Sun Zhisu, Zhang Huicong, He Huiyang, Sun Lingling, Zhang Xiaorui, Wang Qun, Li Kexin, He Zhonggui
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Asian J Pharm Sci. 2019 Nov;14(6):668-676. doi: 10.1016/j.ajps.2018.08.005. Epub 2018 Sep 18.
Solid dispersion (SD) systems have been extensively used to increase the dissolution and bioavailability of poorly water-soluble drugs. To circumvent the limitations of polyvinylpyrrolidone (PVP) dispersions, HPMC E5 was applied in the formulation process and scaling-up techniques, simultaneously. In this study, SD of nimodipine (NMP) and corresponding tablets were prepared through solvent method and fluid bed granulating one step technique, respectively. Discriminatory dissolution media were used to obtain reliable dissolution results. Meanwhile, the stability study of SDs was investigated with storage under high temperature and humidity conditions. Moreover, the solubility of SDs was measured to explore the effect of carriers. The preparations were characterized by DSC, PXRD, and FTIR. Dramatical improvements in the dissolution rate of NMP were achieved by the ingenious combination of the two polymers. Binary NMP/PVP/HPMC-SDs released steadily, while the dissolution of single NMP/PVP-SDs decreased rapidly in water. The fluid-bed tablets (FB-T) possessed a similar dissolution behavior to the commercial Nimotop™ tablets. The characterization patterns implied that NMP existed in an amorphous state in our SDs. Furthermore, the results of stability tests suggested a better stability of the binary SDs. A special cooperative effect of PVP and HPMC was discovered on dissolution characteristics of NMP SDs and tablets, which could be extended to other drugs henceforth. Finally, the bioavailability of FB-T was evaluated in beagle dogs with Nimotop™ as the reference, and the results showed a higher value for FB-T.
固体分散体（SD）系统已被广泛用于提高难溶性药物的溶出度和生物利用度。为了克服聚乙烯吡咯烷酮（PVP）分散体的局限性，羟丙甲纤维素E5（HPMC E5）被同时应用于制剂工艺和放大技术中。在本研究中，尼莫地平（NMP）固体分散体及其相应片剂分别通过溶剂法和流化床一步制粒技术制备。采用区分性溶出介质以获得可靠的溶出结果。同时，在高温高湿条件下储存对固体分散体进行稳定性研究。此外，测定固体分散体的溶解度以探究载体的作用。通过差示扫描量热法（DSC）、粉末X射线衍射法（PXRD）和傅里叶变换红外光谱法（FTIR）对制剂进行表征。通过两种聚合物的巧妙组合，NMP的溶出速率得到了显著提高。二元NMP/PVP/HPMC固体分散体释放稳定，而单一NMP/PVP固体分散体在水中的溶出迅速下降。流化床片剂（FB-T）具有与市售尼莫通™片剂相似的溶出行为。表征图谱表明NMP在我们制备的固体分散体中以无定形状态存在。此外，稳定性试验结果表明二元固体分散体具有更好的稳定性。发现PVP和HPMC对NMP固体分散体和片剂的溶出特性具有特殊的协同作用，这一作用今后可扩展到其他药物。最后，以尼莫通™为参比，在比格犬中评价了FB-T的生物利用度，结果显示FB-T具有更高的[生物利用度相关参数]值。
