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

项目概要/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种多因素的进行性疾病，在全球范围内影响着5000多万人 是最常见的老年痴呆症迄今为止，没有任何干预措施表明 预防、延迟或治疗AD的治疗功效。目前在该领域的想法包括AD的复杂性 病理生理学，这使得一个更多样化的治疗管道，针对多个方面的 疾病神经类固醇allopregnanolone（Allo）正在开发中，作为AD的再生治疗药物。 Allo是一种创新的，再生的，系统生物激活剂，促进再生和修复， 激活机制，减少AD病理学的负担。基于广泛的临床前发现， IND使转化研究，1期临床试验已完成，并确定了Allo的安全性 使用再生治疗方案静脉内施用。为了推进Allo的治疗发展， 作为一种再生疗法，本文提出的项目解决了临床可翻译性的两个关键障碍： 1)老年AD患者长期应用Allo的可行性及2） 给药优化，促进患者依从性。为了应对这些挑战，我们建议制定 一种能够鼻内给药途径的新型Allo制剂。Allo的经粘膜制剂 在老年AD人群中推进临床应用，同时还解决了限制 Allo的口服生物利用度标题为"别孕烯醇酮新型鼻内制剂"的SBIR的目的 AD的再生治疗是：目标1：与以下公司合作开发用于IN递送的Allo制剂： MedPharm;目的2：建立Allo-IN制剂在脑、嗅球和血浆中的药代动力学， 给大鼠施用。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进行IN交付。为了实现这一目标，MedPharm将：1。进行预配制、验证 Allo制剂的概念制剂开发和稳定性评估，并评估可实现的 使用不同浓度的Allo来开发多达5种溶液或悬浮液制剂鼻喷雾剂。2.进行体外 使用原代人鼻上皮细胞的重构鼻上皮（RNE）渗透测试，所述原代人鼻上皮细胞表现出 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 推进到目标2，用于大鼠模型中的药代动力学分析。将在两只雌性动物中进行体内分析 研究鼻内吸收药代动力学的潜在性别差异。本研究是 响应PAS-19 - 316，“进行研究，导致创新产品的开发和/或 可能促进预防和治疗AD和AD相关痴呆（ADRD）进展的服务"， “解决国家阿尔茨海默病项目法案中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.”