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

Allopregnanolone 的新型鼻内制剂，一种阿尔茨海默病的再生疗法

基本信息

批准号：
10698555
负责人：
ROBERTA EILEEN BRINTON
金额：
$ 50.58万
依托单位：
NEUTHERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698555
关键词：
Address Affect Age Aging Allopregnanolone Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Biological Availability Brain Bypass Cells Chronic Clinical Clinical Data Clinical Trials Cognitive Collaborations Coupled Data Dementia Development Diagnosis Disease Double-Blind Method Drug Delivery Systems Drug Kinetics Elderly Epithelial Cells Exhibits Female Formulation Fragile X Syndrome Functional disorder Funding Genes Goals Hippocampus Human In Vitro Infusion procedures Intervention Intravenous infusion procedures Legal patent Life Liver Magnetic Resonance Imaging Metabolism Modeling Mucous Membrane Mucous body substance Nasal Epithelium Natural regeneration Neurodegenerative Disorders Nose Olfactory Pathways Oral Oral Administration Outcome Peer Review Penetration Persons Phase Phase I Clinical Trials Placebo Control Plasma Population Production Rattus Recommendation Regenerative capacity Reproducibility Research Route Safety Services Severity of illness Sex Differences Small Business Innovation Research Grant Structure Suspensions Syndrome Systems Biology Testing Therapeutic Thinking Tight Junctions Time Translational Research Treatment Efficacy Treatment Protocols Tremor Wistar Rats absorption aged aging population brain tissue clinical development clinical translation cognitive function cognitive recovery commercialization compliance behavior demented improved in vivo in-home care innovation intravenous administration male men neural neurosteroids novel novel therapeutic intervention olfactory bulb open label pre-clinical prevent primary outcome reconstitution regenerative regenerative therapy regenerative treatment repaired self-renewal slow potential therapeutic development white matter

项目摘要

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.”

项目摘要/摘要阿尔茨海默氏病（AD）是一种进步的多因素疾病，影响了全球超过5000万人是后期最常见的痴呆症。迄今为止，尚无干预措施证明预防，延迟或治疗AD的治疗效率。当前的思维在现场包含广告的复杂性病理生理学，它使针对多个方面的更多样化的治疗管道疾病。神经类似丙二酮（Allo）正在开发中，作为AD的再生疗法。 Allo是一种创新的，再生的系统生物学激活剂，可促进再生和维修激活机制，以减少AD病理的燃烧。基于广泛的临床前发现和辅助转化研究，完成了1阶段临床试验并确定了Allo的安全性使用再生治疗方案静脉内给药。提高Allo的治疗发展作为一种再生理论，本文提出的项目解决了临床转换性的两个关键障碍： 1）慢性长期对Allo的可行性在具有AD的老年人群中和2）管理优化以促进患者依从性。为了应对这些挑战，我们建议一种新型的Allo公式，可实现鼻内的给药途径。 Allo的透射公式在老年广告人群中进步的临床用途，同时还解决了限制的首次代谢限制 Allo的口服生物利用度。 SBIR的目的，名为“新型鼻鼻内制剂”的目的 AD的再生治疗是：目标1：与与麦当劳； AIM 2：在大脑，嗅球和等离子体中建立异源配方的药代动力学给大鼠给药。为了实现这些目标，公式（Medpharm）的专家将开发解决方案或暂停Allo进行交货。为了实现这一目标，Medpharm将：1。执行预先制定，证明概念公式的开发和稳定性评估以及可实现的评估高达5种溶液或悬浮式鼻喷雾剂的浓度。 2。体外进行使用原发性人鼻上皮细胞进行重构的鼻皮上（RNE）渗透测试粘液产生，睫状活性，紧密连接和屏障功能。最有前途的三个公式将在大鼠模型中进行AIM 2进行药代动力学分析。两位女性将进行体内分析和男性研究鼻内滥用的药代动力学的潜在性别差异。这项研究是对PAS-19-316的响应，“进行研究，从而开发创新产品和/或可能会推动预防和治疗广告和广告相关痴呆症（ADRD）方面进展的服务”和 “针对《国家阿尔茨海默氏症法案》的AD/ADRD研究的建议和里程碑。”