Isosorbide-5-nitrate sustained-release pellets - an example of computer-supported drug development.

To achieve a fast onset and a sufficiently long duration of action in the long-term treatment of angina pectoris a composite dosage form was developed, consisting of a fast-release initial dose Di and a slow-release maintenance dose Dm. The product is designed to be given once daily in the morning to achieve sufficiently high blood levels for clinical response during day-time with declining blood levels during night-time to avoid tolerance. In view of its pharmacokinetic properties, the antianginal drug isosorbide-5-nitrate (IS-5-N) was selected as the model substance. To minimize the influence of physiological factors such as GI-transit time and pH on the in vivo releasing properties, pellets with a membrane-controlled drug release appeared to be suitable. To investigate the in vitro/in vivo correlations, three variants of of this dosage form, differing in the Di:Dm ratio and in the duration of the drug release, were prepared. The pharmacokinetics of these variants were tested in man, and their in vitro dissolution behaviour was characterized by their mean dissolution times (TDiss). The in vivo performance was characterized by the mean residence time (MRT), the bioavailability (ba) relative to standard tablets, and the in vivo absorption rate by the method of Wagner and Nelson. The linear correlation coefficients were: ba vs. MRT, r = - 0.845, p < 0.01; MRT vs. TDiss, r = 0.949, p < 0.001, and ba vs. TDiss, r = - 0.886, p < 0.05. With the known pharmakokinetic and dissolution parameters, a prediction of the time course of the plasma level was attempted.