Frohoff-Hülsmann M A, Schmitz A, Lippold B C
Institut für Pharmazeutische Technologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Int J Pharm. 1999 Jan 15;177(1):69-82. doi: 10.1016/s0378-5173(98)00327-5.
The present work investigates release mechanisms of theophylline pellets coated with an aqueous ethyl cellulose (EC) dispersion containing plasticizers and hydroxypropyl methylcellulose (HPMC) as a water soluble pore former. Three different drug release mechanisms from coated pellets can be determined as a function of the water solubility of the plasticizers and the ionic strength of the release medium. Coated pellets with the addition of more hydrophilic plasticizers such as triethyl citrate (TEC) or diethyl phthalate (DEP) show an approximate zero-order-release rate. In contrast, two-phase release profiles can be observed from pellets coated with dispersions containing hardly soluble plasticizers such as dibutyl phthalate (DBP) or dibutyl sebacate (DBS). Only in a release medium of high ionic strength the water soluble pore former will remain in the coating. Thus the drug diffuses through a hydrated swollen membrane containing EC, HPMC and insoluble plasticizer. The release mechanisms depend on the glass transition temperature of the ethyl cellulose and therefore on the migration of the plasticizers and the pore former. This was shown by investigation of the migration of the additives and the influence of the temperature of the release medium on the release. Additionally, the study investigates the effect of curing and storage conditions of coated pellets on the drug release rate.
本研究考察了用含有增塑剂和作为水溶性致孔剂的羟丙基甲基纤维素（HPMC）的乙基纤维素（EC）水分散体包衣的茶碱微丸的释放机制。根据增塑剂的水溶性和释放介质的离子强度，可以确定包衣微丸有三种不同的药物释放机制。添加了更多亲水性增塑剂（如柠檬酸三乙酯（TEC）或邻苯二甲酸二乙酯（DEP））的包衣微丸显示出近似零级释放速率。相比之下，从用含有难溶性增塑剂（如邻苯二甲酸二丁酯（DBP）或癸二酸二丁酯（DBS））的分散体包衣的微丸中可以观察到两相释放曲线。只有在高离子强度的释放介质中，水溶性致孔剂才会保留在包衣中。因此，药物通过含有EC、HPMC和不溶性增塑剂的水合溶胀膜扩散。释放机制取决于乙基纤维素的玻璃化转变温度，因此取决于增塑剂和致孔剂的迁移。通过研究添加剂的迁移以及释放介质温度对释放的影响证明了这一点。此外，该研究还考察了包衣微丸的固化和储存条件对药物释放速率的影响。
