Absorption and pharmacokinetic studies of melatonin using polymer-coated drug delivery systems

Sleep disorders affect a large portion of the population. Only in Australia 46% of adults were diagnosed with a sleep disorder in 2016. Among the different treatments, melatonin is a natural and safe option, already sold in a variety of formulations. Despite its large use, the actual benefit of melatonin in aiding the treatment of sleep disorders is not clear due to its variable efficacy in clinical studies. This may be related to another more fundamental aspect that has not been systematically studied, its pharmacokinetics. In this thesis, a systematic review on the relation of melatonin formulations with pharmacokinetics and sleep outcomes was performed, concluding that sublingual and transdermal formulations have the potential to increase melatonin bioavailability. Moreover, for oral administration a combination of fast and controlled release formulations may help in controlling the time necessary for melatonin concentration to reach its maximum in blood, Tmax. Topical and buccal administration routes delay melatonin Cmax in blood. Two melatonin formulations were designed for oral and sublingual administration. In both formulations, melatonin is confined inside mesoporous silica particles. The mesopores were capped using polymers: cellulose acetate phthalate (CAP) for the oral, and poly(ethylene) oxide (PEO) for the sublingual formulation. Dissolution experiments show a delay of melatonin release and a decrease in the rate for the oral formulation in simulated gastric fluid (pH 1.2) and the sublingual formulation in simulated saliva fluid (pH 6.8). In vitro experiments conducted in a Caco-2 cell model mimicking the intestinal barrier suggest that the presence of CAP in the oral formulation slows down the absorption of melatonin through the intestinal barrier and increases its enzymatic degradation via the cytochrome P450 enzymatic 6-hydroxylation route. An in vivo study performed in Sprague Dawley rats using exogenous deuterated melatonin in the formulations, reveals a significant variability in the production of endogenous melatonin among rats and a low bioavailability of exogenous melatonin for all test formulations at 10 mg/kg doses. At these levels there was no significant effect on the melatonin concentration in plasma nor in the brain. Overall, this thesis explores melatonin absorption, enzymatic metabolism and bioavailability. These results will contribute to better dosing and formulation design for the treatment of sleep disorders.