The subject has a known hypersensitivity reaction to trospium chloride, a chemically related drug or component excipient. 15. The subject has a known hypersensitivity reaction to the device materials, including silicone and nitinol. 16. The subject is taking oral trospium chloride on his own. 17. New drugs or modified doses of current drugs used to treat OAB (i.e., anticholinergics, beta-3 adrenergic receptor agonists, spasmolytics, antidepressants, or hormones) were added or modified within 30 days prior to the sign of the Informed Consent Form (ICF). The stable dose must be continued until the last study visit. If previously used and discontinued, these drugs must have been discontinued for >2 weeks before day 0. 18. Intravesical botulinum toxin was used within 9 months prior to screening visits. 19. Intravesical anticholinergic drugs were used within 30 days prior to the screening visit. 20. There is a history of non-drug therapy (i.e., Interstim therapy) for treatment of OAB. A history of non-invasive neuromodulation such as transcutaneous tibial nerve stimulation (PTNS) is allowed if discontinued at least 8 weeks prior to day 0. 21. Pregnant (confirmed by urinalysis at screening) or lactating or female subjects with fertility potential and who have not used an acceptable method of contraception. 22. The subject has a medical condition that may lead to non-compliance with the study protocol. 23. Subjects refused to provide written informed consent. 24. Subjects were unable or unwilling to complete questionnaires and/or logs and participate in all protocol-specified study visits. 25. Another drug, device or behavioral study was enrolled within 60 days prior to the screening visit. 26. There is a history of or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder that the investigator deems prohibited participating in the study. 27. Any one of the following medical histories occurred within 3 months prior to the screening visit: major illness/major surgery (requiring hospitalization), including pelvic, lower back surgery, or procedures unrelated to bladder cancer; most outpatient procedures are not excluded; renal or ureteral stone disease or apparatus; and (5) delivering. 28. It is difficult to provide a blood sample. 29. Researchers or tairis consider other unspecified reasons that render a subject unsuitable for group entry.

End point of

a. Primary safety endpoint。

Safety during TAR-302 and 5018 insertion, 42 days of continuous exposure and removal. Safety was assessed via adverse events occurring after Treatment (TEAE), clinical laboratory examinations, vital signs, physical examinations, bladder ultrasound examinations, trial drug events (IPE), bladder PVR assessment, cystoscopy, and concomitant medication.

b. Secondary safety endpoint

Tolerance upon TAR-302-5018 insertion, 42 days of continuous exposure and removal. Tolerance is defined as: need not be removed prior to the scheduled date due to satisfaction of any regimen-specific subject stopping criteria or other drug or device composition related Adverse Events (AEs). PK analysis of plasma and urine (based on samples on day 0, day 3(± 1 day), day 7 (± 1 day), day 21 (± 1 day), day 35 (± 2 days), day 42 and day 56 (± 2 days)). Plasma and urine samples were used to determine the following: maximum concentration (Cmax) for each visit; day of study (Tmax) of maximum concentration; concentration at day 42 removal (Ctau); average concentration from day 0 to day 42 (Cave 42); mean concentration from day 0 to day 56 (Cave 56).

c. Initial end of therapeutic effect。

A reduction in urinary incontinence was defined as a negative change in the number of daily urinary incontinence relative to baseline, where urinary incontinence events were defined as involuntary urine leakage events, as recorded in the subject's bladder log during days 3 before visit day 0 (baseline), day 42, and day 84 (± 7 days). A decrease in the number of daily voidings was defined as a negative change in the number of toilet voidings by the subject from baseline, as recorded in the subject's diary during one 24 hour period prior to day 0 (baseline), day 3(± 1 day), day 7 (± 1 day), day 21 (± 1 day), day 35 (± 2 days), day 42 and day 56 (± 2 days) visit. Exploratory evaluation: the increase in urine output per micturition from baseline was measured and recorded by subjects in the diary over a 24 hour period prior to day 0 (baseline), day 3(± 1 day), day 7 (± 1 day), day 21 (± 1 day), day 35 (± 2 days), day 42 and day 56 (± 2 days) visit.

d. Endpoint of additive therapeutic effect

Evidence of QoL improvement by OAB-q profile assessments done at study center on days 0, 42 and 84 (+ 7 days).

V. statistical method

a. Analysis of population。

The ITT population: subjects who included all enrolled groups and attempted the TAR-302 and 5018 insertion procedures on day 0, regardless of whether the insertion procedures were successfully performed.

And (3) PP population: including all subjects who successfully performed the TAR-302-5018 insertion protocol and retained TAR-302-5018 throughout the 42-day treatment period without significant protocol deviation. Significant schema deviations are defined prior to database locking.

