Cordeiro Teresa, Matos Inês, Danède Florence, Sotomayor João C, Fonseca Isabel M, Corvo Marta C, Dionísio Madalena, Viciosa María Teresa, Affouard Frédéric, Correia Natália T
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal.
Univ. Lille, CNRS, INRAE, Centrale Lille, UMR 8207 - UMET - Unité Matériaux et Transformations, F-59000 Lille, France.
Pharmaceutics. 2023 Apr 22;15(5):1320. doi: 10.3390/pharmaceutics15051320.
A rational design of drug delivery systems requires in-depth knowledge not only of the drug itself, in terms of physical state and molecular mobility, but also of how it is distributed among a carrier and its interactions with the host matrix. In this context, this work reports the behavior of simvastatin (SIM) loaded in mesoporous silica MCM-41 matrix (average pore diameter ~3.5 nm) accessed by a set of experimental techniques, evidencing that it exists in an amorphous state (X-ray diffraction, ssNMR, ATR-FTIR, and DSC). The most significant fraction of SIM molecules corresponds to a high thermal resistant population, as shown by thermogravimetry, and which interacts strongly with the MCM silanol groups, as revealed by ATR-FTIR analysis. These findings are supported by Molecular Dynamics (MD) simulations predicting that SIM molecules anchor to the inner pore wall through multiple hydrogen bonds. This anchored molecular fraction lacks a calorimetric and dielectric signature corresponding to a dynamically rigid population. Furthermore, differential scanning calorimetry showed a weak glass transition that is shifted to lower temperatures compared to bulk amorphous SIM. This accelerated molecular population is coherent with an in-pore fraction of molecules distinct from bulklike SIM, as highlighted by MD simulations. MCM-41 loading proved to be a suitable strategy for a long-term stabilization (at least three years) of simvastatin in the amorphous form, whose unanchored population releases at a much higher rate compared to the crystalline drug dissolution. Oppositely, the surface-attached molecules are kept entrapped inside pores even after long-term release assays.
药物递送系统的合理设计不仅需要深入了解药物本身的物理状态和分子流动性，还需要了解其在载体中的分布情况以及与宿主基质的相互作用。在此背景下，本工作报道了通过一系列实验技术研究辛伐他汀（SIM）负载于介孔二氧化硅MCM - 41基质（平均孔径约3.5 nm）中的行为，证明其以非晶态存在（X射线衍射、固体核磁共振、衰减全反射傅里叶变换红外光谱和差示扫描量热法）。热重分析表明，SIM分子中最主要的部分对应于高热稳定性群体，衰减全反射傅里叶变换红外光谱分析显示其与MCM硅醇基团强烈相互作用。分子动力学（MD）模拟预测SIM分子通过多个氢键锚定在内孔壁上，支持了这些发现。这种锚定的分子部分缺乏对应于动态刚性群体的量热和介电特征。此外，差示扫描量热法显示出较弱的玻璃化转变，与块状非晶态SIM相比，其转变温度向低温偏移。如MD模拟所强调的，这种加速的分子群体与不同于块状SIM的孔内分子部分一致。事实证明，MCM - 41负载是将辛伐他汀长期稳定在非晶态（至少三年）的合适策略，其未锚定的群体释放速率比结晶药物溶解速率高得多。相反，即使经过长期释放试验，表面附着的分子仍被困在孔内。
