Purpose

The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance.

Methods

ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies.

Results

HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD.

Conclusions

In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.

中文翻译：

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基于过饱和动力学和影响制剂性能的分子相互作用，表征伊曲康唑HPMCAS喷雾干燥分散体的等级。

目的

目的是表征羟丙基甲基纤维素乙酸琥珀酸酯（HMPCAS）的L，M和H级，以提高伊曲康唑（ITZ）从喷雾干燥分散液（SDD）中的释放和渗透，并研究支持ITZ-HPMCAS相互作用的分子，这些相互作用可区分级性能。

方法

对ITZ或其SDD进行了溶液稳定性评估，一维质子核磁共振（NMR）光谱，饱和转移差NMR研究，小体积溶解，固态转化研究以及体外溶解/渗透通量研究。

结果

HPMCAS-L是整体性能最好的等级，并且表现出最大的ITZ过饱和浓度，小体积溶解度和体外溶解/渗透通量。同时，在溶液稳定性研究中，H级最大程度地抑制了ITZ沉淀，而在NMR研究中，H级与ITZ表现出更大的疏水相互作用。然而，通过药物-聚合物之间的疏水相互作用获得的H级的明显优势似乎限制了SDD的总体溶解/渗透性能。

结论

体外SDD研究和药物-聚合物相互作用研究提供了对HPMCAS等级性能的了解，以及聚合物可以促进ITZ从SDD吸收的各种机理的相对贡献。