Design and evaluation of an oral controlled release delivery system for melatonin in human subjects

Beom Jin Lee, Keith A. Parrott, James W. Ayres, Robert L. Sack

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Six human subjects were given an oral formulation designed to provide an immediate and controlled release of melatonin (MT). The controlled release formulation consisted of MT-loaded sugar beads coated with 20% Aquacoat®. A computer simulation program (MAXSIM®) was used to estimate the MT dose and ratio of immediate and controlled release MT based on average population pharmacokinetics of MT. When 0.5 mg of MT (immediate release portion of MT, 0.1 mg) was administered to four subjects, average peak plasma MT concentration was reached at about 600 pg/ml and maintained at about 100 pg/ml over 8 h. Observed peak plasma MT concentrations were 3-times greater than predicted by simulation. These results suggest that the MT dose, ratio of immediate release MT to controlled release MT, and the controlled release dosage form must all be considered in order to closely mimic the endogenous plasma MT concentration-time curve. Deconvolution and pharmacokinetic analysis suggested that less than 20% of the orally administered controlled release MT dose reached the systemic circulation from time 0 to 8 h. A good correlation was observed between plasma MT concentration and urinary excretion rate of 6-sulphatoxymelatonin (6-STMT), a major metabolite of MT. As plasma MT concentration increased, the urinary excretion rate of 6-STMT increased concomitantly. This suggests that the urinary excretion rate of 6-STMT may be used as an index of human plasma MT concentration.

Original languageEnglish (US)
Pages (from-to)119-127
Number of pages9
JournalInternational Journal of Pharmaceutics
Issue number1
StatePublished - Sep 19 1995
Externally publishedYes


  • 6-Sulfatoxymelatonin
  • Coated bead
  • Computer simulation
  • Controlled release
  • Deconvolution
  • Immediate release
  • Melatonin

ASJC Scopus subject areas

  • Pharmaceutical Science


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