Université Paris-Sud XI, UMR CNRS 8612, 5 rue JB Clément, 92290 Châtenay Malabry, France.
J Control Release. 2012 Mar 28;158(3):393-402. doi: 10.1016/j.jconrel.2011.11.027. Epub 2011 Nov 29.
This study deals with the development of an oral controlled-release dosage form of a highly water-soluble antiepileptic drug. In this respect, drug-loaded spheroid particles close to 380 μm in diameter and composed of lipid binders were prepared by prilling. The purpose here was to thoroughly characterize the controlled-release mechanism of the drug in aqueous pH-6.8 buffered dissolution medium. Water and drug diffusion pathways as well as related kinetic parameters were determined by theoretical analysis of experimental data. Conventional in-vitro experiments performed by analytical high performance liquid chromatography showed that the released fraction reaches 90 wt.% only after a 24-hour immersion in the dissolution medium, pointing out an effective sustained release mechanism. Interpretation of these data was strengthened by the implementation of an innovative methodology involving X-ray diffraction and microtomography to follow the structural evolution of the drug-loaded microspheres at molecular and microscopic scales. This approach allowed to explicit that water and drug transports obey to Fickian diffusion behaviours in good agreement with Crank's and non-simplified Higuchi's equations, respectively. In the latter case, independent modelling of drug release assimilating the microspheres to a variable-geometry reservoir was considered to refine the kinetic analysis of the diffusion process. The water diffusion coefficient D(w) was found equal to 6.3 × 10(-9) cm(2)/s and the API apparent diffusion coefficient reduced to the tortuosity of the matrix D(API)/τ equal to 2 × 10(-9) cm(2)/s. This study ranks among the rare examples of monolithic dispersion device constituted by a highly soluble drug incorporated inside a perfectly inert lipid matrix. The dissolution liquid penetrates the particles through channels progressively created by the solubilization of the drug itself which occurs instantaneously at the inner front of the liquid.
本研究致力于开发一种高水溶性抗癫痫药物的口服控释剂型。在这方面，通过造粒制备了接近 380 μm 直径的载药球型粒子，由脂质结合剂组成。目的是彻底表征药物在水性 pH-6.8 缓冲溶解介质中的控释机制。通过对实验数据的理论分析，确定了水和药物扩散途径以及相关的动力学参数。通过分析高效液相色谱的常规体外实验表明，在溶解介质中浸泡 24 小时后，仅释放出 90wt.%的药物，表明存在有效的持续释放机制。通过实施涉及 X 射线衍射和微断层扫描的创新方法来跟踪载药微球在分子和微观尺度上的结构演变，对这些数据的解释得到了加强。这种方法明确表明，水和药物的传输符合菲克扩散行为，与 Crank 和非简化 Higuchi 方程分别一致。在后一种情况下，将药物释放的独立建模模拟为一个可变几何储库，以细化扩散过程的动力学分析。发现水扩散系数 D(w)等于 6.3 × 10(-9)cm(2)/s，API 表观扩散系数降低到基质的迂曲度 D(API)/τ等于 2 × 10(-9)cm(2)/s。本研究属于由高度可溶药物掺入完全惰性脂质基质中的单体分散装置的罕见实例之一。溶解液通过由药物自身溶解逐渐形成的通道渗透到颗粒中，这种溶解在液体的内部前沿瞬间发生。
