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

这一STTRI期项目旨在开辟一种使用纳米复合微粒持续递送多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，需要频繁注射。缓释制剂的目标是通过在几周到几个月的时间内缓慢释放治疗药物来减少注射频率。这将改善患者的依从性和生活质量。患者不遵守规定是一种经济负担，估计每年会给医疗保健系统造成超过1000亿美元的损失。现有的缓释技术缺乏商业成功是由于加载效率低，在较高加载时缺乏受控释放，以及复杂的制造。这些限制可以通过新开发的反闪光纳米沉淀(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多肽治疗2型糖尿病的可注射配方，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多肽，这项研究将有助于更快地开发未来的长效制剂。目前生产多肽微球的方法存在载药量低和包封率低的问题，这是影响商业可行性的两个最重要的因素。与现有方法不同，iFNP技术允许在完全可扩展的过程中组装多肽负载量超过50wt%和包封率超过90%的纳米颗粒。然后将纳米颗粒组装成微粒，形成最终的缓释制剂。微粒内的每个含药孔都被一层致密的疏水聚合物层包围，这使得治疗负载量比竞争技术高出10倍。IFNP过程已经在一些概念验证分子上得到了演示。在这个项目中，iFNP将被用来生产一种用于糖尿病治疗的多肽配方，释放曲线长达一个月。这个项目的第一个目标是了解控制多肽稳定性和释放的物理参数。为了支持这一目标，该肽将与不同玻璃化转变温度和降解率的聚合物配制，并将在体外测量释放情况。然后，将在大鼠模型中测试最佳体外配方的有效性。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NSF的法定使命，并通过使用基金会的智力优势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.