Abstract：
The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water-oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = -132.20 kJ mol-1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.
摘要：
肽类药物的降解限制了肽类药物微球的运用。在聚合物降解过程中，肽在水-油界面的结构变化及其在复杂微环境中空间结构的破坏会影响药物的释放和体内生物活性。这项研究表明，向内部水相（W1）中添加羟乙基淀粉（HES）可显着提高司马鲁肽的稳定性，并优化其在PLGA微球中的释放行为。结果表明，这种改善是由于氢键促进的自发放热反应（ΔH=-132.20kJmol-1）。使用水包油包水（W1/O/W2）乳液法将HES掺入内部水相中，得到PLGA微球，包封率为94.38％。此外，具有HES的微球在44天内表现出良好的药物释放控制，不同于在没有HES的微球中缓慢和不完全的释放。在同一时期内,与无HES微球相比,优化的h-MG2制剂实现了更完全的药物释放(83.23%)并防止了30.65%的药物损失。此外,优化的司马鲁肽微球提供了近3周的血糖控制和足够的安全性.总之,内水相中加入HES,提高了司马鲁肽PLGA微球的原位药物稳定性和释放行为,有效增加多肽药物在PLGA微球中的有效载荷。
