Patel Samir G, Rajput Sadhana J
Pharmaceutics Department, Ramanbhai Patel College of Pharmacy, Education Campus Changa, Changa. Dist. Aanand, Gujarat, India.
AAPS PharmSciTech. 2009;10(2):660-9. doi: 10.1208/s12249-009-9249-7. Epub 2009 May 21.
The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like beta-CD, gamma-CD, and the hydrophilic beta-CD derivatives, DM-beta-CD and HP-beta-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-beta-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-beta-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol-cyclodextrins complexes, cilostazol-DM-beta-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.
本研究旨在通过形成包合物来研究环糊精（CDs）对西洛他唑溶解度、溶出速率和生物利用度的影响。使用天然CDs如β-环糊精、γ-环糊精以及亲水性β-环糊精衍生物二甲基-β-环糊精（DM-β-CD）和羟丙基-β-环糊精（HP-β-CD）来制备与西洛他唑的包合物。进行了相溶解度研究，并假设化学计量比为1:1计算了稳定常数。通过共沉淀法和捏合法制备了西洛他唑固体复合物，并与西洛他唑和环糊精的物理混合物进行了比较。通过傅里叶变换红外光谱、差示扫描量热法（DSC）和X射线衍射（XRD）研究对制备的包合物进行了表征。使用pH 6.4的磷酸盐缓冲液、蒸馏水和pH 1.2的盐酸缓冲液作为溶出介质进行了体外溶出研究。对优化后的包合物在兔体内的生物利用度进行了研究，并将结果与纯西洛他唑和Pletoz-50的结果进行了比较。相溶解度研究表明，通过形成复合物，药物的溶解度有显著提高，通过调节pH值进一步提高。与DM-β-CD络合显著提高了西洛他唑的溶出速率。DSC和XRD曲线显示出尖锐的吸热峰，表明西洛他唑的微晶度降低。选定的包合物在环境温度下长达6个月也很稳定。体内研究表明，DM-β-CD提高了西洛他唑的生物利用度，吸收变异性低。在所有西洛他唑-环糊精复合物中，通过共沉淀法制备的西洛他唑-DM-β-CD包合物（1:3）与Pletoz-50和纯西洛他唑相比，吸收分别增加了1.53倍和4.11倍，溶出速率分别增加了2.1倍和2.97倍。
