DESIGN AND EVALUATION OF AN ORAL CONTROLLED-RELEASE DELIVERY SYSTEM FOR MELATONIN IN HUMAN-SUBJECTS

Six human subjects were given an oral formulation designed to provide an immediate and controlled release of melatonin (MT). The controlled release formulation consisted of MT-loaded sugar beads coated with 20% Aquacoat(R). A computer simulation program (MAXSIM(R)) was used to es timate the MT dose and ratio of immediate and controlled release MT ba sed on average population pharmacokinetics of MT. When 0.5 mg of MT (i mmediate release portion of MT, 0.1 mg) was administered to four subje cts, average peak plasma MT concentration was reached at about 600 pg/ ml and maintained at about 100 pg/ml over 8 h. Observed peak plasma MT concentrations were 3-times greater than predicted by simulation. The se results suggest that the MT dose, ratio of immediate release MT to controlled release MT, and the controlled release dosage form must all be considered in order to closely mimic the endogenous plasma MT conc entration-time curve. Deconvolution and pharmacokinetic analysis sugge sted that less than 20% of the orally administered controlled release MT dose reached the systemic circulation from time 0 to 8 h. A good co rrelation was observed between plasma MT concentration and urinary exc retion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of M T. As plasma MT concentration increased, the urinary excretion rate of 6-STMT increased concomitantly. This suggests that the urinary excret ion rate of 6-STMT may be used as an index of human plasma MT concentr ation.