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.

多肽在治疗疾病方面具有极强的效力和选择性，但存在清除速度快的问题。 微粒库制剂，其中多肽被包裹在不溶于水的聚合物基质中，已经被 经过几十年的测试，为慢性病提供了持续的治疗释放。传统的微粒 结构有很大的局限性，包括低治疗含量(&lt；5wt%)和不充分的释放情况。 因此，只有5个微粒库获得批准，占上市多肽的7%。这 应用寻求开发一种使用反向闪光的长效微粒库配方 Optimeos生命科学公司正在商业化的纳米沉淀(IFNP)平台。IFNP使形成成为可能 以可伸缩和连续的方式提供聚合物涂层的多肽负载纳米颗粒。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多肽负载量和更可控、更持久的 从最终的微粒中释放出来。 IFNP技术已经用一种名为利拉鲁肽的模型多肽进行了验证，具有治疗效果 活体观察1个月。拟议的研究将把该平台应用于三种已获批准的多肽 目前缺乏长效配方。这三种多肽治疗慢性疾病，具有不同的生理特性 属性。这项拟议的研究将验证平台的普遍性，并指导选择一名领导 开发候选者： 1)目标1：优化微粒库中三种候选治疗性多肽的包封率 载重量超过30wt% 2)目标2：开发活性多肽缓释曲线超过1个月的微粒库和 3个月，多肽降解率最低。 配方设计将建立在普林斯顿大学与美国国家科学基金会之间的STTR拨款规则的基础上 和Optime os。到目前为止，测试的多肽都经过了化学修饰，以增加循环时间。这个 这项工作中确定的结构-封装-释放关系将促进我们对适用于 候选人由平台制定。稳定性研究，使用LC-MS分析，将确定氨基酸 具有特别易降解的残基，将成为多肽修饰的候选 领导对候选配方的优化。至关重要的是，拟议的工作将转化为持续的交付 目前还没有长效制剂上市的应用。