Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy.
Int J Pharm. 2011 Feb 14;404(1-2):49-56. doi: 10.1016/j.ijpharm.2010.10.050. Epub 2010 Nov 5.
The chemical conversion of simvastatin from the lactone (SVL) to the hydroxyacid (SVA) form is becoming an intriguing issue associated with the pharmacological use of SVL. On this matter, recent findings suggest that SVL complexation with cyclodextrins (CDs) may be a useful strategy to affect its aqueous solubility and chemical stability. In this work, a reverse-phase high-performance liquid chromatography (RP-HPLC) method able to selectively identify and quantify SVL and SVA has been set up, validated and applied to follow SVL hydrolysis in the presence of HPβCD. The combination of stability results with simvastatin/HPβCD stability constants achieved from UV-vis measurements and solubility/dissolution studies allowed to get an insight into SVL/HPβCD, SVA/HPβCD and SVL/SVA equilibria taking place in aqueous solution. Results show that in the presence of HPβCD the aqueous SVL/SVA equilibrium is shifted versus the hydroxyacid form. UV-vis results, showing that the lactone and the open-ring form of simvastatin interact with HPβCD in a similar extent, suggest that hydrolysis occurs also on SVL/HPβCD complex, thus supporting a mode of interaction that does not involve the lactone ring. This hypothesis is strengthened by NMR analysis performed on SVA, HPβCD and their inclusion complex, which indicates that the lactone ring is not included in HPβCD hydrophobic cavity. Finally, results suggest that particular attention must be paid to SVL lactonization in aqueous solution when using CD-based formulations and in demonstrating their effective benefit for a specific therapeutic use.
辛伐他汀（simvastatin）从内酯（SVL）向羟基酸（SVA）形式的化学转化正成为与 SVL 药理学用途相关的一个有趣问题。关于这个问题，最近的研究结果表明，SVL 与环糊精（CD）的络合可能是影响其水溶解度和化学稳定性的一种有用策略。在这项工作中，建立了一种能够选择性鉴定和定量 SVL 和 SVA 的反相高效液相色谱（RP-HPLC）方法，并对其进行了验证，用于在 HPβCD 存在下跟踪 SVL 的水解。将稳定性结果与从紫外-可见测量和溶解度/溶解研究获得的辛伐他汀/HPβCD 稳定常数相结合，使我们能够深入了解 SVL/HPβCD、SVA/HPβCD 和 SVL/SVA 在水溶液中发生的平衡。结果表明，在 HPβCD 的存在下，SVL/SVA 水溶液平衡向羟基酸形式转移。紫外-可见结果表明，辛伐他汀的内酯和开环形式与 HPβCD 以相似的程度相互作用，表明水解也发生在 SVL/HPβCD 络合物上，因此支持一种不涉及内酯环的相互作用模式。NMR 分析对 SVA、HPβCD 及其包合物进行的分析进一步证实了这一假设，表明内酯环不包含在 HPβCD 的疏水性空腔中。最后，结果表明，在使用基于 CD 的配方时，以及在证明它们对特定治疗用途的有效益处时，必须特别注意 SVL 在水溶液中的内酯化。
