Department of Industrial Pharmacy, University of Alexandria, Alexandria, Egypt.
Eur J Pharm Biopharm. 2010 Feb;74(2):397-405. doi: 10.1016/j.ejpb.2009.11.011. Epub 2009 Nov 26.
Flutamide (FLT), an anticancer drug for prostatic carcinoma, has poor aqueous solubility and low oral bioavailability. This study describes the ability of beta-cyclodextrin (betaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) to form complexes with flutamide with enhanced solubility and dissolution rate in vitro. FLT-CD lyophilized dispersions (LDs) were prepared via lyophilization monophase solution technique using tertiary butyl alcohol (TBA) as a cosolvent. FLT showed an A(L)-type phase solubility diagram consistent with a linear increase in drug solubility as a function of CD concentration. Gas chromatography indicated that the LDs contain 0.02-0.03% w/w residual TBA. Based on the data from differential scanning calorimetry (DSC) and X-ray diffractometry (XRD), FLT was fully amorphous in 1:5 FLT-HPbetaCD LD as indicated by complete disappearance of FLT endothermic and diffraction peaks. The Fourier transform infrared (FTIR) spectra indicated that a FLT-CD interaction took place in the lyophilized complex. The particle sizes of 1:1 FLT-betaCD and FLT-HPbetaCD LDs were 0.92 and 0.82microm, with a high surface area (484.55 and 705.68m(2)/g) and porosity (769.46 and 1020.99e(-3)ml/g), respectively. The dissolution rate of FLT from its CD complexes was enhanced significantly. After 30min in 0.1N HCl, about 73% and 86% of FLT were dissolved from 1:5 FLT-betaCD and FLT-HPbetaCD LDs, respectively, compared to only 13.45% of pure drug. No endothermic peak corresponding to FLT melting was detected in 1:5 FLT-HPbetaCD LD after storage at 20 degrees C and 45% relative humidity for 90days thus indicating the stability of this binary system. These data suggest that cyclodextrins might be useful adjuncts in preparation of immediate-release formulations of FLT.
氟他胺（FLT）是一种用于治疗前列腺癌的抗癌药物，水溶性差，口服生物利用度低。本研究描述了β-环糊精（βCD）和羟丙基-β-环糊精（HPβCD）与氟他胺形成复合物的能力，可提高其在体外的溶解度和溶出速率。FLT-CD 冷冻干燥分散体（LD）通过冷冻干燥单相溶液技术制备，使用叔丁醇（TBA）作为共溶剂。FLT 显示出 A（L）-型相溶解度图，表明药物溶解度随 CD 浓度的线性增加。气相色谱表明 LD 中含有 0.02-0.03%w/w 的残留 TBA。基于差示扫描量热法（DSC）和 X 射线衍射法（XRD）的数据，在 1:5 FLT-HPβCD LD 中，FLT 完全无定形，这表明 FLT 的吸热和衍射峰完全消失。傅里叶变换红外（FTIR）光谱表明，在冻干复合物中发生了 FLT-CD 相互作用。1:1 FLT-βCD 和 FLT-HPβCD LD 的粒径分别为 0.92 和 0.82μm，具有高表面积（484.55 和 705.68m2/g）和孔隙率（769.46 和 1020.99e-3ml/g）。FLT 从 CD 配合物中的溶解速率显著提高。在 0.1N HCl 中 30min 后，从 1:5 FLT-βCD 和 FLT-HPβCD LD 中分别溶解了约 73%和 86%的 FLT，而纯药物仅溶解了 13.45%。在 20°C 和 45%相对湿度下储存 90 天后，在 1:5 FLT-HPβCD LD 中未检测到对应于 FLT 熔融的吸热峰，因此表明该二元体系的稳定性。这些数据表明，环糊精可能是制备 FLT 速释制剂的有用辅料。
