Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Drug release and adsorption tendency in the absence and presence of an absorptive sink during dissolution testing

中文翻译：

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吸附，过饱和和吸收性吸收剂的存在对介孔二氧化硅基配方药物释放的相互作用。

目的

难溶性药物的中孔二氧化硅基制剂可能由于药物残留吸附在二氧化硅表面而显示出不完全的药物释放。这项研究的目的是（1）评估阿扎那韦从水溶液到中孔二氧化硅（SBA-15）上的吸附趋势，以及（2）确定是否存在吸收性隔室来促进中孔二氧化硅制剂中的药物释放在溶出度测试中。

方法

通过初始浸渍制备具有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来分析制剂的固态性质。比较了在胃和肠pH值下密闭室与吸收性溶出试验的药物释放情况。

结果

XRD和DSC显示所有制剂都是无定形的。红外光谱表明，SBA-15中的硅烷醇基与阿扎那韦中的羰基之间存在分子间相互作用。通过热分析建议在二氧化硅中孔中纳米限制药物。密闭室溶出度测试显示药物释放不完全，主要是由于ATZ的吸附趋势。然而，耦合的溶出-吸收研究表明在240分钟的时间内可以完全释放。这表明由于药物跨膜扩散而导致的溶出介质中药物的消耗促进了药物的释放。当将制剂首先添加到禁食状态的胃pH条件，然后将pH移至肠道条件时，药物释放得到进一步改善，这归因于阿扎那韦在低pH下的较高溶解度。然而，

结论

这项研究强调吸收吸收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基于介孔二氧化硅的制剂的性能。

溶出度测试中在不存在吸收性吸收池的情况下药物释放和吸附趋势