Safety population: subjects who included all groups and successfully underwent the TAR-302 and 5018 insertion procedures. For this study, the ITT and safety populations were the same and the results for the ITT population are listed.

b. Sample size determination。

The sample size is not based on statistical considerations.

c. Therapeutic effect。

The number of urinary incontinence 3 days before the prescribed visit, the number of urination 3 days before the prescribed visit, and the total urination volume per 24 hour collection period were summarized by time points and changes from baseline. Subject responses at day 42 and 84 were aggregated (subjects with > 50% reduction in number of urinary incontinence relative to baseline, > 75% reduction in number of urinary incontinence relative to baseline, and 100% reduction in number of urinary incontinence relative to baseline). The scores of the OAB-q profile were transformed as defined in the clinical study report. The transformed symptom severity score and the transformed health-related QoL score are illustratively aggregated by time point.

d. Pharmacokinetics。

Plasma and urine trospium chloride were combined descriptively by time point. Cmax, Tmax, Ctau, Cave42, and Cave56 for plasma and urine are illustratively summarized.

e. Safety feature。

AE is encoded using the supervised active medical dictionary (MedDRA), version 20.0. TEAE is summarized in the MedDRA system organ classification and preferred terminology. TEAEs were also summarized in terms of severity, relevance (to the drug component, device composition or TARIS inserter) and time period (day 0 to day 42, day 42 to day 49 [ ± 1 day ], and day 0 to day 49 [ ± 1 day ]). In addition, Severe Adverse Events (SAE) are summarized descriptively. Vital signs and laboratory assessments are summarized descriptively as well as changes from baseline. The physical examination date is listed. The number of subjects tolerated during TAR-302 and 5018 indwelling is listed. The IPE is summarized descriptively. Bladder PVR results are summarized descriptively. The results of bladder ultrasound encrustation are listed for each subject. Cystoscopic evaluation of the urothelium is listed for the subjects. The prior and pooled medications were coded and descriptive summarised using the world health organization drug dictionary enhanced edition (12 months, 2017, version B3).

Summary and conclusion

a. Therapeutic results

The mean number of urinary incontinence in the PP population decreased by about 75% over the 3 day period before day 42 and by about 52% over the 3 day period before day 84 (± 7 days), compared to baseline.

In the PP population, on day 42, approximately 82% of subjects had > 50% reduction in urinary incontinence relative to baseline, 64% of subjects had > 75% reduction relative to baseline, and 27% of subjects had 100% reduction relative to baseline. At day 84 (± 7 days), approximately 46% of these subjects reported > 50% reduction from baseline, and 18% reported > 75% reduction from baseline.

In the PP population, the mean number of urination over a 24 hour period was reduced relative to baseline at all post-baseline time points, with approximately 8%, 12%, 14%, 8% and 11% reductions observed on days 3(± 1 day), 7 (± 1 day), 21 (± 1 day), 35 (± 2 days), 42 and 56 (± 2 days), respectively.

In the PP population, mean 24 hour urine volume decreased relative to baseline on days 3(± 1 day), 7 (± 1 day), 21 (± 1 day), 35 (± 2 days), 42 days and 56 (± 2 days). However, these findings were observed as well as a reduction in bladder PVR.

In the PP population, the mean converted symptom severity score decreased by approximately 55% on day 42 and by approximately 26% on day 84 (± 7 days), indicating that the subject reported a decreased symptom severity.

In the PP population, the mean transformed health-related quality of life (HRQL) score increased by approximately 143% on day 42, and by approximately 58% on day 84 (± 7 days), indicating that the subjects reported better QoL.

b. Pharmacokinetic results

The urine concentration of trospium chloride was quantifiable in 9/11 subjects on day 3 and in all 11 subjects in the PP population on day 7 (+ -1 day) after insertion of the TAR-302-plus 5018 system (mean day 7 concentration was 5258 ng/mL).

The urine concentration for most subjects was within the predicted range of 2000ng/mL to 6000ng/mL, and the target concentration was maintained up to day 42. Mean urinary trospium chloride concentrations were maximal on day 21 (+ -1 day) (mean 5265ng/mL), declined to 3822ng/mL on day 35 (+ -2 days), and declined to 3565ng/mL on day 42.

The detectable plasma concentration is very low. Samples with measurable plasma concentrations of trospium chloride did not exhibit a consistent time course, nor did the observed concentrations correlate with the measured urine concentration, urine volume, or recovery volume. After a confirmatory analysis using the independent bioanalytical method, it was suspected that external contamination of the plasma sample affected the results of 2 of the samples with detectable trospium chloride concentrations. With the exception of these 2 samples, the concentration of trospium chloride throughout the study was consistently low (<0.7 ng/mL).

