Jornal de Pesquisa Farmacêutica e Entrega de Medicamentos

Optimization of Controlled Release Matrix Formulations of the Chronobiotic Hormone Melatonin via Experimental Design

Marilena Vlachou, Angeliki Siamidi, Sofia Konstantinidou and Yannis Dotsikas

Melatonin (MT) is a chronobiotic hormone synthesized by the pineal gland and has a significant role in the regulation of the circadian biological clock. In order to be administered as a drug, the time of melatonin release from its formulation is of great significance. To this purpose, controlled release matrix tablets (200 mg) of MT were developed by using D-optimal experimental design, including 1 categorical and 2 numerical factors, aiming at effecting its sustained release using a USP XXIII dissolution apparatus II at pH 1.2 and 7.4 media. The excipients selected are polyvinyl pyrrolidone (M.W.: 10.000 and 55.000), hydroxylpropyl Methylcellulose K15M and lactose monohydrate. The in vitro release data were fitted to the Korsmeyer-Peppas empirical equation; the n exponent, which refers to release kinetics, was evaluated. The optimal composition was reached via the desirability function, as a compromise to the different responses (the time for 50% drug dissolution at pH=1.2 and the diffusional exponent (n) at pH values 1.2 and 7.4). As the differences in the n values amongst the formulations are closely related to variation in water penetration into the different excipients used, excipients with different physicochemical characteristics were used so that the desired formulation was produced. Overall, this procedure resulted in a suitable excipients’ composition for the controlled release of melatonin with the minimal number of experiments.