Delivery of peptides for inducing voiding associated with neurological retention

递送肽以诱导与神经滞留相关的排尿

• 批准号: 9202636
• 负责人: LESLEY MARSON
• 金额: $ 95.33万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202636
• 关键词: Acute; Adverse effects; Adverse event; Agonist; Animal Model; Award; Behavioral; Biological Availability; Bladder; Blood specimen; Canis familiaris; Catheterization; Catheters; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Trials; Conscious; Development; Diabetes Mellitus; Dose; Drug Delivery Systems; Drug Kinetics; Ensure; Excipients; Exhibits; Experimental Designs; Feasibility Studies; Feces; Formulation; Functional disorder; Future; Goals; Grant; Health; Health Care Costs; Hospitalization; Human; Incidence; Incontinence; Individual; Inferior; Intestines; Intranasal Administration; Measures; Methods; Modeling; Modification; Monitor; Multiple Sclerosis; Neurologic; Oral mucous membrane structure; Oryctolagus cuniculus; Parkinson' s Dementia; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Production; Quality of life; Rattus; Regimen; Rodent; Safety; Sepsis; Small Business Technology Transfer Research; Spinal; Spinal Dysraphism; Spinal cord injury; Stroke; Substance K Receptor; TAC1 gene; Tablets; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Trauma; Ultrasonography; Urethra; Urinary tract infection; Urine; absorption; abstracting; awake; base; dosage; improved; in vivo; keratinization; meetings; novel; novel therapeutics; oral cavity epithelium; phase 1 study; phase 2 study; preclinical safety; pressure; prototype; rational function; response; safety study; stability testing; subcutaneous; success; tablet formulation

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.

抽象的 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) 可能导致自主排尿能力丧失，需要间歇性排尿 膀胱导尿术以排尿。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、尿道创伤和住院治疗。 Dignify Therapeutics 正在开发一种新型药物治疗 DTI-100，以提供“按需、快速起效、 针对那些无法自主排尿的患者进行“短期、药物诱导的排尿疗法”。来自我们 STTR 的结果 第一阶段拨款证明鼻内 (IN) 解决方案和舌下口腔崩解 含有 DTI-100 的片剂 (ODT) 表现出药代动力学 (PK) 和药效 (PD) 特征 支持更多研究在这两种制剂之间进行选择以进行后续的临床开发。 尽管两种制剂均能诱导大鼠排尿，但 ODT 剂量不如 IN 剂量有效或有效， 可能是由于与其他物种相比，大鼠的口腔粘膜高度角化。因为这， 并且由于在进入临床试验之前需要使用“非啮齿动物”物种进行安全研究，因此 STTR II 期申请建议在兔子和狗身上评估 IN 和舌下 ODT 制剂，两种 FDA 可接受进行安全研究的物种。该应用程序的最终目标是选择一个 药物开发的“最终配方”并选择合适的物种进行临床前安全性研究 向 FDA 提交 IND 申请。 在第二阶段，DTI-100 将使用我们最有前途的配方对兔子和狗进行给药。 I 期大鼠研究比较不同物种的 PK 和 PD 反应。具体目标 (SA) 1 将完成一- 在第一阶段启动的一年配方稳定性测试。通过修改配方优化配方 如果 I 期制剂在兔子和狗中的结果不如那些，则也在 SA1 中进行赋形剂 来自老鼠。 SA2 比较了 IN 和 ODT 制剂的 PK 曲线和 PD 效应（等容压 记录和排尿膀胱测压）在急性脊柱和脊柱完整、麻醉的兔子中。 SA3 比较 IN 以及用于狗体内 PK 和 PD 效果的 ODT 制剂。排尿参数在麻醉状态下测量 （等容压记录和排尿膀胱测压）和意识清醒（排尿开始和持续时间，排尿 体积、排尿效率）狗。根据各自的能力来最好的满足我们“理想”的PK和PD 目标产品概况，将选择 IN 或 ODT 配方并用于后续 IND 启用 临床前安全性研究。