Overall, the urine and plasma concentrations in this study were substantially consistent with the results of previous non-clinical studies.

c. Safety results

TAR-302-5018 was well tolerated. Based on the regimen-specific tolerance definitions, no subject was considered to be intolerant to TAR-302-5018.

No subjects were prematurely withdrawn from treatment due to TEAE or IPE. One subject withdrawn the consent and discontinued TAR-302 + 5018 on day 21, and the remaining 11 subjects continued to use TAR-302 + 5018 as planned through the 42 th visit and completed the study.

The most common TEAEs during the 42-day treatment period were hematuria (4/12 subjects; 33.3%), UTI (2/12 subjects; 16.7%), bladder pain (2/12 subjects; 16.7%), bladder discomfort (2/12 subjects; 16.7%) and sinusitis (2/12 subjects; 16.7%). Most AEs were mild.

One example of drug-related TEAE was reported: the mouth is dry. The most common device-related TEAEs were hematuria (4/12 subjects; 33.3%), bladder discomfort (2/12 subjects; 16.7%) and bladder pain (2/12 subjects; 16.7%). Both subjects reported TEAEs associated with at least a TARIS inserter. These events include: nausea, vomiting, chills, fever, UTI, elevated white blood cell counts, lactic acidosis, painful urination, hematuria, and perirenal edema were all seen in one subject (8.3%), and another subject (8.3%) reported 1-fold urethral pain.

The average change in laboratory parameters from baseline is typically small. Post-baseline results for occult blood (any level) were maximal (41.7%) at day 21 (± 1 day) and decreased to 27.3% at day 42 and 9.1% at day 84 (± 7 days). The hematuria results for the four subjects were reported as TEAE; one of these reports relates to subjects with SAE with UTI.

Blood pressure, heart rate, respiratory rate and body temperature are less variable on average from baseline and are clinically insignificant. No subject developed TEAEs associated with vital sign abnormalities.

Mean bladder PVR was reduced by approximately 21%, 42% and 29% at day 7 (± 1 day), day 21 (± 1 day) and day 35 (± 2 days) relative to screening, respectively.

No urothelial bleeding was observed, no evidence of bladder stones, and no evidence of bladder diverticulum was observed on cystoscopy. Ultrasound assessment of the bladder was performed on day 21 (± 1 day) or at removal, and no encrustation cases were observed.

A joint IPE was reported, which included TAR-302 and 5018 damage suspected to occur when the system was grabbed for removal. The subject reported no discomfort or any other TEAE.

d. Conclusion。

Overall, the study found that TAR-302-. A significant reduction in the number of urge incontinence was observed in this patient population, along with a reduction in the number of urination, a reduction in the subject's reported symptom severity score, and an improvement in QoL. The greatest effect was observed at day 42, however, in the final study assessment performed 6 weeks after removal of TAR-302-.

Example 4: exposure to idiopathic overactive bladder (iOAB) and urinary incontinence by TAR-302-5018 Prospective multicenter open label study of intravesical delivery of trospium chloride in subjects-section 2。

On study day 0, trospium chloride releasing intravesical system (TAR-302-. TAR-302-5018 released gradually trospium chloride during the 84 day dwell time.

I. ResultsIndex (I)

TAR-302-. Safety was assessed throughout the study based on reported AE, trial drug events (IPE), Physical Examination (PE), vital signs, clinical laboratory examinations, planned cystoscopies, bladder ultrasound examinations, residual urine volume after bladder voiding (PVR) and use of concomitant medications.

TAR-302 and 5018 were evaluated for their tolerance. The percentage of subjects who were resistant to retain TAR-302-.

Pharmacokinetic analysis of plasma and urine was performed [ time range: from day 0 to day 112 ]. This included analysis of plasma and urine trospium chloride exposure.

Assessment of reduction of urinary incontinence relative to baseline [ time range: from day 0 to day 112 ]. Daily changes from baseline in the number of urinary incontinence defined as involuntary urine leakage events were assessed.

Reduction in the number of daily urination was evaluated [ time frame: from day 0 to day 112 ]. The subject is assessed for a change in the number of toilet urinations relative to baseline.

Increase in urine output per urination was evaluated [ time range: from day 0 to day 112 ]. Changes from baseline (urine output) measured over a separate 24 hour period were evaluated.

