TRANSMUCOSAL, ORAL CONTROLLED-RELEASE, AND TRANSDERMAL DRUG ADMINISTRATION IN HUMAN-SUBJECTS - A CROSSOVER STUDY WITH MELATONIN

The effect of oral controlled-release (CR), oral transmucosal (buccal; TMD) and transdermal (TDD) drug delivery systems on plasma concentrat ions of melatonin (MT) and its principal metabolite in human subjects using a crossover, single dose design was evaluated. Twelve adult male volunteers participated in the study and received all three dosage fo rms on three separate occasions. All patch dosage forms were removed a fter 10 h of wear. Plasma concentrations of the parent drug and its me tabolite, 6-sulfatoxymelatonin (MT6s) were measured by radioimmunoassa y. Between-subject plasma concentrations of MT were very variable foll owing both oral CR and TDD. Use of the oral CR system gave plasma MT p rofiles in some subjects that were initially similar to physiological levels, but then differed substantially from physiological in the rate of MT offset; in a few subjects, plasma MT levels remained consistent ly much below normal nocturnal physiological levels. Also, the ratio o f metabolite to parent drug by the oral CR route was many times greate r than physiological. TDD resulted in a significant delay in systemic drug levels and a gradual decline in drug delivery after patch removal , possibly due to deposition of melatonin in the skin. TDD failed to s imulate the physiological plasma profile of MT (rapid achievement of s teady-state blood levels and rapid decline after removal of the patch; i.e., so-called ''square-wave'' profile). TMD provided prompt systemi c drug levels with less variability than oral CR or TDD delivery. Also , plasma MT levels fell promptly and rapidly after removal of the patc h. No indication of mucosal deposition was observed. TMD was able to m imic the physiological plasma profiles of both MT and its principal me tabolite.