Center for Drug Delivery Systems, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Mater Sci Eng C Mater Biol Appl. 2020 Nov;116:111137. doi: 10.1016/j.msec.2020.111137. Epub 2020 May 30.
Hydrophilic matrix tablets are the most commonly used dosage forms to fabricate oral controlled-release systems. It is highly desirable to design delivery system with novel mechanism to achieve sustained drug release through a simplified preparation process. The chitosan-anionic polymers based matrix tablets is assumed to produce self-assembly in the gastrointestinal tract, then transferring into film-coated tablets from original matrix type. But its dynamic behavior during dissolution process and the on-going internal microstructural changes during drug release were still in the dark. In this study, by using synchrotron radiation X-ray micro-tomography (SR-μCT) with phase contrast imaging, the micro-structure characteristics of chitosan-λ-carrageenan (CS-λ-CG) matrix based tablets during the dissolution were successfully elucidated for the first time. The qualitative and quantitative analyses of intensity distribution distinguished a hydrated CS-λ-CG layer from a solid core. Visualization based on 3D models provided quantitative details on the micro-structural characteristics of hydration dynamics. After CS-λ-CG matrix tablets were immersed in simulated gastric fluid (SGF) pH 1.2 medium for 0.5-2.0 h, the hydrated layer transformed into a gel layer and a solid swollen layer. The erosion front, swelling front, and solvent penetration front were also defined from the distinguishable micro-structures. More importantly, once the matrix tablet was transferred from SGF to the simulated intestinal fluid (SIF) pH 6.8 medium, a new layer with the enhanced strength and compactness in comparison to common gels was formed on the surface of tablets. The temporal and spatial variation of 3D models further provided direct evidence for this cross-linking behavior, the new layer was composed of CS-λ-CG polyelectrolyte complexes (PEC) which subsequently dominated release mechanisms. In summary, the phase contrast SR-μCT technique was utilized to investigate the hydration dynamics of CS-λ-CG matrix tablets which was supposed to provide a novel drug release mechanism. Based on the structure feature obtained from the high contrast image, different hydration region was distinguished and the cross-linked film was identified and visualized directly for the first time.
水凝胶基质片是最常用于制备口服控释系统的剂型。通过简化制备工艺，设计具有新颖机制的给药系统以实现药物持续释放是非常理想的。基于壳聚糖-阴离子聚合物的基质片被认为在胃肠道中产生自组装，然后从原始基质类型转变为薄膜包衣片。但其在溶解过程中的动态行为以及在药物释放过程中持续的内部微观结构变化仍不清楚。在这项研究中，首次使用同步辐射 X 射线微断层扫描（SR-μCT）和相衬成像，成功地阐明了壳聚糖-λ-卡拉胶（CS-λ-CG）基质片在溶解过程中的微观结构特征。强度分布的定性和定量分析将水合 CS-λ-CG 层与固体芯区分开来。基于 3D 模型的可视化提供了关于水合动力学微观结构特征的定量细节。CS-λ-CG 基质片浸入模拟胃液（SGF）pH 1.2 介质 0.5-2.0 h 后，水合层转变为凝胶层和固体溶胀层。还从可区分的微观结构定义了侵蚀前沿、溶胀前沿和溶剂渗透前沿。更重要的是，一旦基质片从 SGF 转移到模拟肠液（SIF）pH 6.8 介质中，片剂表面就会形成一层新的具有增强强度和致密性的层。3D 模型的时变和空间变进一步为这种交联行为提供了直接证据，新层由 CS-λ-CG 聚电解质复合物（PEC）组成，随后主导了释放机制。总之，利用相衬 SR-μCT 技术研究了 CS-λ-CG 基质片的水合动力学，这可能为提供一种新的药物释放机制。基于高对比度图像获得的结构特征，区分了不同的水合区域，并首次直接识别和可视化交联膜。
