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-release dosage forms that deliver MT in accordance with its endogenous secretory pattern as well as preparations that release MT in a pulsatile way. In this paper we describe two oral pulsatile dosage forms containing 10 mg MT each (capsules B and C) and a fast-release form containing 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 10 h p.a. of the MT preparations. Mean peak concentrations of MT in serum were reached between 0.5 h and 0.75 h (Cmax[1] pmol/ml): 20.7 (A), 16.4 (B), 9.7 (C). The capsules B and C released a second MT pulse after about 3.5 h with Cmax[2] of 13.0 and 17.5 pmol/ml, respectively. Dose proportionality for the MT preparations studied was calculated by determining the AUC0-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.
Jenapharm GmbH & Co KG, Friedrich-Schiller-Universität, Jena, Germany.
H
H
Hoffmann
M
M
Dittgen
A
A
Hoffmann
C
C
Bartsch
H
H
Breitbarth
C
C
Timpe
K
K
Farker
U
U
Schmidt
U
U
Mellinger
H
H
Zimmermann
T
T
Gräser
M
M
Oettel
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D006207:Half-Life; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D003692:Delayed-Action Preparations; D008550:Melatonin