Frank Kerstin J, Westedt Ulrich, Rosenblatt Karin M, Hölig Peter, Rosenberg Jörg, Mägerlein Markus, Fricker Gert, Brandl Martin
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, DK-5230, Denmark; Department of Pharmaceutical Technology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, D-69120, Germany.
J Pharm Sci. 2014 Jun;103(6):1779-86. doi: 10.1002/jps.23979. Epub 2014 Apr 24.
Our aim was to explore the influence of micelles and microparticles emerging in aqueous dispersions of amorphous solid dispersions (ASDs) on molecular/apparent solubility and Caco-2 permeation. The ASD, prepared by hot-melt extrusion, contained the poorly soluble model drug ABT-102, a hydrophilic polymer, and three surfactants. Aqueous dispersions of the ASD were investigated at two concentrations, one above and one close to the critical micelle concentration of the surfactants blend in the extrudate. Micelles were detected at the higher concentration and no micelles at the lower concentration. Apparent solubility of ABT-102 was 20-fold higher in concentrated than in diluted dispersions, because of micelles. In contrast, Caco-2 permeation of ABT-102 was independent of the ASD concentration, but three times faster than that of crystalline suspensions. Molecular solubility of ABT-102 (equilibrium dialysis) was also independent of the ASD concentration, but by a factor 2 higher than crystalline ABT-102. The total amount of ABT-102 accumulated in the acceptor during Caco-2 experiments exceeded the initial amount of molecularly dissolved drug in the donor. This may indicate that dissolution of amorphous microparticles present in aqueous dispersions induces lasting supersaturation maintaining enhanced permeation. The hypothesis is supported by a slower drug permeation when the microparticles were removed.
我们的目的是探究无定形固体分散体（ASD）水分散体中出现的胶束和微粒对分子/表观溶解度及Caco-2细胞渗透的影响。通过热熔挤出法制备的ASD包含难溶性模型药物ABT-102、一种亲水性聚合物和三种表面活性剂。对ASD的水分散体在两种浓度下进行了研究，一种高于挤出物中表面活性剂混合物的临界胶束浓度，另一种接近该浓度。在较高浓度下检测到了胶束，而在较低浓度下未检测到胶束。由于胶束的存在，ABT-102在浓缩分散体中的表观溶解度比在稀释分散体中高20倍。相比之下，ABT-102的Caco-2细胞渗透与ASD浓度无关，但比结晶悬浮液快三倍。ABT-102的分子溶解度（平衡透析法）也与ASD浓度无关，但比结晶态ABT-102高2倍。在Caco-2细胞实验中，受体中积累的ABT-102总量超过了供体中分子溶解药物的初始量。这可能表明水分散体中存在的无定形微粒的溶解会诱导持久的过饱和状态，从而维持增强的渗透。当微粒被去除时药物渗透变慢，这一假设得到了支持。
