Semcheddine Farouk, Guissi Nida El Islem, Liu XueYin, Wu ZuoMin, Wang Bo
Department of Pharmaceutics, China Pharmaceutical University, Tongjiaxiang 24#, Nanjing, 210009, China,
AAPS PharmSciTech. 2015 Jun;16(3):704-15. doi: 10.1208/s12249-014-0257-x. Epub 2014 Dec 17.
The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-β-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-β-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-β-CD and ND/HP-β-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an AL-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M(-1) for ND/SBE-β-CD and ND/HP-β-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-β-CD and HP-β-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-β-CD and HP-β-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.
本研究的目的是通过制备尼莫地平（ND）与磺丁基醚 -β-环糊精（SBE-β-CD）和2-羟丙基 -β-环糊精（HP-β-CD）的包合物来提高尼莫地平的溶解度和溶出速率，并研究制备方法对其在不同介质（0.1 N HCl pH 1.2、pH 7.4的磷酸盐缓冲液和蒸馏水）中体外溶出曲线的影响。因此，通过捏合、共沉淀和冷冻干燥法制备了包合物。进行相溶解度研究以表征液态下的复合物。采用差示扫描量热法（DSC）、X射线衍射法（X-RD）和傅里叶变换红外光谱法（FT-IR）对固态包合物进行了研究。如AL型图所示，在蒸馏水中以1:1化学计量比形成了稳定的ND/SBE-β-CD和ND/HP-β-CD包合物。ND/SBE-β-CD和ND/HP-β-CD的表观稳定常数（Ks）分别为1334.4和464.1 M⁻¹。对于SBE-β-CD和HP-β-CD，ND的水溶性平均分别显著提高了22倍和8倍。DSC结果表明，通过捏合法制备的药物与SBE-β-CD和HP-β-CD之间均形成了真正的包合物。相比之下，在所有其他产品中均可检测到结晶药物。溶出度研究表明，在所有介质中，所有产品的溶出速率均高于物理混合物和单独的ND。然而，与药物和其他包合物相比，捏合包合物的溶出速率最高，证实了制备方法对产品理化性质的影响。
