Abstract
The three different batches of an oral sustained release melatonin (MT) delivery system were prepared by aqueous-based fluid-bed coating of the sugar spheres for the evaluation ofin vitro release characteristics and plasma concentration profiles in human subjects. The MT contents in 20% coated sugar spheres of three batches (B1, B2 and B3) were 3.3±0.08, 2.4±0.1 and 2.5±0.13 mg per gram of coated sugar spheres, respectively. The release profiles of three different batches had a very similar fashion. However, the release half-lives (T50%) of MT from B1, B2 and B3 was 3.70±0.2, 5.2±0.2 and 4.9±0.07h, respectively. Plasma concentration profiles of sustained release 0.2mg melatonin-loaded sugar spheres containing 10% immediate release melatonin in gelatin capsules (B1 and B2) were then evaluated in human subjects. Thein vivo plasma concentration profiles of the two batches (B1 and B2) were very similar each other and located between the physiological endogenous ranges. The time to reach the peak concentration (Tmax) was more advanced in case of B1 when compared to B2. However, there was no statistically significant difference in the maximum concentration (Cmax) and the area under the curve (AUC) between B1 and B2. The AUC of melatonin-loaded sugar spheres containing 10% and 20% immediate release MT in human subjects had a good linearity between dose and AUC, regardless of the fraction of immediate release MT, indicating the first order elimination process of MT within these doses. The current oral sustained release MT delivery system may be utilized to treat circadian rhythm disorders if it is proven to be more clinically useful when compared to immediate release MT.
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Benes, L., Brun, J., Claustrat, B., Degrande, G., Ducloux, N., Geoffriau, M., Horriere, F., Karsenty, H., Lagain, D., Plasma melatonin (M) and Sulfatoxymelatonin (aMT6s) kinetics after transmucosal administration to humans. Melatonin and the pineal gland-from basic science to clinical application.Proceedings from the congress on pineal gland. Paris France March, 347–350 (1993).
Cassone, V. M., Chesworth, M. J. and Armstrong, S. M., Dose dependent entrainment of rat circadian rhythms by daily injection of melatonin.J. Biological Rhythm, 1, 219–229 (1986).
Garfinkel, D., Laudon, M., Dof, D. and Zisapel, N., Improvement of sleep quality in elderly people by controlled-release melatonin.Lancet, 346, 541–544 (1995).
Haimov, I., Lavie, P., Laudon, M., Herer, P., Vigder, C. and Zisapel, N., Melatonin replacement therapy of elderly insomniacs.Sleep, 18, 598–603 (1995).
Konsil, J., Parrott, K. A., Ayres, J. W. and Sack, R. L., Development of a transdermal delivery device for melatoninin vitro study.Drug Dev. Ind. Pharm., 21, 1377–1387 (1995).
Lee, B-J. and Lee, J-R., Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin.Arch. Pharm. Res., 18, 22–26 (1995).
Lee, B-J. and Min, G-H., Oral controlled release of melatonin using polymer-reinforced and coated alginate beads.Int. J. Pharm. 144, 37–46 (1996).
Lee, B.-J., Parrott, K. A., Ayres, J. W. and Sack, R. L., Design and evaluation of an oral controlled release delivery system for melatonin in human subjects.Int. J. Pharm., 124, 119–127 (1995).
Lee, B-J., Parrott, K. A., Ayres, J. W. and Sack, R. L., Development and characterization of an oral controlled release delivery system for melatonin.Drug Dev. Ind. Pharm. 22, 269–274 (1996).
Lee, B.-J., Parrott, K. A., Ayres, J. W. and Sack, R. L., Preliminary evaluation of transdermal delivery of melatonin in human subjects.Res. comm. Mol. Pathol. Pharmacol., 85, 337–344 (1994).
Lewy, A. J., Ahmed, S., Latham-Jackson, J. M. and Sack, R. L., Melatonin shifts human circadian rhythms according to a phase-response curve.Chronobiol. Int., 9, 380–392 (1992).
Miles, A., Philbrick, D. S. R. and Thompson, C.,Melatonin, Clinical perspectives, Oxford University Press, NY, 1988.
Waldhauser, F., and Dietzel, M., Daily and annual rhythms in human melatonin secretion: role in puberty.Ann. NY. Acad. Sci. 453, 205–214 (1985).
Wurtman, R. J. and Zhdanova, I., Improvement of sleep quality by melatonin.Lancet, 346, 1491 (1995).
Yu, H. and Reiter, R. J.,Melatonin, Biosynthesis, Physiological Effects and Clinical Application, CRC Press, Boca Raton, FL, 1993.
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Lee, BJ., Ryu, SG., Choi, HG. et al. Batch variation and pharmacokinetics of oral sustained release melatonin-loaded sugar spheres in human subjects. Arch. Pharm. Res. 20, 555–559 (1997). https://doi.org/10.1007/BF02975211
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DOI: https://doi.org/10.1007/BF02975211