New dosage form for pulsatile delivery of melatonin: Development and testing in animal and human subjects

Abstract

In the use of melatonin as a arcadian synchronizer in humans to treat a variety of rhythm disorders, it is desirable to develop controlled-release dosage forms that deliver melatonin in accordance with its endogenous secretory pattern, as well as preparations that release melatonin in a pulsatile manner. This paper describes the study of a new particulate dosage form for pulsatile delivery of melatonin (capsules B and C containing 10 mg each) in comparison with a fast-release form (capsule A containing 5 mg). The in vitro dissolution pattern of the dosage forms was characterized and completed by in vivo studies in dogs and male volunteers. Following oral administration of the melatonin preparations, the concentrations of both melatonin in serum (dogs and humans) and its main metabolite 6-sulfatoxymelatonin (aMEL6s) in urine (humans) were analyzed by means of specific radioimmunoassays. The following mean peak concentrations of melatonin in human serum were reached at 0.5–0.75 h (Cmax1pmol/ml): 20.7(A), 16.4 (B) and 9.1 (C). Capsules B and C released a second melatonin pulse after about 3.5 h, with Cmax2 of 13.0 and 17.5 pmol/ml, respectively. Dose proportionality for the melatonin preparations studied was calculated by determining the area under the curve (AUC0-10h) (pmol/ml, h): 18.4 (A), 36.1 (B) and 42.4 (C). The terminal serum half-lives of melatonin in male subjects ranged between 0.64 and 0.84 h. The time course of the renally excreted aMEL6s correlated with that of the respective melatonin serum concentrations.