BATCH VARIATION AND PHARMACOKINETICS OF ORAL SUSTAINED-RELEASE MELATONIN-LOADED SUGAR SPHERES IN HUMAN-SUBJECTS

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 of in vitro release characteristi cs and plasma concentration profiles in human subjects. The MT content s 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 (T-50%) of MT fr om B1, B2 and B3 was 3.70+/-0.2, 5.2+/-0.2 and 4.9+/-0.07h, respective ly. Plasma concentration profiles of sustained release 0.2mg melatonin -loaded sugar spheres containing 10% immediate release melatonin in ge latin capsules (B1 and B2) were then evaluated in human subjects. The in vivo plasma concentration profiles of the two batches (B1 and B2) w ere very similar each other and located between the physiological endo genous ranges. The time to reach the peak concentration (T-max) was mo re advanced in case of B1 when compared to B2. However, there was no s tatistically significant difference in the maximum concentration (C-ma x) and the area under the curve (AUG) between B1 and B2. The AUC of me latonin-loaded sugar spheres containing 10% and 20% immediate release MT in human subjects had a good linearity between dose and AUG, regard less of the fraction of immediate release MT, indicating the first ord er elimination process of MT within these doses. The current oral sust ained release MT delivery system may be utilized to treat circadian rh ythm disorders if it is proven to be more clinically useful when compa red to immediate release MT.