盐酸地尔硫延迟缓释微丸组合系统释药行为的研究及其数学解析

The release behavior of the combined system of diltiazem hydrochloride delayed-onset sustained-release pellets and modeling by mathematics method

目的将两种不同释药规律的微丸按一定比例组合成多单元系统,制备释药时滞约为5h,平稳释约并维持药物浓度至24 h 的盐酸地尔硫(艹卓)延迟缓释微丸胶囊,针对疾病发作的时辰节律性,实现择时释药.方法用非线性最小二乘法模型嵌合通用程序对两种微丸体外释药速率经时过程进行模型嵌合,得到其速率经时方程,按一定比例进行迭加,对初始阶段释药曲线用零级动力学方程拟合,选取线性系数最大比例作为最佳组合比例;再用模型嵌合通用程序对组合系统体外释药速率经时过程进行最佳模型嵌合,并得到速率经时方程。结果确定两种微丸的最佳组合比例,用模型嵌合程序对释药速率经时曲线进行嵌合,效果较好,得到两种微丸及其组合系统的释药速率经时方程,实测值与模型嵌合得到的理论值较接近,表明组合释药行为可用数学方程理论表征.结论对微丸系统释药行为的数学解析结果说明,组合系统的释药行为是可预测的,能更准确地解析和表征组合系统的体外释药行为。

Aim To prepare the combined system of diltiazem hydrochloride delayed-onset sustained- release pellets in order to make time-specific drug delivery system.The drug can release from the system sustained after a predetermined lag time,and the release behavior can continue till 24 hour after administrating the formulation.According to the concept of chronotherapy,the combined system is useful to improve the pharmacotherapy of cardiovascular diseases.Methods The velocity-time curve of the drug release from the multiple-unit system containing pellets was consistent with the fluctuation curve following time of blood pressure and heart ratio.So the velocity-time curve was selected to describe the release behavior of the combined system.The velocity-time equation describing the release behavior of two kinds of pellets was deduced by non-linear least square model fit.And zero-order kinetics equation was adopted to fit the release behavior of different combinations which were composed of different proportion of two kinds of pellets.The velocity-time equation describing the release behavior of the combinations was deduced by non-linear least square model fit,too.The difference of combinations in velocity-time curves between theoretical value and test value was compared.Results The results showed that the test values were closely approximate to the theoretical values.Therefore,the multiple unit drug delivery system can be described by adding the velocity-time equations of different pellets to calculate the theoretical equations. Conclusion A multiple-unit combined system containing different coated pellets,as a novel delayed- onset sustained-release system,was prepared.Then a time-specific drug delivery system has been made. The programmed drug delivery system could be predicted by adding the velocity-time equation of each kind of pellets to calculate the theoretical equations.The release behavior of pellets system could be characterized by mathematics equation.