Other outcome measures include quality of life scores and distress scores as assessed by OAB-q profiles.

Inclusion criteria II

Subjects with symptoms of idiopathic overactive bladder (iOAB) (urinary frequency/urgency) with urge incontinence or mixed incontinence with a major urge component were enrolled for at least 6 months. These patients may have 8 or more urination per 24 hours recorded in the diary, and/or at least 4 urinary incontinence events associated with urgency recorded in a 3 day diary (or at least 1 episode per 24 hours).

Patients may also be included in the study if the investigator believes that the subject has failed to respond adequately or has limited side effects to oral medications previously used to treat OAB.

Exclusion criteria

Patients who met any of the following conditions were excluded. 1. Age <18 years. 2. Neurological bladder disorders. 3. Subjects with diabetes (both type 1 and type 2) must exhibit optimal glycemic control with HbA1c levels < 7.5%, and the absence of significant diabetes, defined as 3+ glucose, at screening as checked via dipstick. 4. Screening found there was significant polyuria (urine volume >3,000 mL/day) for any reason. 5. Nocturnal polyuria was found at study screening, defined as 30% of the total urine collected >24 hours from night (P.M.) while sleeping, and included morning (A.M.) first urination. 6. There is history of radiotherapy of pelvic cavity. 7. There is a history of bladder cancer or bladder lesions that the investigator considered unsuitable for inclusion in the study. 8. Intermittent Catheterization (IC) is currently used to empty the bladder 30 days prior to day 0. 9. Researchers believe that the subject has any bladder or urethra anatomical features (e.g., urethral strictures) that may interfere with the safe placement, indwelling use, or removal of IP. 10. Subjects had active bladder stones or had a history of bladder stones <6 months prior to study enrollment. 11. Macroscopic hematuria appeared within 30 days before day 0. 12. There was a history of uncontrolled bleeding, bleeding diathesis, or potential clotting within 30 days prior to day 0. 13. Researchers believe that subjects have a history of predominantly stress urinary incontinence. 14. There were >2 history of symptomatic urinary tract infections within 6 months prior to day 0. 15. Within 90 days before day 0, the subject suffers from urinary or gastric retention or uncontrolled narrow angle glaucoma. 16. The residual urine volume (PVR) after urination is 100mL or more. 17. The subject has a known hypersensitivity reaction to trospium chloride, a chemically related drug or component excipient. 18. The subject has a known hypersensitivity reaction to the device materials, including silicone and nitinol. 19. Anticholinergic agents or beta-3 agonists are used to treat urge incontinence within <2 weeks before day 0. 20. There was a history of intravesical botulinum toxin use within 9 months prior to the screening visit. 21. Intravesical anticholinergic drugs were used within 14 days prior to the screening visit. 22. There is a history of protocol-based neuromodulation therapies (e.g., InterStim therapy, percutaneous tibial nerve stimulation [ PTNS ]) for the treatment of OAB. 23. Pregnant (confirmed by serological examination at screening) or lactating female subjects. 24. Researchers believe that subjects suffer from medical conditions that may lead to non-compliance with the study protocol. 25. Subjects were unable or unwilling to complete a questionnaire, log or participate in all protocol-prescribed study visits. 26. Another drug, device or behavioral study was enrolled within 60 days prior to the screening visit. 27. There is a history of or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder or other unspecified cause that the investigator or TARIS believes results in a subject not being eligible for inclusion in the group. 28. Any one of the following medical histories occurred within 3 months prior to the screening visit: major illness/major surgery (requiring hospitalization), including pelvic, lower back surgery or procedures; most outpatient procedures are not excluded; and ii, delivery. 29. History of prostate biopsy or surgery (ablative or non-ablative) within 6 months prior to day 0. 30. Has a remarkable history of pelvic organ prolapse (grade is more than or equal to 3). 31. It is difficult to provide a blood sample. 32. A history of drug or alcohol dependence is known within 12 months prior to screening. 33. Researchers or tairis consider other unspecified reasons that render a subject unsuitable for group entry.

Daily urinary incontinence events were assessed on days 0, 14, 56, 84, and 112, as shown in fig. 15A. As shown in fig. 15B, prior to treatment, patients experienced, on average, 5.23 urinary incontinence per day. On day 14, the average daily urinary incontinence number was reduced to 2.9, 44% relative to baseline. On day 56, the average daily urinary incontinence was reduced to 3.0, a 43% reduction from baseline. On day 84, the average daily urinary incontinence was reduced to 2.3, a 56% reduction from baseline. This indicates that prolonged local delivery of trospium chloride to the bladder may be effective in treating overactive bladder.