Liu Chang, Zhang Wang, Yang Hao, Sun Weidong, Gong Xiangdong, Zhao Junxian, Sun Yun, Diao Guowang
College of Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China.
College of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu, P. R. China.
PLoS One. 2014 Jul 11;9(7):e101761. doi: 10.1371/journal.pone.0101761. eCollection 2014.
More than 50% of new drug candidates in drug discovery are lipophilic and exhibit poor aqueous solubility, which results in poor bioavailability and a lack of dose proportionality. Here, we improved the solubility of pedunculoside (PE) by generating a water-soluble inclusion complex composed of PE and the polymer β-cyclodextrin (CDP). We characterized this novel complex by 1H NMR, FT-IR, UV-vis spectroscopy, powder X-ray diffractometry and thermogravimetric analysis. The ratio of β-cyclodextrin (β-CD) units in CDP to PE was determined to be 2∶1. The KD value of the inclusion complex was determined to be 4.29×10(-3) mol•L(-1). In contrast to the low solubility of PE, the water-solubility of the PE-CDP complex was greatly enhanced. A preclinical toxicological study indicated that PE-CDP was well tolerated for a single administration. Importantly, the anti-inflammation potency of the PE-CDP complex was higher than that of PE. As a result, the formation of inclusion complexes by water-soluble CDP opens up possible aqueous applications of insoluble drug candidates in drug delivery.
在药物研发中，超过50%的新药候选物具有亲脂性，且水溶性较差，这导致生物利用度低以及缺乏剂量比例性。在此，我们通过生成由pedunculoside（PE）与聚合物β-环糊精（CDP）组成的水溶性包合物来提高PE的溶解度。我们通过1H NMR、FT-IR、紫外可见光谱、粉末X射线衍射和热重分析对这种新型复合物进行了表征。确定CDP中β-环糊精（β-CD）单元与PE的比例为2∶1。该包合物的KD值确定为4.29×10(-3) mol•L(-1)。与PE的低溶解度相比，PE-CDP复合物的水溶性大大提高。一项临床前毒理学研究表明，PE-CDP单次给药耐受性良好。重要的是，PE-CDP复合物的抗炎效力高于PE。因此，通过水溶性CDP形成包合物为难溶性候选药物在药物递送中的水性应用开辟了可能性。
