Imam Syed Sarim, Alshehri Sultan, Altamimi Mohammad A, Mahdi Wael A, Qamar Wajhul
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
ACS Omega. 2023 Sep 11;8(38):34898-34907. doi: 10.1021/acsomega.3c04225. eCollection 2023 Sep 26.
Silymarin (SIL) is a poorly water-soluble flavonoid reported for different pharmacological properties. Its therapeutic applications are limited due to poor water solubility. In this study, the solubility of silymarin has been enhanced by preparing freeze-dried binary and ternary complexes using beta cyclodextrin (βCD) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). The stoichiometry of the drug and the carrier was selected from the phase solubility study. The dissolution study was performed to assess the effect of complexation on the release pattern of SIL. The formation of inclusion complexes was confirmed by different physicochemical studies. Finally, a cell viability assay (MCF 7; breast cancer cell line) was performed to compare the activity with free SIL. The phase solubilization results revealed the formation of a stable complex (binary) with a stability constant and complexation efficiency (CE) value of 288 mol L and 0.045%. The ternary sample depicted a significantly enhanced stability constant and CE value (890 mol L and 0.14%). The release study results showed a marked increase in the release pattern after addition of βCD (alone) in the binary mixture (49.4 ± 3.1%) as well as inclusion complex (66.2 ± 3.2%) compared to free SIL (32.7 ± 1.85%). Furthermore, with the addition of TPGS in SIL-βCD (ternary), the SIL release was found to be significantly enhanced from the SIL ternary mixture (79.2 ± 2.13%) in 120 min. However, fast SIL release was achieved with 99.2 ± 1.7% in 45 min for the SIL ternary complex. IR and NMR spectral analysis results revealed the formation of a stable complex with no drug-polymer interaction. The formation of complexes was also confirmed by the molecular docking study (docking scores of 4.1 and -6.4 kcal/mol). The in vitro cell viability result showed a concentration-dependent activity. The IC value of the SIL ternary complex was found to be significantly lower than that of free SIL. The findings of the study concluded that the prepared SIL inclusion complex can be used as an alternative oral delivery system to enhance solubility, dissolution, and biological activity against the tested cancer cell line.
水飞蓟素（SIL）是一种水溶性较差的黄酮类化合物，具有多种药理特性。由于其水溶性差，其治疗应用受到限制。在本研究中，通过使用β-环糊精（βCD）和d-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）制备冻干二元和三元复合物，提高了水飞蓟素的溶解度。从相溶解度研究中选择药物与载体的化学计量比。进行溶出度研究以评估络合对SIL释放模式的影响。通过不同的物理化学研究证实了包合物的形成。最后，进行细胞活力测定（MCF 7；乳腺癌细胞系）以比较与游离SIL的活性。相增溶结果表明形成了稳定的二元复合物，其稳定常数和络合效率（CE）值分别为288 mol/L和0.045%。三元样品的稳定常数和CE值显著提高（890 mol/L和0.14%）。释放研究结果表明，与游离SIL（32.7±1.85%）相比，在二元混合物中加入βCD（单独）后（49.4±3.1%）以及包合物（66.2±3.2%），释放模式有显著增加。此外，在SIL-βCD（三元）中加入TPGS后，发现SIL从三元混合物中的释放（79.2±2.13%）在120分钟内显著增强。然而，对于SIL三元复合物，在45分钟内快速释放率达到99.2±1.7%。红外光谱和核磁共振光谱分析结果表明形成了稳定的复合物，不存在药物-聚合物相互作用。分子对接研究（对接分数为4.1和-6.4 kcal/mol）也证实了复合物的形成。体外细胞活力结果显示出浓度依赖性活性。发现SIL三元复合物的IC值显著低于游离SIL。该研究结果得出结论，所制备的SIL包合物可作为一种替代口服给药系统，以提高溶解度、溶出度以及对受试癌细胞系的生物活性。
