Effects of Melatonin-Loaded Poly(N-vinylcaprolactam) Transdermal Gel on Sleep Quality

Abstract

The rapid pace of modern life has contributed to a significant decline in sleep quality, which has become an urgent global public health issue. Melatonin, an endogenous hormone that regulates circadian rhythms, is vital in maintaining normal sleep cycles. While oral melatonin supplementation is widely used, transdermal delivery systems present advantages that include the avoidance of first-pass metabolism effects and enhanced bioavailability. In this study, a novel melatonin transdermal delivery system was successfully developed using a thermosensitive poly(N-vinylcaprolactam) [p(NVCL)]-based carrier. The p(NVCL) polymer was synthesized through free radical polymerization and characterized for its structural properties and phase transition temperature, in alignment with skin surface conditions. Orthogonal optimization experiments identified 3% azone, 3% menthol, and 4% borneol as the optimal enhancer combination for enhanced transdermal absorption. The formulation demonstrated exceptional melatonin loading characteristics with high encapsulation efficiency and stable physicochemical properties, including an appropriate pH and optimal moisture content. Comprehensive in vivo evaluation using normal mouse models revealed significant sleep quality improvements, specifically a shortened sleep latency and extended non-rapid eye movement sleep duration, with elevated serum melatonin and serotonin levels. Safety assessments including histopathological examination, biochemical analysis, and 28-day continuous administration studies confirmed excellent biocompatibility with no adverse reactions or systemic toxicity. Near-infrared fluorescence imaging provided direct evidence of enhanced transdermal absorption and superior biodistribution compared to oral administration. These findings indicate that the p(NVCL)-based melatonin transdermal gel system offers a safe, effective and convenient non-prescription option for sleep regulation, with promising potential for clinical translation as a consumer sleep aid.

Keywords: melatonin; poly(N-vinylcaprolactam); sleep quality; transdermal gel; transdermal permeation enhancers.

Figure 1

FTIR spectra comparison of NVCL monomer, p(NVCL) polymer, melatonin, and melatonin-loaded p(NVCL) gel.

Figure 2

Powder X-ray diffraction (PXRD) patterns comparing pure melatonin, melatonin-loaded gel, and unloaded gel.

Figure 3

Characterization of melatonin-loaded p(NVCL) transdermal gel. (a) Physical appearance showing translucent, homogeneous gel formulation. (b) Cryo-SEM micrograph at 1500× magnification revealing microporous network structure.

Figure 4

Effects and optimization of transdermal penetration enhancers on the cumulative permeation of melatonin. (a) Effects of single transdermal penetration enhancers (azone, menthol and borneol) at varying concentrations on the cumulative permeation of melatonin; (b) Evaluation of different combinations of three transdermal penetration enhancers using L9(3³) orthogonal experimental design on the 24 h cumulative permeation of melatonin.

Figure 5

Rheological and thixotropic properties of melatonin-loaded p(NVCL) transdermal gel. (a) Strain sweep analysis showing storage modulus (G′) and loss modulus (G″) versus strain percentage; (b) Frequency sweep analysis displaying storage modulus (G′) and loss modulus (G″) versus frequency (0.1–10 Hz); (c) Temperature sweep analysis showing storage modulus (G′) and loss modulus (G″) versus temperature (15–45 °C); (d) Thixotropic behavior evaluation showing viscosity changes during three-step shear testing over time.

Figure 6

Comparison of the effects of melatonin gel, oral melatonin administration and a blank group on sleep parameters in mice. Data are expressed as mean ± standard deviation. (a–c) Behavioral parameters measured using 12 mice per group: (a) total activity distance, (b) time spent in the central area, (c) upright frequency; (d,e) pentobarbital-induced sleep test parameters using the same 12 mice per group: (d) total sleep time, (e) sleep latency period; (f) sleep–wake state distribution showing wakefulness (WAKE) time, NREM time, and rapid eye movement (REM) time derived from 24 h EEG recordings on day 28 using the same 12 mice per group; (g,h) serum biochemical indicators measured using six mice per group at each timepoint: (g) serum melatonin levels and (h) serum 5-HT levels, measured on days 14, 28 and 42. Statistical significance notation across all figures: * p < 0.05; ns = not significant.

Figure 7

Histological sections of major organs and the application site in mice (H&E staining). Representative optical microscope images of the heart, liver, spleen, lung, kidney and skin tissue from the administration site (from top to bottom). All images were captured at 200× magnification.

Figure 8

Ex vivo organ biodistribution analysis of Cy5.5-melatonin. Representative fluorescence images of excised organs including the brain, heart, liver, spleen, lung, kidney, and dorsal skin tissue.