ARC Special Research Centre for Particle and Material Interfaces, Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia.
Mol Pharm. 2010 Apr 5;7(2):522-32. doi: 10.1021/mp9002442.
We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.
我们研究了亲水性气相法二氧化硅在控制脂质乳液消化动力学中的作用，从而进一步探讨了硅脂质杂化（SLH）微胶囊促进难溶性药物口服吸收的机制。采用体外脂肪酶解模型来量化一系列含有辛酸/癸酸三酸甘油酯的脂质载体的脂肪酶介导的消化动力学：脂质溶液、亚微米级脂质乳液（存在和不存在二氧化硅）以及 SLH 微胶囊。SLH 微胶囊和脂质乳液（比脂质溶液高 15 倍以上）具有显著更高的初始消化速率常数，这证明了乳化对脂质消化性的重要性。无论二氧化硅颗粒最初位于水相还是油相，它们都会对亚微米级脂质乳液的消化产生抑制作用。然而，对于 SLH 微胶囊，并未观察到这种抑制作用。这突出了与由二氧化硅稳定的亚微米级脂质乳液相比，混合微胶囊系统的基质结构和多孔性对增强脂质消化性的重要性。对于每种研究的制剂，通过多点相关性（R(2)＞0.97），消化动力学与模型药物塞来昔布的相应体内血浆浓度很好地相关。这支持使用脂质消化模型来预测口服给予脂质制剂的体内结果。SLH 微胶囊通过提高脂质消化性和改善药物溶解/分散性，为增强难溶性药物的口服吸收提供了潜力。
