Karavas Evangelos, Ktistis Georgios, Xenakis Aristotelis, Georgarakis Emmanouel
Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Eur J Pharm Biopharm. 2006 Jun;63(2):103-14. doi: 10.1016/j.ejpb.2006.01.016. Epub 2006 May 3.
Solid dispersion systems are widely investigated for the dissolution enhancement of poorly water soluble drugs. Nevertheless, very limited commercial use has been achieved due to the poor predictability of such systems caused by the lack of a basic understanding of the dissolution optimization mechanism. In the present study an investigation of the release mechanism is performed for solid dispersion systems composed by polyvinylpyrrolidone (PVP) and felodipine (FEL), based on a correlation of their hydrophilicity with the intensity of interactions. The existing interactions were evaluated by using NMR and UV spectroscopy while molecular simulation techniques were also enabled. It was found that the interactions that take place correspond to the creation of hydrogen bonds. The correlation between the intensity of interactions and the concentration of PVP in the matrix showed a sigmoid function. The interactions are impressively increased for polymer concentration exceeding 75% (w/w). This phenomenon was well explained by using the molecular simulation technique. A similar sigmoid pattern was found for the function between dissolution profiles and polymer concentration in the matrix, indicating that the intensity of interactions promotes the dissolution enhancement. Investigation of the solubility and the particle size distribution of FEL in the binary system appeared to have similar behaviour indicating that the interactions affect the release profile through these two factors. The hydrophilicity of PVP does not significantly affect this enhancement as the contact angle was found to be linear to PVP concentration. Microscopic observation of the dissolution behaviour showed that FEL remains in fine dispersion in aqueous solution, verifying the release mechanism.
固体分散体系统因能提高难溶性药物的溶出度而得到广泛研究。然而，由于对溶出优化机制缺乏基本了解，这类系统的可预测性较差，因此商业应用非常有限。在本研究中，基于聚乙烯吡咯烷酮（PVP）和非洛地平（FEL）的亲水性与相互作用强度的相关性，对由它们组成的固体分散体系统的释放机制进行了研究。通过核磁共振（NMR）和紫外光谱（UV）评估了现有的相互作用，同时也采用了分子模拟技术。结果发现，发生的相互作用对应于氢键的形成。相互作用强度与基质中PVP浓度之间的相关性呈现出S形函数。当聚合物浓度超过75%（w/w）时，相互作用显著增强。利用分子模拟技术很好地解释了这一现象。在溶出曲线与基质中聚合物浓度之间的函数关系中也发现了类似的S形模式，表明相互作用强度促进了溶出度的提高。对二元体系中非洛地平的溶解度和粒径分布的研究似乎也有类似的行为，表明相互作用通过这两个因素影响释放曲线。由于发现接触角与PVP浓度呈线性关系，PVP的亲水性对这种增强作用没有显著影响。对溶出行为的微观观察表明，非洛地平在水溶液中保持良好的分散状态，验证了释放机制。
