分子模拟技术对布洛芬固体分散体稳定性分子机制的预测

Study on molecular stabilization mechanism of ibuprofen solid dispersions based on molecular simulation technology

目的采用分子对接技术预测聚合物诱导的布洛芬固体分散体超饱和分子机制,并采用试验进行验证,为选择合理的辅料将布洛芬制成固体分散体提供依据。方法以PVP-K30、Soluplus、PVP-VA、HPMC-E5和HPMC-AS共5种常见制备固体分散体的载体为研究对象,首先,采用分子对接技术将布洛芬分别与5种载体进行分子对接,预测药物与载体分子间的相互作用;其次,将预测得到且与药物结合比较稳定的载体用来制备固体分散体,并采用差示扫描量热分析法和红外光谱法对固体分散体进行表征,进一步采用溶出度试验对方法的可行性进行验证,从而阐明固体分散体稳定性的机制。结果采用分子对接方法得到了5种辅料和药物的结合能值,其中布洛芬分别与PVP-K30和Soluplus结合的能量较低,其结合能ΔG值分别为(-28.38±0.67)k J·mol-1和(-10.93±0.25)k J·mol-1,得出PVP-K30与布洛芬的结合能强于Soluplus。除此之外,溶出度验证试验结果显示:不仅在p H值为1.2的溶出介质中,以PVP-K30为载体的布洛芬固体分散体较Soluplus易溶出,而且在p H值为7.4的溶出介质中,两种布洛芬固体分散体在30 min时累积溶出量均达到85%,随着试验时间的推移,Soluplus组累积释放度降低,而PVP-K30组累积释放度几乎无变化,表明PVP-K30与布洛芬结合的稳定性较Soluplus好,此验证结果与分子对接预测结果一致。结论通过分子模拟技术可以对固体分散体稳定性分子机制进行预测,并筛选出PVP-K30作为制备布洛芬固体分散体的最佳辅料,为难溶性药物选择合适的辅料制成固体分散体提供了参考依据。

Objective To invetigate the molecular mechanism of supersaturation of ibuprofen （IBU） solid dispersion, a molecular simulation method was established and verified. Methods Molecular docking was applied to predict the interaction between ibuprofen and five different polymers, i. e. PVP-K30, Soluplus, PVP-VA, HPMC-E5 and HPMC-AS. According to the results of molecular docking, PVP-K30 and Soluplus were better than the others in the term of stabilization. Therefore,ibuprofen solid dispersions with PVP-K30 or Soluplusas carriers was prepared separately and characterized by DSC analysis and IR spectrum. The in vitro dissolution test and stability of these two kinds of solid dispersion were also studied. Results The binding energy between drug and various polymers obtained by molecular docking technology showed that the combinations of ibuprofen with PVP-K30 or with Soluplus were better since they have the lowest binding energy of（ -28.38 _0. 67）kJ.mol-1 for PVP-K30 and（ - 10.93 ±0.25）kJ.mol-1for Soluplus. It was evident that the binding energy between PVP-K30 and ibuprofen was stronger than that of Soluplus. In addition, it was shown that in pH 1.2 medium, the dissolution rate of IBU-PVP-K30 was more faster than that of IBU-Soluplus, even through both of them had more than 85% dissolution within 30 min. After 30 min, the cumulative release of Soluplus group was dropped down, but the dissolution of IBU-PVP-K30 has almost no change. The results of dissolution were consistent with the prediction of molecular docking. Conclusions The molecular docking method can be used to predict the molecular stabilization mechanism of solid dispersion. For IBU, PVP-K30 was the best carrier to prepare its solid dispersion. All results obtained in current study provided some references for the selection of suitable materials for solid dispersion.