Novel Intranasal Formulations of Allopregnanolone, a Regenerative Therapeutic for Alzheimer's Disease

项目概要/摘要 阿尔茨海默病 (AD) 是一种进行性多因素疾病，影响全球超过 5000 万人 是晚年最常见的痴呆症。迄今为止，还没有任何干预措施显示出实质性的 预防、延迟或治疗 AD 的治疗功效。当前该领域的想法包含 AD 的复杂性 病理生理学，这使得针对疾病多个方面的更多样化的治疗途径成为可能 疾病。神经类固醇四氢孕酮 (Allo) 正在开发中，作为 AD 的再生疗法。 Allo 是一种创新的再生系统生物学激活剂，可促进再生和修复，同时 激活减轻 AD 病理负担的机制。基于广泛的临床前发现和 支持 IND 的转化研究，完成了 1 期临床试验并确定了 Allo 的安全性 使用再生治疗方案静脉内给药。推进 Allo 的治疗开发 作为一种再生疗法，本文提出的项目解决了临床可转化性的两个关键障碍： 1) 在患有 AD 的老年人群中长期长期服用 Allo 的可行性；2) 治疗途径 优化给药以提高患者的依从性。为了应对这些挑战，我们建议开发 一种新型 Allo 制剂，可实现鼻内给药途径。 Allo 的跨粘膜制剂 推进老年 AD 人群的临床应用，同时还解决限制 Allo 的口服生物利用度。 SBIR 的目标为 Allopregnanolone 新型鼻内制剂，一种 AD 的再生疗法是： 目标 1：与以下机构合作开发用于 IN 递送的 Allo 制剂： 医学制药；目标 2：建立 Allo-IN 制剂在大脑、嗅球和血浆中的药代动力学 对大鼠给药。为了实现这些目标，配方专家 (MedPharm) 将开发一种解决方案或 暂停 Allo 的 IN 交付。为了实现这一目标，MedPharm 将： 1. 进行预配制、验证 Allo 配方的概念配方开发和稳定性评估以及可实现的评估 Allo 浓度可开发多达 5 种溶液或悬浮液制剂鼻喷雾剂。 2. 体外进行 使用原代人鼻上皮细胞进行重建鼻上皮 (RNE) 渗透测试，显示 粘液产生、纤毛活动、紧密连接和屏障功能。 3种最有前途的配方将 前进到目标 2，在大鼠模型中进行药代动力学分析。将对两名女性进行体内分析 和男性研究鼻内吸收药代动力学的潜在性别差异。这项研究是 响应 PAS-19-316“进行导致创新产品开发的研究和/或 可以推动预防和治疗 AD 和 AD 相关痴呆症 (ADRD) 方面取得进展的服务”以及 “根据《国家阿尔茨海默病项目法案》提出 AD/ADRD 研究的建议和里程碑。”

Project Summary/Abstract Alzheimer’s disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwide and is the most common dementia of late-life. To date, no interventions have demonstrated substantial therapeutic efficacy to prevent, delay or treat AD. Current thinking in the field embraces the complexity of AD pathophysiology, which has enabled a more diverse therapeutic pipeline targeting multiple aspects of the disease. The neurosteroid allopregnanolone (Allo) is under development as a regenerative therapeutic for AD. Allo is an innovative, regenerative, systems biology activator that promotes regeneration and repair while activating mechanisms that reduce the burden of AD pathology. Based on extensive preclinical discovery and IND-enabling translational research, a Phase 1 clinical trial was completed and established safety for Allo administered intravenously using a regenerative treatment regimen. To advance therapeutic development of Allo as a regenerative therapeutic, the project proposed herein addresses two critical barriers to clinical translatability: 1) Feasibility of chronic long-term administration of Allo in an aged population with AD and 2) Route of administration optimization to promote patient compliance. To address these challenges, we propose to develop a novel Allo formulation to enable an intranasal route of administration. A transmucosal formulation of Allo advances clinical use in an aged AD population while also addressing first-pass metabolism constraints that limit oral bioavailability of Allo. Aims of the SBIR entitled Novel Intranasal Formulations of Allopregnanolone, a Regenerative Therapeutic for AD are: Aim 1: Develop Allo formulations for IN delivery in collaboration with MedPharm; Aim 2: Establish pharmacokinetics of Allo-IN formulations in brain, olfactory bulb and plasma after administration to a rat. To achieve these aims, experts in formulation (MedPharm) will develop a solution or a suspension of Allo for IN delivery. To achieve this objective, MedPharm will: 1. Perform pre-formulation, proof of concept formulation development and stability assessments of Allo formulations and assess achievable concentrations of Allo to develop up to 5 solution or suspension formulation nasal sprays. 2. Conduct in vitro reconstituted nasal epithelial (RNE) permeation testing using primary human nasal epithelial cells which exhibit mucus production, ciliary activity, tight junctions, and barrier function. The 3 most promising formulations will advance to Aim 2 for pharmacokinetic analysis in a rat model. In vivo analyses will be conducted in both female and males to investigate potential sex differences in pharmacokinetics of intranasal absorption. This research is responsive to PAS-19-316 to “conduct research leading to the development of innovative products and/or services that may advance progress in preventing and treating AD and AD-related dementias (ADRD)” and “address recommendations and milestones for AD/ADRD research from the National Alzheimer’s Project Act.”