Siepmann J, Lecomte F, Bodmeier R
College of Pharmacy, Freie Universität Berlin, Kelchstrasse 31, 12169, Berlin, Germany.
J Control Release. 1999 Aug 5;60(2-3):379-89. doi: 10.1016/s0168-3659(99)00093-0.
The aim of this study was to investigate the effect of the composition of diffusion-controlled release devices (type and amount of plasticizer, type of polymer) on the drug diffusivity and the resulting release kinetics in a quantitative way. Diltiazem hydrochloride and theophylline were investigated in ethyl cellulose (EC) and Eudragit((R)) RS 100, plasticized with various amounts of acetyltributyl citrate (ATBC), acetyltriethyl citrate (ATEC), dibutyl phthalate (DBP), dibutyl sebacate (DBS), diethyl phthalate (DEP), and tributyl citrate (TBC). Thin drug-containing films (monolithic solutions) were used to determine the diffusion coefficients experimentally. The effect of the type and amount of plasticizer on the drug diffusivity was found to be significant, whereas the chain length of the polymer only played a minor rule in the investigated systems. Interestingly, a quantitative relationship between the diffusion coefficient of the drug and the plasticizer level could be established. Based on these results, the release kinetics of diffusion-controlled drug delivery systems could be predicted. In this study, the release patterns from microparticles were calculated and the significant effect of the composition of the device on the resulting release rate was simulated. The latter could be effectively modified by varying the type and amount of plasticizer. Independent experiments verified the theoretical predictions. The practical benefit of the presented method is to calculate the required composition of diffusion-controlled drug delivery systems (monolithic solutions) to achieve desired release profiles.
本研究的目的是定量研究扩散控释制剂的组成（增塑剂的类型和用量、聚合物的类型）对药物扩散率及由此产生的释放动力学的影响。以盐酸地尔硫䓬和茶碱为研究对象，采用乙基纤维素（EC）和Eudragit((R)) RS 100作为聚合物，分别用不同量的柠檬酸乙酰三丁酯（ATBC）、柠檬酸乙酰三乙酯（ATEC）、邻苯二甲酸二丁酯（DBP）、癸二酸二丁酯（DBS）、邻苯二甲酸二乙酯（DEP）和柠檬酸三丁酯（TBC）进行增塑。通过含药薄膜（整体溶液）实验测定扩散系数。结果发现，增塑剂的类型和用量对药物扩散率有显著影响，而聚合物的链长在所研究的体系中作用较小。有趣的是，药物扩散系数与增塑剂水平之间可以建立定量关系。基于这些结果，可以预测扩散控释给药系统的释放动力学。在本研究中，计算了微粒的释放模式，并模拟了制剂组成对释放速率的显著影响。通过改变增塑剂的类型和用量可以有效地改变后者。独立实验验证了理论预测。本方法的实际益处在于计算扩散控释给药系统（整体溶液）所需的组成，以实现所需的释放曲线。
