Wang Qiao-Han, Yang Xiao-Lin, Xiao Wei, Wang Zhen-Zhong, Ding Gang, Huang Wen-Ze, Yang Zhong-Lin, Zhang Chun-Feng
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.
Am J Chin Med. 2015;43(3):513-28. doi: 10.1142/S0192415X15500329. Epub 2015 May 4.
Akebia Saponin D (ASD) or asperosaponin VI is the most abundant constituent of the rhizome of Dipsacus asper, which has been used for the treatment of lower back pain, traumatic hematoma and bone fractures. In recent years, it was reported that ASD was a potential treatment strategy for Alzheimer's disease (AD). However, the low bioavailability of ASD limited its clinical utility. Microcrystalline preparation is one of the effective methods to improve drug absorption. The drugs prepared by different methods can present different solid forms (polymorphs), and different polymorphs have significantly different bioavailabilities. The objective of this study was to prepare ASD polymorphs using the different preparation processes and to evaluate their physicochemical properties and oral absorption. ASD-2 obtained by the antisolvent process was simpler and had higher recovery (78.5%) than that of ASD-1 by a two-step macroporous resin column separation (56.5%). The ASD polymorphs were characterized using differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The results revealed that ASD-2 existed in microcrystalline form, while ASD-1 was amorphous. Furthermore, the equilibrium solubility, dissolution in aqueous solution and pharmacokinetic parameters of the samples were determined. ASD-2 showed lower aqueous solubility than that of ASD-1 (p < 0.01). In addition, ASD-2 showed lower dissolution with only 65% of the drug released while ASD-1 had a higher dissolution with 99% of drug released at the end of the 180 min testing period. Although ASD-1 significantly increased solubility and dissolution, the AUC 0-20h of ASD-2 was 4.3 times that of the amorphous ASD-1 in vivo. Data suggest that the microcrystalline preparation of ASD-2 is not only reasonable in economy and suitable for large-scale preparation, but also a promising method to enhance bioavailability of ASD.
紫菀皂苷D（ASD）或地榆皂苷VI是川续断根茎中含量最丰富的成分，川续断已被用于治疗腰痛、创伤性血肿和骨折。近年来，有报道称ASD是治疗阿尔茨海默病（AD）的一种潜在策略。然而，ASD的低生物利用度限制了其临床应用。微晶制剂是提高药物吸收的有效方法之一。通过不同方法制备的药物可以呈现不同的固体形式（多晶型物），不同的多晶型物具有显著不同的生物利用度。本研究的目的是使用不同的制备工艺制备ASD多晶型物，并评估其理化性质和口服吸收情况。通过反溶剂法获得的ASD-2比通过两步大孔树脂柱分离法获得的ASD-1（回收率56.5%）更简单，回收率更高（78.5%）。使用差示扫描量热法（DSC）、热重分析（TGA）、粉末X射线衍射（PXRD）和扫描电子显微镜（SEM）对ASD多晶型物进行了表征。结果表明，ASD-2以微晶形式存在，而ASD-1为无定形。此外还测定了样品的平衡溶解度、在水溶液中的溶出度和药代动力学参数。ASD-2的水溶解度低于ASD-1（p < 0.01）。此外，ASD-2的溶出度较低，在180分钟测试期结束时仅释放65%的药物，而ASD-1的溶出度较高，释放99%的药物。尽管ASD-1显著提高了溶解度和溶出度，但ASD-2在体内的AUC 0-20h是无定形ASD-1的4.3倍。数据表明，ASD-2的微晶制剂不仅在经济上合理且适合大规模制备，而且是提高ASD生物利用度的一种有前景的方法。
