Clinical data presented today highlight findings on non-prescription sleep product, REMfresh, a continuous release and absorption melatonin (CRA-melatonin). REMfresh is designed to mimic the body’s 7-hour Mesa Wave, a natural pattern of melatonin blood levels during a normal night’s sleep cycle. The study demonstrated the continuous release and absorption of 99% ultra-pure melatonin in REMfresh. The patented formulation, called Ion Powered Pump (IPP) technology, replicates the way in which the body naturally releases and absorbs melatonin. The findings are based on REMAKT (REM Absorption Kinetics Trial), a US-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh (CRA-melatonin) with an immediate-release melatonin (IR-melatonin). The study found that melatonin levels with REMfresh exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the IR-melatonin. Conversely, the levels of the IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours. “These results represent an unparalleled breakthrough in drug-free sleep maintenance therapy that physicians and their patients have been waiting for,” says David C. Brodner, MD, a sleep specialist who is double board-certified in otolaryngology-head and neck surgery and sleep medicine, founder and principle physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach Country, Fla, and senior medical advisor for Physician’s Seal LLC, in a release. “Melatonin products have been used primarily as a chronobiotic to address sleep disorders associated with abnormal timing of the circadian system, such as jet lag and shift work, but that has now changed. With its patented IPP delivery system that mimics the body’s own natural sleep pattern, REMfresh may allow more individuals having trouble sleeping to experience drug-free, consistent, restorative sleep and have an improved quality of life.” Analysis presented at SLEEP 2017 showed that REMfresh builds upon the body of evidence from prolonged-release melatonin (PR-M), which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency, and quality of life in patients aged 55 years and older compared with placebo. REMfresh was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night. There was a faster time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave may help to improve sleep maintenance and morning alertness. Sleep/wake cycles are regulated by melatonin, levels of which normally begin to rise in the mid- to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle in triggered. Melatonin levels typically decline with age, with a significant decrease after age 40. The REMAKT data will be submitted for peer review and publication in a medical journal. REMfresh (CRA-melatonin) Results Analysis of the REMfresh (CRA-melatonin) data showed that use of REMfresh resulted in: Melatonin levels exceeding the target sleep maintenance threshold of 1,000 pg/mL for a median of 6.7 hours, compared with 3.7 hours for immediate-release melatonin (IR-melatonin). A burst of release and absorption of approximately 50% of the melatonin within the first 3 hours, facilitating sleep onset. Sustained release and absorption of approximately 50% of the remaining melatonin within the next 4 hours to help with sleep maintenance. Median maximum concentrations of 5 mg doses was 4,690 pg/mL for REMfresh (CRA-melatonin) versus 23,352 pg/mL for the IR-melatonin formulation (23-fold higher than the targeted levels for sleep onset). Median time to maximum concentration was 1.5 hours. Additional clinical findings of REMfresh data presented at SLEEP 2017 included an analysis of several modified-release formulations of melatonin, which have had difficulties overcoming the challenges of release and absorption of melatonin in the higher pH environments in the small and large intestines. This may explain why other melatonin products have difficulties with continuous absorption through the night. Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave. The scientific work behind REMfresh sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption. Various approaches to overcome the challenges of melatonin release and absorption have been tried, including adding a controlled-release coating to melatonin beads, administering immediate-release and controlled-release melatonin tablets simultaneously, using melatonin soft gels instead of powder, and slow-release pills of melatonin suspended in an 80:20 mixture of peanut oil:beeswax. Designed as a hydrogel matrix tablet, REMfresh provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet maintains the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.