In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin-based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3-palmitate (EV-P), an ester lipidic prodrug for entecavir (EV), was employed. The EV-P-loaded TS was prepared by ultra-sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 μm), crystallinity (melting point of 160–165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS-injected site, drug aggregates of up to 500 μm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS-injected site, with >4 weeks remaining of the oily vehicle in micro-computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long-acting delivery, with improved local tolerability.

中文翻译：

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基于三辛酸的药物结晶混悬液，用于肌内长效递送恩替卡韦并减轻局部炎症

为了确保延长的药代动力学特征以及注射部位的局部耐受性，设计了基于三辛精的药物结晶混悬液（TS），并用传统的水混悬液（AS）评估其局部分布、药代动力学和炎症反应。使用恩替卡韦 (EV) 的酯类脂质前药恩替卡韦 3-棕榈酸酯 (EV-P) 作为模型药物颗粒。采用超声法制备了负载EV-P的TS。制备的 TS 和传统 AS 表现出相似的形态（棒状或矩形）、中值直径（2.7 和 2.6 μm）、结晶度（熔点 160–165°C）和体外溶出曲线。然而，药物微粒的体内性能明显不同，具体取决于递送载体。在AS注射部位，肌肉注射后形成高达500μm的药物聚集体，并被炎症细胞和成纤维细胞带包围。相比之下，在 TS 注射部位没有观察到明显的颗粒聚集和相邻颗粒化，在微计算机断层扫描观察中，油性媒介物剩余时间超过 4 周。令人惊讶的是，与 AS 相比，TS 的局部炎症明显减轻，坏死、纤维化厚度、炎症面积和巨噬细胞浸润明显减少。与 AS 相比，TS 观察到较高的初始全身暴露，但 TS 提供了 EV 的延长 3 周。因此，我们认为新型 TS 系统可以成为设计肠外长效给药的有前途的工具，并具有改善的局部耐受性。