Badr-Eldin Shaimaa M, Elkheshen Seham A, Ghorab Mahmoud M
Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo, Egypt.
Eur J Pharm Biopharm. 2008 Nov;70(3):819-27. doi: 10.1016/j.ejpb.2008.06.024. Epub 2008 Jul 4.
The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified beta-cyclodextrins: hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and heptakis-[2,6-di-O-methyl]-beta-cyclodextrin (DM-beta-CD), in comparison with the natural beta-cyclodextrin (beta-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest-host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A(p)-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-beta-CD>HP-beta-CD>beta-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-beta-CD and DM-beta-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-beta-CD and DM-beta-CD yielded better performance than the corresponding ones prepared using beta-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the beta-CD derivatives.
本研究旨在考察他达拉非（一种几乎不溶的选择性磷酸二酯酶-5抑制剂（PDE5））与两种化学修饰的β-环糊精：羟丙基-β-环糊精（HP-β-CD）和七（2,6-二-O-甲基）-β-环糊精（DM-β-CD）之间的包合络合作用，并与天然β-环糊精（β-CD）进行比较，以提高药物的溶解度和溶出速率，从而提高其生物利用度。在溶液和固态中均对包合络合作用进行了研究。紫外光谱位移法表明他达拉非与三种环糊精（CDs）之间形成了客体-主体络合物。所有使用的CDs的相溶解度曲线均归类为A(p)型，表明形成了高阶络合物。反映CDs对药物增溶能力的络合效率值（CE）可按以下顺序排列：DM-β-CD>HP-β-CD>β-CD。他达拉非与CDs的固体二元体系通过捏合和冷冻干燥技术以1:1、1:3和1:5（药物与CD）的摩尔比制备。以相同摩尔比制备物理混合物用于比较。使用差示扫描量热法（DSC）、X射线衍射法（XRD）和傅里叶变换红外光谱法（FTIR）对摩尔比为1:5的制备体系进行了物理化学表征。结果表明，在摩尔比为1:5时，使用冷冻干燥法，药物与HP-β-CD和DM-β-CD之间形成了真正的包合络合物。相比之下，在所有其他产品中均可检测到结晶药物。对所有制备的二元体系中的他达拉非进行溶出实验，以确定制备用于口服他达拉非片剂制剂的包合络合物的最合适的CD类型、摩尔比和制备技术。在所有制备的体系中，随着CD比例的增加，溶出增强效果增加。CD类型和制备技术在体系性能中均起重要作用。无论制备技术如何，使用HP-β-CD和DM-β-CD制备的体系比使用β-CD制备的相应体系性能更好。此外，冷冻干燥技术显示出比其他方法更好的溶出增强效果，特别是与β-CD衍生物结合使用时。
