Huang Jingjun, Wigent Rodney J, Bentzley Catherine M, Schwartz Joseph B
Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 S 43rd Street, Philadelphia, PA 19104, USA.
Int J Pharm. 2006 Aug 17;319(1-2):44-54. doi: 10.1016/j.ijpharm.2006.03.035. Epub 2006 Apr 25.
In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.
为阐明通过相分离法制备的甲基丙烯酸铵共聚物和乙基纤维素二元共混物微粒中难溶性药物的控释机制，通过粉体学性质、药物物理状态、基质内部结构、药物溶出及释放模型对不同载药量的硝苯地平载药微粒进行了评价。药物释放研究表明，硝苯地平从微粒中的释放遵循菲克扩散机制，这支持了研究假设，即由于硝苯地平分子分散体的形成，基质内硝苯地平的溶解不再是药物释放的限速步骤，而药物在基质中的扩散反而成为最慢的步骤。此外，研究结果表明，尽管载药量对微粒的粒径分布和形态没有显著影响，但这些微粒中硝苯地平的释放速率或多或少受载药量水平的影响，这取决于基质配方。在较低载药量水平下，贝克和朗斯代尔的含溶解药物微球基质扩散模型能很好地描述硝苯地平的释放，且硝苯地平对聚合物具有增塑作用，导致药物有效扩散系数随载药量增加而增大。然而，在较高载药量水平下，可能由于微粒中形成了固体硝苯地平区域，观察到释放动力学发生了变化。
