EVALUATION OF AN ORAL PULSATILE DELIVERY SYSTEM FOR MELATONIN IN HUMANS

Using melatonin (MT) as a circadian synchroniser in humans to treat a variety of rhythm disorders, it is desirable to develop controlled-rel ease dosage forms that deliver MT in accordance with its endogenous se cretory pattern as well as preparations that release MT in a pulsatile way. In this paper we describe two oral pulsatile dosage forms contai ning 10 mg MT each (capsules B and C) and a fast-release form containi ng 5 mg MT (capsule A) studied in a randomised, single-dose, threefold cross-over study in 15 healthy male volunteers. The concentrations of both MT in serum and its main metabolite 6-sulfatoxymelatonin (aMT6s) in urine were analysed by means of specific radioimmunoassays up to 1 0 h p.a. of the MT preparations Mean peak concentrations of MT in seru m were reached between 0.5 h and 0.75 h (C-max[1] pmol/ml): 20.7 (A), 16.4 (B), 9.7 (C). The capsules B and C released a second MT pulse aft er about 3.5 h with C-max[2] of 13.0 and 17.5 pmol/ml, respectively. D ose proportionality for the MT preparations studied was calculated by determining the AUC(0-infinity) (pmol/ml.h): 18.4 (A), 36.1 (B), 42.4 (C). The terminal serum half-lives of MT ranged between 0.64 and 0.84 h. The time course of the renally excreted aMT6s correlated with that of changes in MT serum concentrations.