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

这个STTR一期项目旨在开拓一种使用纳米复合微粒持续递送肽治疗药物的新方法。多肽疗法往往遭受快速的酶降解和清除，半衰期约为几分钟，需要经常注射。缓释制剂的目标是通过在数周至数月的时间内缓慢释放治疗药物来减少注射频率。这将提高患者的依从性和生活质量。患者不遵守医嘱是一种经济负担，据估计，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上的成功是由于加载效率低，在高加载时缺乏控制释放，以及复杂的制造。这些限制可以通过新开发的逆闪速纳米沉淀（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每月一次的2型糖尿病肽治疗注射剂配方，目前每天注射。这项研究将有助于理解控制纳米复合微粒治疗释放的基础材料科学和工程原理。控制释放的规则将广泛应用于其他肽，这项研究将有助于更快地开发未来的长效制剂。目前生产多肽负载微颗粒的方法存在药物负载低和封装效率差的问题，这是影响商业可行性的两个最重要因素。与现有方法相比，iFNP技术允许在完全可扩展的过程中组装肽负载大于50wt%的纳米颗粒，封装效率大于90%。然后将纳米颗粒组装成微粒，形成最终的缓释制剂。微粒内部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过程已经在许多概念验证分子上得到了证明。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，其释放期为一个月。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。为了实现这一目标，肽将与不同玻璃化转变温度和降解速率的聚合物配制，并在体外测量释放曲线。最佳体外配方的功效将在大鼠模型中进行测试。这些研究是开发能够对患者护理产生积极影响的商业产品的重要一步。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.