Complexation and enhancement of temozolomide solubility with cyclodextrins

ABSTRACT Temozolomide is a poorly soluble anti-cancer drug used in the treatment of some brain cancers. Following literature reports about the enhancement of solubility and stability for these kinds of drugs upon complexation with cyclodextrins, we aimed to form an inclusion complex between temozolomide and the different types of cyclodextrins (CDs) to enhance its solubility. In this study, three different cyclodextrins (β -CD, hydroxyl-β-CD and γ-CD) were used, and changes in solubility was measured by UV-Vis Spectroscopy and HPLC. Morphological changes upon complexation were shown by the Scanning Electron Microscope (SEM), and weight loss profiles with respect to temperatures which were unique to the compounds were shown by Thermogravimetric Analysis. Changes in heat release profiles were shown by Differential Scanning Calorimeter (DSC). Drug solubility was measured to be increased to around 25% for 1:1 molar ratio for all used CD complexations. Changes of morphology, heat release and weight loss profiles are consistent with the formation of an inclusion complex between CDs and temozolomide. In this study, success was shown in the enhancement of temozolomide solubility upon complexation with different types of CDs. It has been demonstrated that cyclodextrins can be used as complexing agents for poorly soluble anti-cancer drugs, increasing their solubility and hence drug availability.

摘要：替莫唑胺（Temozolomide）是一种难溶性抗癌药物，用于治疗部分脑癌。已有文献报道，环糊精（cyclodextrins, CDs）与此类药物形成包合物可提升其溶解度与稳定性，本研究旨在制备替莫唑胺与不同类型环糊精的包合物以改善其溶解度。本研究选用β-环糊精（β-CD）、羟基-β-环糊精（hydroxyl-β-CD）与γ-环糊精（γ-CD）三种环糊精，通过紫外-可见分光光度法（UV-Vis Spectroscopy）与高效液相色谱法（HPLC）测定溶解度变化。采用扫描电子显微镜（Scanning Electron Microscope, SEM）观察包合后的形貌变化，借助热重分析（Thermogravimetric Analysis）表征各化合物特有的温度依赖性失重曲线，利用差示扫描量热仪（Differential Scanning Calorimeter, DSC）分析放热曲线变化。实验测得，当所有受试环糊精与替莫唑胺以1:1摩尔比复合时，药物溶解度提升至约25%。形貌、放热曲线及失重曲线的变化均与环糊精与替莫唑胺形成包合物的结果一致。本研究证实，通过与不同类型环糊精复合可有效提升替莫唑胺的溶解度。研究表明，环糊精可作为难溶性抗癌药物的包合载体，提升其溶解度并改善药物生物利用度。