School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Targeted Therapy and Diagnosis for Critical Diseases, Zhengzhou, China.
Pharm Dev Technol. 2021 Jun;26(5):592-598. doi: 10.1080/10837450.2021.1904259. Epub 2021 Apr 6.
This study investigated the efficiency and the related mechanisms of a new absorption enhancer, DL-malic acid (MA), on the oral bioavailability of docetaxel (DTX). Polyethylene glycol polycarbonate (PEG-PCL) modified liposomes (PLip) were prepared for DTX, and incorporated into the pH-sensitive microspheres (MS) with sustained release. MA decreased the transepithelial electrical resistance (TEER) across a Caco-2 cell monolayer by 20% and 57% after 2 and 3 h of co-incubation with DTX-PLip and the cells, respectively, indicating that MA could open tight junctions but not instantaneously. After long enough exposure (4 h) of MA to the small intestine of rats, only the absorption rate constant () of DTX-PLip, but not Duopafei, was increased, which could be related to the intestinal mucosal permeability of DTX. After co-administration in rats, MA significantly enhanced the oral bioavailability of DTX in DTX-PLip-MS from 44.67% to 81.27%, rather than DTX-PLip and Duopafei, which could be related to the prolonged intestinal retention time of DTX-PLip via the MS and the promoted drug intercellular transport by MA. The absorption-enhancing effects of MA on DTX-PLip-MS were further confirmed by imaging. The above findings suggest that MA served as a new and efficient absorption enhancer for DTX-PLip-MS.HIGHlIGHTSIn this study, malic acid as a new absorption enhancer for DTX in polymer-liposome (PLip) embedded in pH-sensitive microspheres (MS) was found for the first time.The malic acid could significantly enhance oral bioavailability of DTX in DTX-PLip-MS (from 44.67 % to 81.27%) rather than Duopafei and DTX-PLip after co-administration.The absorption enhancement may be closely related to the intestinal retention time and mucosal permeability.These findings will provide an important reference for the study of absorption enhancers for promoting intercellular insoluble drug transport.
本研究考察了新型吸收增强剂 DL-苹果酸（MA）对多西紫杉醇（DTX）口服生物利用度的效率和相关机制。聚乙二醇聚碳酸酯（PEG-PCL）修饰的脂质体（PLip）被制备用于 DTX，并与具有持续释放的 pH 敏感微球（MS）结合。MA 分别与 DTX-PLip 和细胞共孵育 2 和 3 小时后，使 Caco-2 细胞单层的跨上皮电阻（TEER）降低了 20%和 57%，表明 MA 可以打开紧密连接，但不是瞬间打开。在 MA 足够长时间（4 小时）暴露于大鼠小肠后，只有 DTX-PLip 的吸收速率常数（）增加，而不是 Duopafei，这可能与 DTX 的肠黏膜通透性有关。在大鼠中共同给予后，MA 可显著提高 DTX-PLip-MS 的 DTX 口服生物利用度，从 44.67%增加到 81.27%，而不是 DTX-PLip 和 Duopafei，这可能与 MS 延长 DTX-PLip 的肠道保留时间和 MA 促进药物细胞间转运有关。MA 对 DTX-PLip-MS 的吸收增强作用通过 成像进一步得到证实。上述发现表明，MA 可作为聚合物脂质体（PLip）中 DTX 的新型高效吸收增强剂。
