Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Int J Pharm. 2019 Oct 5;569:118586. doi: 10.1016/j.ijpharm.2019.118586. Epub 2019 Aug 1.
The main objective of this study was to develop a novel self-assembled micelle system to improve the oral bioavailability of the water-insoluble and thermal instable germacrone (GEM). Micelles were prepared with an improved supercritical reverse phase evaporation (ISCRPE) method, and the thin-film hydration (TFH) method was used for comparison. Physicochemical characterization confirmed the nanospherical morphology of the micelles prepared by the ISCRPE method (GEM@SDL-SCF Micelles) had smaller particle size and greater encapsulation efficiency than that of the micelles prepared by the TFH method (GEM@SDL-THF Micelles). Dilution resistance and stability experiments were performed to assess the structural integrity. In vitro GEM release was analyzed by the dialysis diffusion method, and the micelle system showed sustained and cumulative release. Furthermore, the fluorescence results from the cellular uptake study revealed improved drug absorption of GEM since the green fluorescence intensity of C6@SDL-SCF Micelles were stronger than that of C6@SDL-TFH Micelles. The transcellular transport study showed a distinct increase in the apparent permeability coefficient (AP → BL) in a Caco-2 cell transport model, and free GEM solution, GEM@SDL-TFH Micelles and GEM@SDL-SCF Micelles had permeability coefficients of 7.30 × 10, 8.01 × 10, and 10.57 × 10 cm·s, respectively. The pharmacokinetics study in Sprague-Dawley rats showed that the oral absorption capacity of the GEM@SDL-SCF Micelles was obviously enhanced, with a relative oral bioavailability of 298% and 147% compared with that of free GEM solution and GEM@SDL-TFH Micelles, respectively. The gastrointestinal safety assessment demonstrated that the micelles used in the experiment did not cause gastrointestinal toxicity. These results indicated that self-assembled micelles are promising nanocarriers aimed at enhancing the oral absorption of drugs with thermal sensitivity and low aqueous solubility, and micelles prepared by supercritical fluid (SCF) technology showed better performance than those prepared by the TFH method.
本研究的主要目的是开发一种新型自组装胶束系统，以提高水不溶性和热不稳定性的倍半萜烯（GEM）的口服生物利用度。胶束采用改良的超临界反相蒸发（ISCRPE）法制备，并与薄膜水化（TFH）法进行比较。物理化学特性证实，采用 ISCRPE 法制备的胶束（GEM@SDL-SCF 胶束）具有比采用 TFH 法制备的胶束（GEM@SDL-THF 胶束）更小的粒径和更高的包封效率。进行稀释阻力和稳定性实验以评估结构完整性。通过透析扩散法分析体外 GEM 释放，胶束系统显示出持续和累积释放。此外，细胞摄取研究的荧光结果表明，由于 C6@SDL-SCF 胶束的绿色荧光强度强于 C6@SDL-TFH 胶束，因此 GEM 的药物吸收得到了改善。跨细胞转运研究表明，在 Caco-2 细胞转运模型中，表观渗透系数（AP→BL）明显增加，游离 GEM 溶液、GEM@SDL-TFH 胶束和 GEM@SDL-SCF 胶束的渗透系数分别为 7.30×10、8.01×10 和 10.57×10 cm·s。在 Sprague-Dawley 大鼠中的药代动力学研究表明，GEM@SDL-SCF 胶束的口服吸收能力明显增强，与游离 GEM 溶液和 GEM@SDL-TFH 胶束相比，相对口服生物利用度分别为 298%和 147%。胃肠道安全性评估表明，实验中使用的胶束不会引起胃肠道毒性。这些结果表明，自组装胶束是一种有前途的纳米载体，旨在增强具有热敏感性和低水溶性的药物的口服吸收，并且由超临界流体（SCF）技术制备的胶束比由 TFH 法制备的胶束表现出更好的性能。
