Yang Bin, Devalla Durga, Sonzini Silvia, Boberg Mikael, Gopaul Sashi, Sundqvist Monika, Grant Iain, Jones Christopher, Brookes Stephanie, Weidauer Cindy, Paladino Eleonora, Mahmoudi Najet, van Rooyen Jason, Dos Santos Ana Gomes, Laru Johanna, Campbell Andy, Jermutus Lutz, Bak Annette
Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Biomedical Campus, Cambridge, UK.
Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Biomedical Campus, Cambridge, UK.
J Control Release. 2025 Apr 10;380:647-663. doi: 10.1016/j.jconrel.2025.01.064. Epub 2025 Feb 17.
Cotadutide (Cota) is a lipidated dual GLP-1 and Glucagon receptor agonist that was investigated for the treatment of various metabolic diseases, it is designed for once daily subcutaneous (SC) administration. Invasive daily injections can result in poor patient compliance with chronic disease, and here, we demonstrate an innovative strategy of encapsulating reversible cota self-assembled fibers within an in-situ forming depot of low molecular weight poly(lactic-co-glycolic) acid (LWPLGA) for sustained delivery GLP-1 and Glucagon receptor agonist with controlled burst release. This could be a suitable alternative to other sustained delivery strategies for fibrillating peptides. We investigated a range of cationic ions (Na, Ca, Zn) and studied their influence on the secondary structure, morphology and the monomer release profile of cota fibers. Fibers forming hierarchy structures such as twisted filament and ribbons with beta sheet secondary structure resulted in better controlled burst. The subcutaneous administration of Ca fiber/LWPLGA depot formulation in rats resulted in 60-fold reduction in maximum concentration (Cmax) compared with cota immediate release (IR) SC formulation and a prolonged plasma exposure over a month with plasma half-life extended from the 10 h observed with the cota daily formulation to 100 h. This extended-release formulation also maintains smaller peak and trough fluctuation within therapeutic window, and PK modelling of repeated dose indicates this formulation could enable a possible dose frequency of 14 days in rat with assumed therapeutic concentration (ratios of the maximum concentration and the trough concentration) C/C window. This new long-acting injectable (LAI) method could open the door to transforming short-life peptides with sub-optimal half-life into candidates for weekly or even monthly dosing regimens, potentially leading to novel drug products with increased patient comfort.
可他肽（Cota）是一种脂质化的胰高血糖素样肽-1（GLP-1）和胰高血糖素受体双重激动剂，已针对多种代谢性疾病进行了研究，其设计为每日一次皮下注射给药。侵入性的每日注射可能导致患者对慢性病的依从性较差，在此，我们展示了一种创新策略，即将可逆的可他肽自组装纤维封装在低分子量聚乳酸-羟基乙酸共聚物（LWPLGA）的原位形成储库中，以持续递送GLP-1和胰高血糖素受体激动剂，并控制突释。这可能是用于纤维状肽的其他持续递送策略的合适替代方案。我们研究了一系列阳离子（钠、钙、锌），并研究了它们对可他肽纤维的二级结构、形态和单体释放曲线的影响。形成具有β-折叠二级结构的扭曲细丝和带状等层次结构的纤维导致了更好的突释控制。在大鼠中皮下注射钙纤维/LWPLGA储库制剂，与可他肽速释（IR）皮下制剂相比，最大浓度（Cmax）降低了60倍，血浆暴露时间延长了一个月，血浆半衰期从可他肽每日制剂观察到的10小时延长至100小时。这种缓释制剂在治疗窗内也保持较小的峰谷波动，重复给药的药代动力学模型表明，该制剂在大鼠中假设治疗浓度（最大浓度与谷浓度之比）C/C窗下可能实现14天的给药频率。这种新的长效注射（LAI）方法可能为将半衰期不理想的短效肽转化为每周甚至每月给药方案的候选药物打开大门，有可能带来提高患者舒适度的新型药物产品。
