Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackého tř. 1, 61242, Brno, Czech Republic.
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague 1, Czech Republic.
AAPS PharmSciTech. 2018 Feb;19(2):681-692. doi: 10.1208/s12249-017-0870-6. Epub 2017 Oct 2.
Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/EudragitNE matrices using magnesium aluminometasilicate (Neusilin US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin allowed the application of Eudragit dispersion to API/Neusilin mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150-500 nm) in granules as effect of surfactant present in dispersion in dependence on EudragitNE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.
突释现象通常被认为是一种负面现象，会导致意外的毒性或组织刺激。高度水溶性活性药物成分（API）从羟丙甲纤维素（HPMC）基质中最佳释放是技术上不可能的；因此，需要聚合物的组合来减少突释效应。在 HPMC 和不溶性 Eudragits 作为水分散体的组合中可以看到有希望的变体。这些只能应用于 API/不溶性填充剂混合物上，以防止过度润湿。主要障碍是填充剂的吸水率（WAC）有限。因此，本研究的目的是研究使用具有优异 WAC 的镁铝硅酸盐（Neusilin US2）作为填充剂的 HPMC/EudragitNE 基质中左乙拉西坦的溶解行为。本研究的一部分还评估了热处理对基质质量参数的影响。使用 Neusilin 允许在高剪切湿法制粒过程中将 Eudragit 分散体一步应用于 API/Neusilin 混合物。HPMC 是额外添加到颗粒外的。对所得基质进行定性特性、NMR 固态光谱（ssNMR）、凝胶层动态参数、SEM 和主成分分析（PCA）研究。随着 Eudragit NE 浓度的增加，突释效应（最大 33.6%）和溶解速率降低，拟合至零级动力学增加，凝胶层厚度的反常降低。ssNMR 清楚地表明，在颗粒中，由于分散体中存在的表面活性剂，API 粒径（150-500nm）显著减小，这是解释突释效应降低的原因，并且与 EudragitNE 的量有关。API 粒径的这种变化导致这两个实体之间的界面显著增大。基于方差分析和 PCA，热处理未被发现是该系统有用的程序。
