Delivery of peptides for inducing voiding associated with neurological retention

摘要 神经系统疾病，如多发性硬化症、帕金森病、痴呆、脊柱裂、糖尿病， 中风和脊髓损伤（SCI）可导致尿的自主排泄的丧失， 膀胱插管排尿导管的使用与健康问题的发生率增加有关， 主要是反复尿路感染、败血症、尿道创伤和住院。 Dignify Therapeutics正在开发一种新型药物治疗，DTI-100，以提供一种“按需，快速起效， 短期、药物诱导的排尿治疗”，用于那些不能自愿排尿的人。来自我们STTR的结果 第一阶段的资助证明，鼻内（IN）溶液和舌下口腔崩解剂 含有DTI-100的片剂（ODT）表现出药代动力学（PK）和药效学（PD）特征 支持在这两种制剂之间进行选择以用于后续临床开发的额外研究。 尽管两种制剂都诱导大鼠排尿，但ODT给药不如IN给药有效或有效， 推测是由于与其它物种相比大鼠的口腔粘膜高度角化。正因为如此， 并且由于在进入临床试验之前，安全性研究需要使用“非啮齿类”物种， STTR II期申请建议在兔和犬中评价IN和舌下ODT制剂， FDA可接受用于安全性研究的种属。这个应用程序的最终目标是选择一个 药物开发的“最终制剂”，并选择合适的种属进行临床前安全性研究， 使我们的IND申请能够提交给FDA。 在第二阶段，DTI-100将使用来自我们的最有前途的制剂给予兔和狗。 比较不同种属间PK和PD反应的I期大鼠研究。具体目标（SA）1将完成一个- 年制剂稳定性试验，在I期开始。通过修改配方优化 如果I期制剂在兔和犬中的结果劣于这些结果， 从老鼠。SA 2比较了IN和ODT制剂的PK特征和PD效应（等容压 记录和排尿膀胱测压）。SA 3比较IN 和ODT制剂在狗中的PK和PD作用。在麻醉状态下测量排尿参数。 （等容压记录和排尿膀胱测压）和清醒（排尿开始和持续时间，排尿 容量、排尿效率）狗。基于各自的能力，以最佳的PK和PD来满足我们的“理想” 目标产品概况，IN或ODT配方将被选择并用于随后的IND启用 临床前安全性研究。

Abstract Neurological conditions, such as multiple sclerosis, Parkinson’s disease, dementia, spina bifida, diabetes, stroke, and spinal cord injury (SCI), can result in loss of voluntary voiding of urine and require intermittent bladder catheterization for voiding. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, urethral trauma and hospitalization. Dignify Therapeutics is developing a novel drug treatment, DTI-100, to provide an “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” for those who cannot void voluntarily. Results from our STTR Phase I grant award demonstrated that both intranasal (IN) solutions and sublingual orally disintegrating tablets (ODTs) that contain DTI-100 exhibit pharmacokinetic (PK) and pharmacodynamic (PD) characteristics that support additional studies to select between these two formulations for subsequent clinical development. Although both formulations induced voiding in rats, ODT dosing was not as potent or effective as IN dosing, presumably due to the highly keratinized oral mucosa of the rat compared to other species. Because of this, and because a “non-rodent” species is required for use in safety studies prior to entering clinical trials, this STTR Phase II application proposes to evaluate IN and sublingual ODT formulations in rabbits and dogs, two species which are acceptable to the FDA for safety studies. The ultimate goal of this application is to pick a “final formulation” for pharmaceutical development and select a suitable species for preclinical safety studies to enable our IND application to the FDA. In Phase II, DTI-100 will be administered to rabbits and dogs using the most promising formulations from our Phase I rat studies to compare PK and PD responses across species. Specific Aim (SA) 1 will complete one- year formulation stability tests that were initiated in Phase I. Formulation optimization by modification of excipients is also performed in SA1 if results with Phase I formulations in rabbits and dogs are inferior to those from rats. SA2 compares the IN and ODT formulations for PK profile and PD effects (isovolumetric pressure recording and voiding cystometry) in acute spinal and spinal intact, anesthetized rabbits. SA3 compares IN and ODT formulations for PK and PD effects in dogs. Voiding parameters are measured in anesthetized (isovolumetric pressure recording and voiding cystometry) and conscious (voiding onset and duration, voided volume, voiding efficiency) dogs. Based on their respective abilities to best meet the PK and PD of our “ideal” target product profile, an IN or ODT formulation will be selected and used for subsequent IND-enabling preclinical safety studies.