TECHNICAL FIELD

The present application relates to methods of treating overactive bladder, training or retraining bladder, prolonging symptom relief, improving the quality of life and/or neuronal remodeling in an individual having overactive bladder, by locally delivering trospium to the bladder.

BACKGROUND

Lower urinary tract disorders, including overactive bladder, detrusor instability, and urinary incontinence can arise from numerous pathologies. These pathologies are commonly classified as neuropathic, myogenic, or idiopathic. The majority of patients usually are characterized as idiopathic due to the lack of observable disease etiology.

Recent studies have suggested the sensory system of the urothelium may play an important role in afferent signaling and detrusor activity. See de Groat and Yoshimura, Handb Exp Pharmacol. 2009; (194): 91-138; Daly et al. Current Opinion in Urology 2011, 21:268-274; Birder and Andersson Physiol Rev 93: 653-680, 2013. Pathologies of this system have been suggested to play a significant role in many patients with lower urinary tract idiopathic disease.

Standard drug therapies for patients with idiopathic lower urinary tract disorders are systemic treatments typically administered orally or trans-dermally. These therapies often lack adequate efficacy due to either dose limiting side effects, low potency, or both.

Currently patients failing systemic drug therapy have only two alternatives. The first alternative is Botox injections directly into the bladder wall, which may provide symptom relief, but which also undesirably can produce prolonged urinary retention requiring self-catheterization. The second alternative is neurosacral stimulation as produced by the InterStim® device which is surgically implanted and shown to provide symptomatic relief. However, the equipment and surgical procedure is expensive, highly invasive, and carries a 30% adverse event rate requiring corrective surgeries or removals.

Overactive bladder is a chronic condition characterized by the lower urinary tract symptoms of urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia. Overactive bladder is the most common cause of urinary incontinence or loss of bladder control in adults and affects approximately 33 million, or about 17%, of adults in the U.S.A. Although the prevalence among men and women in the U.S.A. is similar (16.0% vs. 16.9%, respectively), the severity and nature of symptom expression does differ, with women demonstrating a higher incidence of urge incontinence. There is also a marked increase in prevalence with increasing age. Overactive bladder has a significant impact on the health-related quality of life, mental health, and quality of sleep of affected individuals; whether or not they display the symptom of urge incontinence. The economic burden of overactive bladder is also significant, estimated at approximately $12 billion per annum in the U.S.A. alone. Overactive bladder is distinct from stress urinary incontinence, but when they occur together is usually known as mixed incontinence.

The urothelial sensory system is comprised of numerous receptors and signaling pathways, many of which exhibit significant “cross talk.” Due to the complexity of the urothelial sensory system, selective agents, such as darifenasin, may not adequately modulate urothelial sensory activation following nonspecific noxious stimuli. Similarly, non-specific agents, such as oxybutynin which exhibits antimuscarinic and calcium channel activity, do not inhibit urothelial response as measured by intercontraction intervals but can lead to urinary retention.

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

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

SUMMARY

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

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

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

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

In some embodiments according to any of the methods described above, trospium is continuously administered locally to the bladder for at least about 42 days.

In some embodiments according to any of the methods described above, the method further comprises administering an effective amount of trospium locally to the bladder about every 3 months or on an as needed (prn) basis.

In some embodiments, provided herein is method of treating overactive bladder comprising continuously administering an effective amount of trospium locally to the bladder of the individual for at least about 42 days.

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

In some embodiments also provided herein is a method of maintenance therapy for overactive bladder in an individual comprising administering trospium continuously and locally to the bladder for at least about 24 hours, wherein the individual has received a previous therapy for overactive bladder. In some embodiments, the maintenance therapy comprises administering an effective amount of trospium locally to the bladder for at least about 24 hours every 3 months. In some embodiments, the maintenance therapy comprises administering an effective amount of trospium locally to the bladder for at least about 24 hours on an as needed (prn) basis. In some embodiments, the maintenance therapy comprises administering an effective amount of trospium locally to the bladder for at least about 24 hours upon symptom recurrence. In some embodiments, the maintenance therapy comprises administering an effective amount of trospium locally to the bladder for at least about 24 hours when the individual experiences at least a 50% recurrence in baseline symptoms. In some embodiments, the previous therapy comprises administering an effective amount of trospium locally 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 methods described above, the concentration of trospium in the bladder is between about 0.1 to 100 μg/ml during administration of trospium. In some embodiments, the concentration of trospium in the plasma of the individual is less than about 2 ng/ml during administration of trospium.

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

In some embodiments according to any of the methods described above, the individual has multiple sclerosis, Alzheimer's disease, Parkinson's disease, or has previously had a stroke.

In some embodiments according to any of the methods described above, the individual has failed a previous treatment for overactive bladder.

In some embodiments according to any of the methods described above, the individual has not received a previous treatment for overactive bladder.

In some embodiments according to any of the methods described above, the individual has failed or is not eligible for oral therapy.

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

In some embodiments according to any of the methods described 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 the individual is improved. In some embodiments, the urinary bother score of the individual is reduced. In some embodiments, the method reduces an aberrant urge to urinate.

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

