Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Blvd, Ann Arbor, MI, 48109, USA.
Nat Commun. 2022 Jun 8;13(1):3282. doi: 10.1038/s41467-022-30813-7.
Poly(lactic-co-glycolic acid) (PLGA) long-acting release depots are effective for extending the duration of action of peptide drugs. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common uncapped PLGA to bind and absorb into the polymer phase net positively charged peptides from aqueous solution after short exposure at modest temperature. Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional methods. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products. Remote absorption encapsulation further removes the need for a critical organic solvent removal step after encapsulation, allowing for simple and cost-effective sterilization of the drug-free microspheres before encapsulation of the peptide.
聚（乳酸-共-乙醇酸）（PLGA）长效释放储库可有效延长肽类药物的作用持续时间。我们描述了一种有效的无有机溶剂远程包封方法，该方法基于未封端的 PLGA 能够在适度温度下短时间暴露后从水溶液中结合并吸收带正电荷的肽进入聚合物相中。通过这种方法包封的低分子量 PLGA 75/25 微球中的亮丙瑞林缓慢且持续地释放肽，在体外超过 56 天，并且以与 1 个月 Lupron Depot®相当的方式抑制大鼠的睾丸酮产生。该技术可推广用于包封各种大小的带正电荷的肽，包括奥曲肽，具有与传统方法相当的竞争装载和包封效率。在某些情况下，远程加载的 PLGA 微球的体外和体内性能优于市售产品。远程吸收包封进一步消除了包封后去除关键有机溶剂步骤的需要，允许在封装肽之前对无药物微球进行简单且具有成本效益的灭菌。
