Nie Shufang, Fan Xiaowen, Peng Ying, Yang Xingang, Wang Chao, Pan Weisan
Department of Pharmaceutics, Shenyang Pharmaceutical University, Wen Hua RD NO 103, Shenyang, China.
Arch Pharm Res. 2007 Aug;30(8):991-1001. doi: 10.1007/BF02993968.
The purpose of this study was to evaluate complexes of vinpocetine (VIN), a poorly water-soluble base type drug, with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous environment and in solid state, with or without citric acid (CA) as an acidifier of the complexation medium. The apparent stability constant (Kc) calculated by phase solubility was 282 M(-1) and the complexation in solution was structurally characterized by 1H-NMR which showed VIN was likely to fit into the cyclodextrin cavity with its phenyl ring and ethyl ester bond. Solid complexes of VIN and HP-beta-CD were prepared by kneading (KE), co-evaporating (CE) and freeze-drying (FD) methods. Physical mixtures were prepared for comparison. The study in the solid state included the differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and infrared absorption spectroscopy (IR). From these analyses, CE and FD products were found in amorphous state, allowing to the conclusion of strong evidences of inclusion complex formation. However, the dissolution test showed that only VIN/HP-beta-CD+CA complexes by CE and FD method could provide satisfying dissolution behavior (rapid, complete and lasting) when compared to that of VIN/HP-beta-CD complexes. Interestingly, the addition of CA in inclusion complexes could significantly decrease the amount of HP-beta-CD needed to solubilize the same amount of VIN and thereby reducing the formulation bulk. Furthermore, in-vivo study revealed that the bioavailability of VIN after oral administration to rabbits (n=6) was significantly improved by VIN/HP-beta-CD+CA inclusion complex.
本研究的目的是评估水溶性差的碱型药物长春西汀(VIN)与羟丙基-β-环糊精(HP-β-CD)在水性环境和固态下形成的复合物,络合介质中添加或不添加柠檬酸(CA)作为酸化剂。通过相溶解度计算得到的表观稳定常数(Kc)为282 M(-1),溶液中的络合作用通过1H-NMR进行结构表征,结果表明VIN可能通过其苯环和乙酯键嵌入环糊精腔内。采用捏合(KE)、共蒸发(CE)和冷冻干燥(FD)法制备了VIN与HP-β-CD的固体复合物。制备了物理混合物用于比较。固态研究包括差示扫描量热法(DSC)、X射线衍射法(XRD)和红外吸收光谱法(IR)。通过这些分析,发现CE和FD产物为非晶态,有力地证明了包合物的形成。然而,溶出度试验表明,与VIN/HP-β-CD复合物相比,只有通过CE和FD法制备的VIN/HP-β-CD+CA复合物具有令人满意的溶出行为(快速、完全和持久)。有趣的是,在包合物中添加CA可以显著减少溶解相同量VIN所需的HP-β-CD量,从而减小制剂体积。此外,体内研究表明,VIN/HP-β-CD+CA包合物可显著提高家兔(n=6)口服VIN后的生物利用度。