STTR Phase I: Sustained Delivery of Peptides with Inverse Flash Nanoprecipitation

STTR 第一阶段：通过反向闪蒸纳米沉淀持续输送肽

• 批准号: 1843551
• 负责人: Robert Pagels
• 金额: $ 22.5万
• 依托单位: Optimeos Life Sciences, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1843551&HistoricalAwards=false
• 关键词: STTR; Phase; Sustained; Delivery; Peptides

This STTR Phase I project aims to pioneer a novel approach for the sustained delivery of peptide therapeutics using nano-composite microparticles. Peptide therapeutics tend to suffer from rapid enzymatic degradation and clearance, with half-lives on the order of minutes, and require frequent injections. The goal of a sustained release formulation is to reduce the frequency of injections by slowly releasing the therapeutic over a period of weeks to months. This will result in improved patient compliance and quality of life. Patient non-compliance is an economic burden that is estimated to cost the healthcare system over $100 billion/year. The lack of commercial success of existing sustained release technologies is due to low loading efficiencies, lack of controlled release at higher loading, and complex manufacturing. These limitations can be overcome with the newly-developed inverse Flash NanoPrecipitation (iFNP) process to produce nano-composite microparticles. This project aims to develop and test a once-monthly injectable formulation of a peptide therapeutic for type 2 diabetes that is currently injected daily. This research will aid in the understanding of the fundamental materials science and engineering principles that control therapeutic release from nano-composite microparticles. The rules for controlling release will apply broadly to other peptides, and this research will help to more rapidly develop future long-acting formulations.Current methods to produce peptide-loaded microparticles suffer from low drug loadings and poor encapsulation efficiencies, two of the most important factors for commercial viability. In contrast to existing methods, the iFNP technology allows for the assembly of nanoparticles with peptide loadings greater than 50wt% and encapsulation efficiencies greater than 90% in a fully scalable process. The nanoparticles are then assembled into microparticles to create the final sustained release formulation. Each drug-containing pore inside the microparticle is surrounded by a dense hydrophobic polymer layer which allows for therapeutic loadings 10x higher than competing technologies. The iFNP process has been demonstrated on a number of proof-of-concept molecules. In this project, iFNP will be used to produce a formulation of a peptide for diabetes therapy with a month-long release profile. The first goal of this project is to develop an understanding of the physical parameters that control the peptide stability and release. Supporting this goal, the peptide will be formulated with polymers of varying glass transition temperatures and degradation rates, and the release profiles will be measured in vitro. The efficacy of the optimal in vitro formulation will then be tested in a rat model. These studies are an important step in developing a commercial product that can positively impact patient care.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该STTR I期项目的目的是为使用纳米复合材料微粒持续递送肽疗法的新方法。肽疗法往往会遭受快速的酶促降解和清除率，半衰期为几分钟，需要频繁注射。持续释放配方的目的是通过在数周到几个月内缓慢释放治疗性来减少注射频率。这将改善患者的依从性和生活质量。患者不合规是一种经济负担，估计会使医疗保健系统耗资超过1000亿美元/年。现有持续释放技术缺乏商业成功是由于负载效率低，负载较高时缺乏受控释放以及复杂的制造。这些局限性可以通过新开发的逆闪光纳米重沉淀（IFNP）过程来克服，以产生纳米复合材料微粒。该项目旨在开发和测试一次每天注射的2型糖尿病的肽治疗的一次性注射式配方。这项研究将有助于理解从纳米复合材料微粒控制治疗释放的基本材料科学和工程原理。控制释放的规则将广泛适用于其他肽，这项研究将有助于更快地开发未来的长效配方。产生负载肽的微粒的方法遭受低药物负荷和不良的封装效率的影响，这是商业稳定性的两个最重要的因素。与现有方法相反，IFNP技术允许在完全可扩展的过程中组装肽载荷大于50wt％的纳米颗粒，并且封装效率大于90％。然后将纳米颗粒组装到微粒中，以创建最终的持续释放公式。微粒内部的每个含药孔都被密集的疏水聚合物层所包围，该层可使治疗载荷比竞争技术高10​​倍。 IFNP过程已在许多概念验证分子上证明。在该项目中，IFNP将用于生产具有长达一个月释放特征的糖尿病治疗肽的制定。该项目的第一个目标是对控制肽稳定性和释放的物理参数有了解。在支持此目标的支持下，将使用不同玻璃过渡温度和降解速率的聚合物配制肽，并且将在体外测量释放曲线。然后将在大鼠模型中测试最佳体外配方的功效。这些研究是开发可以对患者护理产生积极影响的商业产品的重要一步。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来评估值得支持的。