Highly loaded long-acting depots of therapeutic peptides

高负载长效治疗性肽库

• 批准号: 10382992
• 负责人: Robert Frederick Pagels
• 金额: $ 28.77万
• 依托单位: OPTIMEOS LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382992
• 关键词: Address; Albumins; Amino Acids; Animal Model; Architecture; Beta Carotene; Biological Sciences; Blood Circulation; Chemicals; Chronic; Chronic Disease; Clinical Trials; Development; Diabetic mouse; Disease; Dose; Emulsions; Encapsulated; Enhancers; Exhibits; Formulation; Forteo; Frequencies; Funding; Future; Grant; Half-Life; Hormones; Hydrophobicity; Hypoparathyroidism; Individual; Injectable; Injections; Knowledge; Lead; Legal patent; Lipids; Mechanics; Messenger RNA; Methods; Modeling; Modification; Monitor; Obesity; Oral; Patients; Peptides; Performance; Phase; Polymers; Predisposition; Process; Production; Proteins; Research; Schedule; Short Bowel Syndrome; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Treatment Efficacy; Universities; Water; Work; biodegradable polymer; biopharmaceutical industry; chemical stability; clinically relevant; commercialization; controlled release; design; efficacy evaluation; experience; improved; in vivo; innovation; interest; lead candidate; lead optimization; lipid nanoparticle; liraglutide; mouse model; nanocomposite; nanoparticle; parenteral administration; peptide drug; peptide hormone; phase 2 study; physical property; preclinical development; success; teduglutide

Peptides can have exquisite potency and selectivity in treating disease, but suffer from rapid clearance. Microparticle depot formulations, where the peptide is entrapped in a water-insoluble polymer matrix, have been tested for decades to provide sustained therapeutic release for chronic disease. The traditional microparticle structure has significant limitations, including low therapeutic content (<5 wt%) and inadequate release profiles. Consequently, only 5 microparticle depots have been approved, representing 7% of marketed peptides. This application seeks to develop a long-acting microparticle depot formulation using the inverse Flash NanoPrecipitation (iFNP) platform being commercialized by Optimeos Life Sciences. iFNP enables the formation of polymer-coated peptide-loaded nanoparticles in a scalable and continuous manner. These nanoparticles are then clustered together to produce mechanically strong nanocomposite microparticles. The polymer coating surrounding each individual nanoparticle allows for much higher peptide loadings and more controlled, sustained release from the final microparticle. The iFNP technology has been validated using a model peptide, liraglutide, with therapeutic efficacy demonstrated in vivo for 1 month. The proposed research will apply the platform to three approved peptides that currently lack long-acting formulations. The three peptides treat chronic disease and possess varying physical properties. This proposed study will validate the universality of the platform and guide the selection of a lead candidate for development: 1) Aim 1: Optimize encapsulation of three therapeutic peptide candidates in microparticle depots with loadings above 30 wt% 2) Aim 2: Develop microparticle depots with sustained release profiles of active peptide over 1 month and 3 months with minimized peptide degradation. The formulation design will build on the rules derived under an NSF STTR grant between Princeton University and Optimeos. Peptides tested to date have all been chemically modified to increase circulation time. The structure-encapsulation-release relationships identified in this work will advance our knowledge of suitable candidates for formulation by the platform. Stability studies, using LC-MS analysis, will identify amino acid residues with particular susceptibility to degradation that would be candidates for peptide modifications during lead optimization of formulation candidates. Crucially, the proposed work will translate to the sustained delivery of proteins, an application where no long-acting formulations are currently marketed.

肽在治疗疾病方面具有出色的效力和选择性，但其清除速度很快。 微粒储库制剂，其中肽被包埋在水不溶性聚合物基质中， 经过数十年的测试，可为慢性疾病提供持续的治疗释放。传统微粒子 结构具有显着的局限性，包括治疗含量低（<5 wt%）和释放曲线不足。 因此，只有 5 个微粒长效制剂获得批准，占市售肽的 7%。这 该申请旨在利用逆闪技术开发长效微粒储库配方 NanoPrecipitation (iFNP) 平台由 Optimeos Life Sciences 进行商业化。 iFNP 能够形成 以可扩展和连续的方式制备聚合物涂覆的肽负载纳米颗粒。这些纳米粒子是 然后聚集在一起产生机械强度高的纳米复合微粒。聚合物涂层 围绕每个单独的纳米颗粒允许更高的肽负载和更可控、更持久的 从最终的微粒中释放。 iFNP 技术已使用模型肽利拉鲁肽进行验证，具有治疗功效 体内验证1个月。拟议的研究将将该平台应用于三种已批准的肽， 目前缺乏长效制剂。这三种肽可治疗慢性疾病并具有不同的物理作用 特性。这项拟议的研究将验证该平台的普遍性并指导先导药物的选择 发展候选人： 1) 目标 1：优化三种治疗性肽候选物在微粒储库中的封装 负载量超过 30 wt% 2) 目标 2：开发具有 1 个月以上活性肽缓释特性的微粒储库，以及 3 个月，肽降解最小化。 配方设计将建立在普林斯顿大学与 NSF STTR 资助下得出的规则基础上 和优化。迄今为止测试的肽都经过化学修饰以延长循环时间。这 这项工作中确定的结构-封装-释放关系将增进我们对合适的 平台制定的候选人。使用 LC-MS 分析的稳定性研究将鉴定氨基酸 具有特别易降解性的残基，可以作为肽修饰的候选者 主导候选配方的优化。至关重要的是，拟议的工作将转化为持续交付 蛋白质的应用，目前尚未上市长效制剂。