Research Article Transmucosal delivery of melatonin-encapsulated niosomes in a mucoadhesive gel Aroonsri Priprem 1,2 , Chatchanok Nukulkit 2 , Nutjaree P Johns 2,3 , Supawan Laohasiriwong 2,4 , Kwanchanok Yimtae 2,4 & Cheardchai Soontornpas* ,2,3 1 Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand 2 Melatonin Research Group, Khon Kaen University, Khon Kaen 40002, Thailand 3 Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand 4 Department of Otorhinolaryngology, Faculty of Medicines, Khon Kaen University, Khon Kaen 40002, Thailand * Author for correspondence: Tel.: +66 43202378; Fax: +66 43202379; chesoo@kku.ac.th Aim: A transmucosal niosome gel was developed to improve the pharmacokinetics of exogenous mela- tonin. Materials & methods: The melatonin niosomes (MN) gel was characterized and melatonin levels were determined in healthy volunteers. Results: Micron-sized MN in a gel, mean ex vivo residence time of more than 3 h with maximum adhesiveness at 25 and 37 ◦ C showed similar in vitro release but dif- ferent in vitro permeation to melatonin gel. Oral transmucosal MN gels, at 2.5, 5 and 10 mg, topically applied in 14 healthy volunteers in a randomized double-blinded crossover design with 7-day washout, gave dose-proportional pharmacokinetics, with improved absorption and prolonged systemic circulation. Conclusion: The transmucosal MN gel provides a topical option for melatonin administration with sub- stantial prolonged systemic delivery. First draft submitted: 3 January 2018; Accepted for publication: 23 February 2018; Published online: 23 April 2018 Keywords: melatonin • mucoadhesive gel • niosomes Melatonin, N-acetyl-5-methoxytryptamine, a hormone synthesized at nighttime in the pineal gland and in other organs, influences circadian rhythms and cellular functions [1,2]. Exogenous melatonin, commonly known for its uses in induction or efficiency improvement of nighttime sleep [3], has been investigated for daytime uses with various oral health products including toothpastes, mouthwashes and gel [4], as well as for induction of perioperative sedation [5], particularly in children [7]. High safety profiles of nighttime melatonin are well established [8,9]. Although undesirable adverse effects of melatonin were not observed with single-dose daytime administration [10,11], daytime use of melatonin is still controversial [12]. Oral melatonin, extemporaneously prepared by crushing tablets and dissolving in juices, shows potential in induced sleep with no adverse effect at 5, 10 and 20 mg doses, based on the ages of the children who underwent brainstem audiometric procedures [7]. Also, sedation with oral melatonin has the advantage of fostering recovery by inhibiting postoperative excitement [13]. To induce daytime sleep in children, product development to enable effective delivery of melatonin must overcome several challenges. First, oral melatonin doses provide variable absorption, short plasma half-life (<1 h) and extensive first-pass metabolism with poor bioavailability (<33%) [14,15], which is not acceptable for sleep induction in clinical uses. Second, children do not tolerate the unpleasant and unacceptable taste of extemporaneous melatonin preparations [7,16,17]. Finally, unavoidable aqueous conditions used for pediatric preparations do not favor melatonin dissolution and stability, limiting it to extemporaneous preparations [18]. Buccal films, transdermal patches and controlled release tablets were compared in the delivery of melatonin and it was found that buccal films gave twice as much absorption as oral tablets [19]. Oral transmucosal drug delivery with high vascularization and rapid absorption is considered as a primary route for drugs, which undergo extensive first-pass metabolism [20]. Transmucosal melatonin provides much higher in vitro permeation than transdermal delivery [21]. To improve transmucosal absorption of melatonin, mucoadhesive gels with strong affinity for mucosal surfaces have been introduced to retain and allow for increased contact time Ther. Deliv. (2018) 9(5), 343–357 ISSN 2041-5990 343 10.4155/tde-2018-0001 C  2018 Newlands Press For reprint orders, please contact: reprints@futuremedicine.com