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第一阶段项目旨在开创一种使用纳米复合微粒持续递送肽治疗剂的新方法。肽治疗剂倾向于遭受快速酶降解和清除，半衰期为几分钟量级，并且需要频繁注射。缓释制剂的目标是通过在数周到数月的时间内缓慢释放治疗剂来减少注射频率。这将改善患者的依从性和生活质量。患者不依从性是一种经济负担，估计医疗保健系统每年的成本超过1000亿美元。现有的持续释放技术缺乏商业成功是由于低装载效率、缺乏在较高装载下的受控释放以及复杂的制造。这些限制可以通过新开发的反相快速纳米沉淀（iFNP）工艺来克服，以生产纳米复合微粒。该项目旨在开发和测试一种每月一次的2型糖尿病肽治疗剂注射制剂，目前每天注射。这项研究将有助于理解控制纳米复合微粒释放治疗药物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迅速地开发未来的长效formulation.Current方法来生产肽负载微粒遭受低载药量和低封装效率，商业可行性的两个最重要的因素。与现有方法相比，iFNP技术允许在完全可扩展的过程中组装具有大于50wt%的肽负载和大于90%的封装效率的纳米颗粒。然后将纳米颗粒组装成微粒以产生最终的持续释放制剂。微粒内的每个含药孔都被致密的疏水聚合物层包围，这使得治疗负荷比竞争技术高10倍。iFNP过程已在许多概念验证分子上得到证明。在这个项目中，iFNP将用于生产一种用于糖尿病治疗的肽制剂，其释放曲线长达一个月。该项目的第一个目标是了解控制肽稳定性和释放的物理参数。为了支持这一目标，将用不同玻璃化转变温度和降解速率的聚合物配制肽，并在体外测量释放曲线。然后将在大鼠模型中测试最佳体外制剂的功效。这些研究是开发商业产品的重要一步，可以积极影响病人护理。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。