A novel oral multiple-unit delivery system for melatonin, (Ca) alginate/polyethyleneimine (PEI) gel microcapsules containing melatonin-resin (Dowex 1-X8 Cl-) complex, which overcome many of the problems encountered with the conventional dosage forms, Ca-alginate gel beads was designed through an ionic crosslinking/interpolyelectrolyte complexation technique. The effect of different processing variables viz., gelation time, PEI concentration, melatonin/resin ratio, core/coat ratio, pH and ionic strength of the dissolution medium on the release characteristics of microcapsules in comparison with alginate beads was investigated. The results obtained indicated that a PEI concentration of 2% and gelation time of 24 h. were the optimal conditions for a marked release retardation. Of ultimate importance is the ionic character of the synthetic polyelectrolyte complex (PEC) membrane (alginate/ PEI) that produced microcapsules which did not disintegrate in simulated intestinal fluid (S.I.F., pH 7.4) over a period of 3 days of testing and allowed a pH-independent release rate of melatonin up to 2 h. in phosphate buffer (0.154 M Na+ ions) (K1 = 5.42x10-1, 5.995x10-1 and 5.78x10-1 hr-1 for pHs of 5.5, 7.4 and 9.0, respectively). The metatonin release rate of microcapsules (K1= 1.144z`0-1 hr-1) in S.I.F. (pH 7.4) was significantly reduced when compared to that of the original alginate beads (K1= 19.59x10-1 hr-1) which showed a dramatic disintegration and dissolution in S.I.F. (pH 7.4) within 1 h. Most importantly, successful attempts to prepared crosslinked protein or polyamide/PEI-graft co-polymer membranes-coated alginate microcapsules were achieved by making use of a modified interfacial polymerization process. The coated microcapsules offered a remarkable reduction of the release rate in simulated gastric fluid (S.G.F., pH 1.2) as compared to alginate beads. The modulatory influence of melatonin (biological half-life = 24 min) on liver detoxifying and antioxidant enzyme systems (glutathione-S-transferases (GSTs) and glutathione peroxidase (GSH-Px), as well as lipid peroxides (LPER) levels was studied in rats. The obtained results revealed that melatonin resonates-loaded (Ca) alginate/PEI gel microcapsules (T50% = 6.06 h) produced a significant marked elevation in hepatic cytosolic activities levels of GSTs and GSH-Px as well as glutathione (GSH) content with a reduction in (LPER) levels, when compared with the corresponding controls, suggesting that alginate/PEI gel microcapsules could be a useful reservoir system for controlled-release melatonin delivery.