Gido C, Langguth P, Mutschler E
Department of Pharmacology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
Pharm Res. 1994 Jun;11(6):800-8. doi: 10.1023/a:1018913321164.
A flow through dissolution system was applied to obtain biorelevant dissolution rates from controlled release systems for parenteral administration using the antidepressant doxepin as a model compound. Plasma concentrations were simulated using the disposition function of doxepin obtained from administration of an aqueous doxepin solution (AponalR) to beagle dogs. Input functions were obtained from in vitro dissolution experiments with three parenteral controlled release suspensions of doxepin hydrochloride (DHCl), doxepin pamoate (DP-1), and microspheres of doxepin hydrochloride in poly D,L-lactid-co-glycolid (MC-1) in isopropyl myristate. The predicted plasma concentrations were compared with experimentally obtained concentrations in vivo. Good correlations (r > 0.88) between observed and predicted data were obtained for all formulations investigated. Similarly, in vivo release kinetics calculated by the Loo-Riegelman method were compard with release kinetics measured in vitro and showed good correlations (r > 0.89). It is anticipated that the in vitro dissolution system permits assessment of the clinical relevance of observed variations in dissolution rates e.g. between batches of one formulation.
采用流通式溶解系统，以抗抑郁药多塞平作为模型化合物，从用于肠胃外给药的控释系统中获取生物相关溶解速率。利用给比格犬静脉注射多塞平水溶液（阿普诺尔R）后得到的多塞平处置函数来模拟血浆浓度。输入函数通过在肉豆蔻酸异丙酯中对三种肠胃外控释悬浮液进行体外溶解实验获得，这三种悬浮液分别为盐酸多塞平（DHCl）、双羟萘酸多塞平（DP - 1）以及聚D，L - 丙交酯 - 乙交酯中的盐酸多塞平微球（MC - 1）。将预测的血浆浓度与体内实验获得的浓度进行比较。对于所有研究的制剂，观察到的数据与预测数据之间均具有良好的相关性（r > 0.88）。同样，通过Loo - Riegelman方法计算的体内释放动力学与体外测量的释放动力学进行比较，显示出良好的相关性（r > 0.89）。预计体外溶解系统能够评估观察到的溶解速率变化（例如同一制剂不同批次之间）的临床相关性。
