Delivery of peptides for inducing voiding associated with neurological retention

 描述(申请人提供)：神经系统疾病，如多发性硬化症、帕金森氏病、痴呆症、脊柱裂、糖尿病、中风和脊髓损伤(SCI)；可导致失去对膀胱和肠道功能的自主控制，通常导致同一患者出现大小便失禁和大小便滞留。这对患者的身心健康状况和生活质量产生了深远的影响，也对医疗费用产生了很大的影响。例如，尿潴留通常是不可逆转的，可能危及生命。唯一可用的药物治疗方法是胆碱能激动剂，其疗效极低，副作用严重。因此，患者每天都要多次导尿以排空膀胱。导尿管的使用与尿路感染、败血症、隔离、抑郁和住院的发生率增加有关。“按需”、SAF和有效的药物替代导尿术将是改变患者日常膀胱管理的生活改善，更不用说显著降低个人和社区卫生保健成本了。同样，“按需”排便控制将大幅改善神经源性肠病患者的“生活质量”。Diguify Treeutics正在开发一种使用神经激肽A-[Lys5，MeLeu9，Nle10]-NKA(4-10)-(又名DTI-100)的类似物的按需、起效快、持续时间短的药物诱导排尿疗法。DTI-100是一种有效的选择性NK2受体激动剂，可在体外诱导人膀胱和直肠的强烈收缩，并在静脉注射后在各种狗和大鼠模型(脊髓完整、脊髓损伤和糖尿病)中提供非常有希望的体内疗效、安全性和药效学(PD)谱。目前，ITS的总体目标是 开发计划是为了发现一种对患有神经疾病的人更方便的配方，同时保持静脉配方的治疗益处。目前第一阶段应用的具体目标是检查鼻腔(IN)配方和口腔溶解薄膜(ODF)配方的适宜性。根据以前对每种制剂中类似多肽的系统递送的工作，预计任何一种都可以提供稳定的剂量，从而提供快速释放、系统吸收和PD活性。第一阶段应用的具体目的是比较包含不同介质的每种配方的稳定性和释放率，并使用简单但临床相关的麻醉急性脊髓大鼠膀胱测压模型比较最优化配方的体内活性。如果获得阳性结果，详细的药代动力学研究和测试将在 为第二阶段的研究提出了物种和神经病理模型。

 DESCRIPTION (provided by applicant): 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 control over bladder and bowel function, often producing both incontinence and retention of urine and stools in the same patient. This has a profound impact on the mental and physical health status and quality of life of patients as well as a large impact on health care costs. For example, urinary retention is generally irreversible and can be life threatening. The only available pharmacotherapy consists of cholinergic agonists, which have minimal efficacy and severe side effects. Consequently, patients catheterize themselves multiple times daily to empty their bladder. Catheter use is associated with increased incidence of urinary tract infections, sepsis, isolation, depression and hospitalization. An 'on demand', saf and effective, pharmaceutical alternative to catheterization would be a life-changing improvement in the daily routine of bladder management for patients, not to mention a significant reduction in individual and community health care costs. Similarly, 'on-demand' bowel control would provide substantial improvement in 'quality of life' for people with neurogenic bowel. Dignify Therapeutics is developing an 'on-demand, rapid-onset, short-duration, drug-induced voiding' therapy using an analogue of neurokinin A - [Lys5,MeLeu9,Nle10]-NKA(4-10) - (aka DTI-100). DTI-100 is a potent and selective agonist of the NK2 receptor, which induces powerful contractions of the human bladder and rectum in vitro and provides highly promising in vivo efficacy, safety, and pharmacodynamic (PD) profiles in various dog and rat models (spinal intact, SCI, and diabetes) following IV administration. Presently, the overarching objective of its development program is to discover a formulation that is more convenient for people with neurological conditions but maintains the therapeutic benefit of the IV formulation. The specific aims of the current Phase I application are to examine the suitability of an intranasal (IN) formulation and an orally- dissolving film (ODF) formulation. Based on previous work with systemic delivery of similar peptides from each of the formulations, it is anticipated that either may provide a stable dosage that provides rapid release, systemic absorption, and PD activity. The specific aims of this Phase I application are to compare stability and release rates of each formulation containing various media and to compare the in vivo activity of the most optimized formulations using a simple, but clinically relevant, anesthetized, acute spinal rat cystometry model. If positive results are obtained, detailed pharmacokinetic studies and testing in additional species and neuropathological models are proposed for Phase II studies.