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

项目摘要/摘要 阿尔茨海默病(AD)是一种进行性多因素疾病，全世界有5000多万人受到影响 是晚年最常见的痴呆症。到目前为止，没有任何干预措施证明是实质性的。 预防、延迟或治疗阿尔茨海默病的疗效。目前该领域的思维方式包含了AD的复杂性 病理生理学，这使得更多样化的治疗管道针对多个方面的 疾病。神经类固醇别孕酮(Allo)正在开发中，作为AD的再生疗法。 Allo是一种创新的、可再生的系统生物激活剂，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 启用IND的转化研究，一期临床试验已经完成，并确定了Allo的安全性 使用再生治疗方案静脉给药。促进ALLO治疗的发展 作为一种再生疗法，这里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患者长期长期服用ALLO的可行性和2)途径 优化给药以促进患者的依从性。为了应对这些挑战，我们建议开发 一种新的ALLO配方，能够实现鼻腔给药途径。一种经粘膜给药的别洛制剂 促进老年AD人群的临床应用，同时解决限制首次通过代谢的限制 Allo的口服生物利用度。名为别孕酮新鼻腔制剂的SBIR的目标 AD的再生疗法是：目标1：与以下机构合作开发用于In Delivery的Allo制剂 目的2：建立别蒜素制剂在脑、嗅球和血浆中的药代动力学 给老鼠用药。为了实现这些目标，配方专家(MedPharm)将开发一种解决方案或 暂停异物交割。为了实现这一目标，MedPharm将：1.进行预配方、证明 概念配方开发和ALLO配方的稳定性评估，并评估可实现的 Allo浓度最多可开发5个溶液或悬浮剂鼻腔喷雾剂。2.体外试验 利用原代人鼻上皮细胞进行重组鼻上皮渗透试验 粘液产生、纤毛活动、紧密连接和屏障功能。最有希望的3种配方将是 进展到目标2，用于大鼠模型的药代动力学分析。体内分析将在两名女性中进行 和男性研究鼻腔吸收药代动力学中潜在的性别差异。这项研究是 响应PAS-19-316的要求，“进行研究以开发创新产品和/或 可促进预防和治疗阿尔茨海默病和阿尔茨海默病相关痴呆的服务“和 “阐述国家阿尔茨海默氏症项目法案对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.”