School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
AAPS PharmSciTech. 2019 Sep 5;20(7):302. doi: 10.1208/s12249-019-1520-y.
Docetaxel (DTX) was effective in the treatment of neoplasm but could only be administered intravenously with the poor oral bioavailability owing to its undesirable solubility, remarkably metabolic conversion, and other factors. Cimetidine (CMD), a classic CYP3A4 isozyme inhibitor, had exhibited a wide range of inhibition on the metabolism of many drugs. The aim of this study was to construct the novel docetaxel-cimetidine (DTX-CMD) complex and the chitosan-deoxycholate nanoparticles based on it to confirm whether this formulation could show advantages in terms of solubility, dissolution rate, small intestinal absorption, and oral bioavailability in comparison with the pure drug. The solid-state characterization was carried out by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and simultaneous DSC-TGA (SDT). Dissolution rate and kinetic solubility study were determined by evaluating the amount of DTX in distilled water and phosphate buffer solution (pH = 7.4), respectively. And small intestinal absorption and pharmacokinetics study were conducted in rats. The results of this study demonstrated that we successfully constructed DTX-CMD complex and its chitosan-deoxycholate nanoparticles. Furthermore, the DTX-CMD complex increased the solubility of DTX by 2.3-fold and 2.1-fold in distilled water and phosphate buffer solution, respectively. The ultimate accumulative amount of DTX-CMD complex nanoparticles through rat small intestinal in 2 h was approximately 4.9-fold and the oral bioavailability of the novel nanoparticles was enhanced 2.8-fold, compared with the pure DTX. The superior properties of the complex nanoparticles could both improve oral bioavailability and provide much more feasibility for other formulations of DTX.
多西他赛（DTX）在治疗肿瘤方面有效，但由于其不理想的溶解度、显著的代谢转化和其他因素，只能静脉注射，口服生物利用度差。西咪替丁（CMD）是一种经典的 CYP3A4 同工酶抑制剂，对许多药物的代谢表现出广泛的抑制作用。本研究旨在构建新型多西他赛-西咪替丁（DTX-CMD）复合物及其基于该复合物的壳聚糖-去氧胆酸钠纳米粒，以确认与纯药物相比，该制剂在溶解度、溶出速率、小肠吸收和口服生物利用度方面是否具有优势。通过粉末 X 射线衍射（PXRD）、傅里叶变换红外光谱（FT-IR）和同步 DSC-TGA（SDT）对其进行固态特性表征。通过评估多西他赛在蒸馏水中和磷酸盐缓冲液（pH=7.4）中的量来分别进行溶出速率和动力学溶解度研究。并在大鼠体内进行小肠吸收和药代动力学研究。研究结果表明，我们成功构建了 DTX-CMD 复合物及其壳聚糖-去氧胆酸钠纳米粒。此外，DTX-CMD 复合物分别使 DTX 在蒸馏水中和磷酸盐缓冲液中的溶解度提高了 2.3 倍和 2.1 倍。2 h 内大鼠小肠中 DTX-CMD 复合纳米粒的累积量约为纯 DTX 的 4.9 倍，新型纳米粒的口服生物利用度提高了 2.8 倍。该复合物纳米粒的优异性能既能提高口服生物利用度，又能为 DTX 的其他制剂提供更多的可行性。
