Hate Siddhi S, Reutzel-Edens Susan M, Taylor Lynne S
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA.
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, 46285, USA.
Pharm Res. 2020 Aug 4;37(8):163. doi: 10.1007/s11095-020-02879-9.
Mesoporous silica-based formulations of poorly soluble drugs may exhibit incomplete drug release due to drug remaining adsorbed on the silica surface. The goal of this study was (1) to evaluate the adsorption tendency of atazanavir from aqueous solution onto mesoporous silica (SBA-15) and (2) to determine if the drug release from mesoporous silica formulations was promoted by the presence of an absorptive compartment during dissolution testing.
Atazanavir (ATZ) formulations with different drug loadings were prepared by incipient impregnation. The solid-state properties of the formulations were analyzed by X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectroscopy and thermogravimetric analysis. Drug release was compared for closed compartment versus absorptive dissolution testing at gastric and intestinal pH.
XRD and DSC showed that all formulations were amorphous. Infrared spectra indicated intermolecular interactions between silanol groups in SBA-15 and carbonyl groups in atazanavir. Nanoconfinement of drug in silica mesopores was suggested by thermal analysis. Closed compartment dissolution testing showed incomplete drug release, largely due to the adsorption tendency of ATZ. However, coupled dissolution-absorption studies showed complete release over a 240 min time period. This suggested that the depletion of drug in the dissolution medium due to drug diffusion across the membrane promotes drug release. Drug release was further improved when the formulation was first added to fasted state gastric pH conditions followed by pH-shift to intestinal conditions, which was attributed to the higher solubility of atazanavir at low pH. However, ATZ mesoporous silica formulations showed a poorer overall absorption behavior relative to a polymer-based amorphous solid dispersion formulation.
This study highlights that absorptive dissolution conditions promote drug desorption from the silica surface and hence, enhance drug release. Further, the influence of solution pH on drug release underscores the need to consider how variations in physiological conditions may impact the performance of mesoporous silica-based formulations. Graphical Abstract Drug release and adsorption tendency in the absence and presence of an absorptive sink during dissolution testing.
由于药物仍吸附在二氧化硅表面，难溶性药物的介孔二氧化硅基制剂可能表现出不完全的药物释放。本研究的目的是：（1）评估阿扎那韦从水溶液到介孔二氧化硅（SBA-15）的吸附倾向；（2）确定在溶出度测试期间，吸收室的存在是否促进了介孔二氧化硅制剂的药物释放。
采用初湿浸渍法制备了不同载药量的阿扎那韦（ATZ）制剂。通过X射线衍射（XRD）、差示扫描量热法（DSC）、红外光谱和热重分析对制剂的固态性质进行了分析。比较了在胃和肠pH值下封闭室与吸收性溶出度测试的药物释放情况。
XRD和DSC表明所有制剂均为无定形。红外光谱表明SBA-15中的硅醇基团与阿扎那韦中的羰基之间存在分子间相互作用。热分析表明药物在二氧化硅介孔中存在纳米限域效应。封闭室溶出度测试显示药物释放不完全，主要是由于ATZ的吸附倾向。然而，耦合溶出-吸收研究表明在240分钟内药物完全释放。这表明由于药物跨膜扩散导致溶出介质中药物的消耗促进了药物释放。当制剂首先添加到空腹状态的胃pH条件下，然后pH值转变为肠条件时，药物释放进一步改善，这归因于阿扎那韦在低pH下的较高溶解度。然而，与基于聚合物的无定形固体分散体制剂相比，ATZ介孔二氧化硅制剂的总体吸收行为较差。
本研究强调吸收性溶出条件促进药物从二氧化硅表面解吸，从而增强药物释放。此外，溶液pH值对药物释放的影响强调了需要考虑生理条件的变化如何影响介孔二氧化硅基制剂的性能。图形摘要：溶出度测试期间在不存在和存在吸收性汇的情况下的药物释放和吸附倾向。
