//CLINICAL DATA SHOWING REMfresh®, THE FIRST AND ONLY CONTINUOUS RELEASE AND ABSORPTION MELATONIN

6/5/2017- SCIENTIFICALLY ADVANCED DELIVERY TECHNOLOGY IN SLEEP MANAGEMENT DEBUTS AT SLEEP 2017 WITH CLINICAL DATA SHOWING REMfresh®, THE FIRST AND ONLY CONTINUOUS RELEASE AND ABSORPTION MELATONIN, HELPS MAINTAIN SLEEP FOR UP TO 7 HOURS

  • Melatonin levels decline with age and an estimated 50 to 70 million Americans are affected by sleep difficulties, a process regulated by melatonin
  • First-ever clinical study points to the potential of non-prescription REMfresh®, a continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin), as a new, drug-free product designed for 7-hour sleep
  • Data show the patented Ion Powered Pump (IPP™) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the shape of the body’s natural melatonin blood levels during the nightly sleep cycle
  • REMfresh® builds upon the body of evidence from well-conducted prolonged-release melatonin (PR-M) studies, extending the continuous release and absorption of melatonin (known as the Mesa Wave) to 6.7 hours, which may further improve sleep onset, maintenance and morning alertness

 

BOSTON – (June 5, 2017) – Landmark clinical data presented today highlight a scientific breakthrough in the management of sleep with a drug-free, non-prescription sleep product, REMfresh®, the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 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 percent ultra-pure melatonin in REMfresh® (CRA-melatonin) was designed to induce sleep onset and provide continuous, lasting restorative sleep over 7 hours. The scientifically advanced, patented formulation, called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

The data are being presented in three posters on Sunday, June 4, and Tuesday, June 6, during SLEEP 2017, the 31st Annual Meeting of the Associated Professional Sleep Societies LLC (APSS). The meeting is a joint meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).

“These results represent an unparalleled breakthrough in drug-free sleep maintenance therapy that physicians and their patients have been waiting for,” said David C. Brodner, M.D., a leading 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, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®. “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.”

The findings are based on REMAKT™ (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, 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 leading IR-melatonin. Conversely, the levels of the market-leading 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.

Analysis presented at SLEEP 2017 showed that REMfresh® (CRA-melatonin) 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® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave™, a flat-topped hill with steep sides). 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.

Chronic sleep and wakefulness disorders affect an estimated 50 to 70 million Americans, and long-term sleep deprivation has been associated with negative health consequences, including an increased risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[1]

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.[2]

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 percent of the melatonin within the first 3 hours, facilitating sleep onset.
  • Sustained release and absorption of approximately 50 percent 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® (CRA-melatonin) 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® (CRA-melatonin) 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,[3]administering immediate-release and controlled-release melatonin tablets simultaneously,[4] using melatonin soft gels instead of powder,[5] and slow-release pills of melatonin suspended in an 80:20 mixture of peanut oil: beeswax.[6] Further improvement in these delivery systems was needed to get closer to the body’s own Mesa Wave™-shaped profile.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) 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.

REMAKT® Study Design

REMAKT® (REM Absorption Kinetics Trial) was a U.S.-based randomized, crossover, pharmacokinetics (PK) evaluation study conducted through a well-regarded contract research organization (Palm Beach CRO). The study was designed to compare the PK profile of REMfresh® (CRA-melatonin) with that of a leading immediate-release melatonin (IR-melatonin) formulation.

  • There were 10 healthy, white, non-smoking study participants (6 female, 4 male), ages 18 to 40.
  • Participants received either 5 mg REMfresh® (CRA-melatonin) or 5 mg immediate-release melatonin (IR-melatonin) formulation.
  • PK parameters were determined through melatonin levels in the blood before the first dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8 and 12 hours following first dose.
  • PK parameters, including the time course, Cmax, Tmax and plateau time for melatonin, were determined by inspection.
  • Time to reach initial target (1,000 pg/mL) and duration of time above the target threshold for melatonin were determined by interpolation.
  • Over the course of the study, no serious treatment-emergent adverse events were reported with REMfresh®, and five treatment-emergent adverse events occurred with the leading, marketed IR-melatonin.
  • The IR-melatonin formulation had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

 

Role of Melatonin in the Body

Melatonin is produced by the pineal gland in the brain and helps to regulate natural sleep and wake cycles. Melatonin levels 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 is triggered. As people age, their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (20-50 minutes).

In addition to difficulties falling asleep, sleep in older populations can include fragmented and sustained sleep problems. Melatonin supplementation has been shown to promote and maintain sleep in older populations.[7]

 

 

Role of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

 

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of 2 mg UltraMel™ melatonin. UltraMel™ melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) caplets continuously release bioavailable, 99 percent ultra-pure melatonin over 7 hours, which may help a person fall asleep faster, stay asleep longer and experience quality sleep, such as deep sleep and REM sleep.

REMfresh® (CRA-melatonin) was designed as a hydrogel matrix tablet with its patented, scientifically advanced Ion-Powered Pump (IPP™) technology, pioneered by Physician’s Seal®. There is rapid release of the melatonin from the surface of the tablet in the acidic environment of the stomach. As the tablet moves into the higher pH of the small intestine, where melatonin is unlikely to dissolve, acidic factors in the tablet maintain a lower pH within the tablet over 7 hours to allow for continuous release of active melatonin into the intestines.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) retails for $29.99 for 36 caplets and is available at Amazon.com and www.remfresh.com.

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com.

Data Presented at SLEEP 2017 Poster Sessions on Sleep Maintenance

 

Sunday, June 4

 

  • (Abstract 0385) A Continuous Release Ion Powered Pump Melatonin Delivery System that Overcomes Challenges of Release and Absorption in the Intestines.
    • Dr. Syed M. Shah and Dr. David C. Brodner

 

  • (Abstract 0388) Clinical Evaluation of the Ion Powered Pump Melatonin Delivery System.
    • Dr. David C. Brodner and Dr. Syed M. Shah

 

Tuesday, June 6

 

  • (Abstract 0396) REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin formulation versus a Same Strength Immediate Release Formulation, in Healthy Adults
    • Dr. David C. Brodner and Dr. Syed M. Shah

 

The abstracts are published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/abstract-supplements.

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[1] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[2] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[3] Lee B.J., Parrott, K.A, Ayres, J.W., & Sack, R.L. (1995). Design and evaluation of an oral controlled release delivery system for melatonin in human subjects. International Journal of Pharmaceutics, 124(1):119-127. doi: 10.1016/0378-5173(95)00088-Z.

[4] Gooneratne, N.S., Edwards, A.Y., Zhou, C., Cuellar, N., Grandner, M.A., & Barrett, J.S. (2012). Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults. Journal of Pineal Research, 52(4):437-445.

[5] Proietti, S., Carlomagno, G., Dinicola, S., & Bizzarri. M. (2014). Soft gel capsules improve melatonin’s bioavailability in humans. Expert Opinion on Drug Metabolism & Toxicology, 10(9):1193-1198. doi: 10.1517/17425255.2014.943183.

[6] Aldhous, M., Franey, C., Wright, J., & Arendt, J. (1985) Plasma concentrations of melatonin in man following oral absorption of different preparations. British Journal of Clinical Pharmacology19(4):517-521.

[7] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

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