Pharmacokinetics of a Sustained-Release Dosage Form of Isosorbide Dinitrate (Frandol®)

Abstract

A sustained-release dosage form of isosorbide dinitrate (Frandol®) has been developed for the purpose of prolonging the preventive effect of isosorbide dinitrate (ISDN) against attacks of angina pectoris.According to the JP IX disintegration test (with slight modification), the dissolution rate of Frandol was slow, with a 50% dissolution time of about 3 hr on the other hand, disintegration of the standard tablet (Nitorol®) was very rapid, almost entirely dissolving within 10 min.After administration of Frandol (20 mg) to six healthy volunteers, the plasma level of ISDN slowly increased to the maximum level at 3 hr and remained at a high level for 6 to 8 hr. However, after administration of the standard tablet (5 mg), the plasma level of ISDN rapidly increased to the maximum level within 30 min, but thereafter decreased rapidly.According to the pharmacokinetic analysis based on a two-compartment open model, the bioavailability of ISDN after dosing of the standerd tablet was about 7%, while the bioavailability of Frandol relative to the standard tablet was 95%.Computer-simulated pharmacokinetic data at the steady-states by repeated administrations of the standard tablet (8 hr interval) and Frandol (12 hr interval) were as follows: the average plasma concentrations of ISDN with the standard tablet and Frandol were 0.93 and 2.56 ng/ml, respectively ; and the minimum plasma concentrations with the standard tablet and Frandol were 0.11 and 1.40 ng/ ml, respectively ; and the maximum plasma concentrations with the standard tablet and Frandol were 5.32 and 3.52 ng/ml, respectively.These results indicated that Frandol may be an ideal sustained-release dosage form of ISDN for the prevention of angina pectoris, since the plasma ISDN level is maintained at a high level constantly without the production of an excessively high plasma level.