Abstract Urinary incontinence (UI) and symptoms of overactive bladder (OAB) become more prevalent with age. The impact on elderly and their caregivers makes it difficult to continue at-home care, and UI is a top reason for institutionalizing the elderly. More than half of nursing home residents have UI and over ¾ of those with dementia have UI. The current application proposes to develop new formulations of drugs that are instilled into the bladder and produce long-term relief of symptoms (> 3 months) in patients who are refractory to current therapies. This project dovetails nicely with the PI’s basic science doctoral and post-doctoral studies of “somatic nociception” and pain. Our drugs block nociceptor terminals in bladder that are responsible for causing UI and OAB symptoms, i.e. “visceral nociception”. Thus, Dignify and the PI provide valuable complementary perspectives and insight into control of nociceptors. As described in the Research Approach, the scientific rationale for our drugs’ ability to block nociceptors, and for the formulation proposed to deliver drugs directly to the drug target inside the bladder (i.e. intravesical), are strongly supported by both basic science and clinical literature. Intravesical delivery should maximize efficacy at the target and minimize plasma concentrations of the drugs, keeping side-effects, metabolism issues, and drug-drug interactions to a minimum. Aim 1 creates novel formulations for the drugs tested in Aims 2 and 3. Aim 2 provides rapid screening of new formulations of the drugs in acute, in vivo, proof-of-concept, dose-ranging studies in anesthetized rats. Drug formulations that produce positive results in Aim 2 are then studied across 4 weeks in Aim 3 to determine duration of therapeutic effects after a single pre-treatment with drug formulations. Protocols for determining blockade of visceral nociceptors in the bladder are standard cystometrogram methods used in Dignify’s laboratory for decades, and the results are straight-forward changes in bladder pressures that are induced by nociceptive stimuli, and the blockade of those changes by our novel therapy. Rigorous analyses, inclusion of positive and negative internal controls, and other techniques are part of Dignify’s routine for ensuring reproducible results and confident conclusions. Mastering these in vivo methods and analyses of bladder nociception will allow the PI to expand into various other bladder, bowel, and sexual conditions that present symptoms of visceral nociception, as well as an opportunity to become an expert in general CNS and peripheral neuronal control of sacral pelvic viscera in the elderly under supervision of Dignify mentors. Assuming positive results, an SBIR Phase 2 application will be submitted to select a lead candidate and refine the formulation to maximize efficacy and minimize systemic absorption (if any). Subsequently, IND- enabling studies will begin with the lead candidate to allow clinical study, in which ...