(P22-060-25) Characterization of a Novel Customized-Release Capsule Technology: In Vitro Performance, Pharmacokinetics and Physiological Impact

Objectives: To characterize the performance of a novel customized-release capsule technology by evaluating the relationship between in vitro dissolution, in vivo pharmacokinetics, and physiological effects on sleep.

Methods: In vitro dissolution was conducted under gastrointestinal conditions per U.S. Pharmacopeia guidelines. Healthy adults (18–40) with poor sleep (Pittsburgh Sleep Quality Index > 5) participated in two studies: pharmacokinetic (PK, N=10) and sleep quality (SQ, N=13). Both studies used a double-blind, crossover design. Participants received either an intervention (MLT) or a placebo (PLA) in separate phases, with a washout period between treatments. MLT was a 5 mg melatonin oral supplement (Sleep BioSeries™ Melatonin, Ritual, USA) with instant and extended-release tablets in a capsule. In the PK study, participants consumed 200 mL water with MLT or PLA and stayed overnight in a darkened laboratory. Blood samples were collected every 30 minutes for up to 10 hours and analyzed via HPLC with UV/VIS detection. The SQ study lasted two weeks, with sleep quality data collected using Fitbits and self-reported sleep onset.

Results: In vitro dissolution confirmed peaks in the MLT melatonin release profile at 30 minutes and 2 hours, with complete release by 6 hours. Consistently, the PK study showed an 8.6-fold increase in serum melatonin by 30 minutes (p < 0.01), with levels peaking at 3400.7 pg/mL at 2.5 hours and tapering off from 6 hours. Subjects fell asleep faster with MLT than with PLA (16.2 vs. 28.67 minutes, ANCOVA: F=4.6, p < 0.05). MLT also improved nocturnal deep sleep 1.5–3 hours (p < 0.05) and increased light sleep 6+ hours (p < 0.05) into sleep compared to PLA.

Conclusions: The initial in vitro melatonin peak corresponded with the significant increase in serum melatonin levels at 30 minutes which may explain the faster sleep onset in the MLT group. The second dissolution peak corresponded with the in vivo peak and the increased deep sleep in the MLT group. The 100% melatonin release at 6 hours corresponded with the tapering off of serum melatonin and increased light sleep in the MLT group. The in vitro dissolution results are correlated with the clinical data and provide evidence of an in vitro-in vivo (IVIVC) correlation, which can be explored further in future studies.

Funding Sources: The study was conducted at University of Exeter and sponsored by Ritual (Natals, Inc.).