溶胀型脉冲释药系统的包衣受力分析和有限元爆破模拟

Coating burst would significantly affect the performance of swelling pulsatile drug delivery system and should be strictly controlled. Up to now, investigation about coating burst mainly focused on the influence of amount and composition on the lag time. However, little studies on stress analysis and burst simulation of coating have been reported. The aim of this study is to simulate and evaluate the coating burst behavior by finite element method based on engineering mechanics principle. In this study, three-dimensional finite element mesh models will be developed. The simulated stress distribution will be used to predict the coating burst parameters, assess the quantitative relationship and investigate the coating burst mechanism. Tablets-coating burst have been simulated and evaluated in our preliminary study. The results suggested that both the internal swelling behavior and the coating mesh models had significant effect on the accuracy of simulation. In this study, an improved method with higher precision and wider application for swelling pressure determination will be established. Water absorption will be determined to calculate the time-swelling pressure curve. Moreover, to improve the simulation, dimensions of coatings will be determined by projection and micro-examination; and the expansion coefficient and mechanical properties of film under the medium will be investigated. The result of this study could be used to optimize formulations either to obtain a desired burst lag time for pulsatile delivery systems or to estimate the coating level necessary to obtain integrity tablets. It could also provide a better understanding into the mechanism of coating burst.

定量分析和精密控制“包衣爆破行为”是溶胀型脉冲释药系统开发和应用的关键。现有研究主要通过测定释药时滞，间接评价“包衣爆破行为”，只针对具体品种，仅限于影响因素考察。本课题拟借鉴工程力学原理和有限元方法，对“包衣爆破行为”进行直接评价：建立包衣爆破模型、研究爆破行为定量关系和分析包衣爆破可能机理。本课题组通过模拟脉冲片的包衣爆破行为发现，提高模拟效果，开展定量分析的关键在于：1）提高内芯溶胀行为测定的准确度和精度；2）增强包衣模型的仿真程度。因此，本课题拟对自制溶胀压测定装置和方法进行优化，研究溶胀行为规律，通过测定吸水量计算溶胀压经时曲线，从而提高检测准确度和精度，扩大应用范围。此外，本课题拟将投影和显微观察相结合，精确测定包衣三维大小，考查包衣在释放介质中的膨胀性和力学性，提高模型的仿真程度。本课题的结果将揭示“包衣爆破”的普遍规律，可为溶胀型脉冲制剂的处方工艺设计提供理论指导。

严格控制包衣爆破过程，探索包衣爆破的普通性规律是爆破型脉冲释药系统开发的应用的关键。本研究采用有限元方法模拟和评价包衣片、包衣胶囊和包衣微丸的爆破行为。通过精确测定包衣内表面载荷，精确模拟包衣在释放介质中的形态和力学属性，建立仿真几何模型和精细网格模型，大大提高了爆破模拟的准确性和预测的有效性。基于最大应力准则所预测的爆破行为和爆破位置与实验结果基本吻合。. 本研究对爆破时滞、爆破压、最小包衣厚度和临界膨胀剂用量等参数都进行了定量关系研究。建立了爆破时滞/包衣增重；爆破时滞/临界膨胀剂用量/膜厚的相关方程，预测结果有较好的准确性。可为膜控制剂处方工艺研究和安全性评价提供理论基础。优化的美托洛尔和硝苯地平脉冲包衣释药系统时滞均在5h-7h之间。. 本研究还对包衣爆破的机理进行了研究。揭示了包衣爆破的原因在于内部膨胀压引起衣膜变形，形成内部较高的抗张应力。脆性包衣的爆破遵循“最大应力准则”，当包衣单元的最大主应力大于材料的抗张强度时，衣膜会发生脆性断裂，内容物从大裂口快速倾泻，药物脉冲释放。. 本研究揭示了包衣爆破的普遍规律和爆破机理，不仅能用于指导处方优化设计，实现脉冲释药体系的定时爆破；也能用于计算最小包衣厚度和最大膨胀剂用量，保障肠溶或缓释包衣的完整性。在本研究基础上设计专家系统，可指导一系列药物的膜控释药系统开发。