Zingerone-Encapsulated Nanoethosomes for Transdermal Delivery: Factorial Design-Assisted Optimization and Evaluation for Systemic Drug Delivery

Transdermal drug delivery offers the benefits of first-pass metabolism avoidance, high bioavailability, a low dose, and high patient compliance. Ethosomes are lipid-based vesicles containing phospholipids, ethanol, and water that enhance drug penetration by overcoming the barrier of the skin. Ethosomes can encapsulate lipophilic as well as hydrophilic drugs to increase their efficacy. Zingerone (ZNE) is a major component found in gingerroot and has potent antidiabetic, antioxidant, and antispasmodic activities. ZNE has low solubility in aqueous media, which leads to low oral bioavailability. ZNE-loaded ethosomes were prepared via the cold method. The ethosomes were optimized by a 3-level and 2-factor full factorial design. The independent variables selected were ethanol (%) and soy lecithin (%). The dependent variables selected were flux (μg/cm 2 /h) and entrapment efficiency (%). The optimized formulation was evaluated for size, polydispersity index, zeta potential, entrapment efficiency, in vitro drug release, and ex vivo skin drug permeation. The optimized formulation had an average vesicle size of 77.12 ± 1.89 nm, a polydispersity index of 0.350 ± 0.013, a zeta potential of −56.9 ± 1.25 mV, an entrapment efficiency of 75.83% ± 1.53%, in vitro drug release of 85.97% ± 1.92% (after 24 h), and ex vivo skin drug permeation of 78.52% ± 1.62%. The optimized formulation was converted to a gel formulation and characterized for in vitro parameters. The percent permeation of ZNE through rat skin (ex vivo) from the ethosomal gel was greater (73.12% ± 1.76%) than that from the conventional gel (38.17% ± 1.82%). This study reveals the substantial potential of ZNE-loaded ethosomes for transdermal delivery and for use in the management of systemic diseases.