Curcumin-Loaded Liposomes for Transdermal Delivery: A 2² Factorial Screening and Ex Vivo Skin Permeation Study

Abstract

Background: Curcumin has potent anti-inflammatory and antioxidant activities relevant to inflammatory skin diseases; however, its dermal use is limited by its negligible aqueous solubility, instability, and the stratum corneum barrier. Objectives: This study screened phospholipid liposomes loaded exclusively with curcumin and quantified their permeation across excised rat skin, compared with a free-curcumin control. Methods: Four formulations were prepared by thin-film hydration according to a two-level full factorial design (22), varying cholesterol (10 and 20 mg) and lecithin (30 and 60 mg) at constant curcumin content. Particle size, polydispersity index (PDI), encapsulation efficiency (EE%), zeta potential, and morphology (scanning electron microscopy) were determined, and coded models were fitted by ordinary least squares with analysis of variance. Release was evaluated using mean squared error and the small-sample-corrected Akaike Information Criterion; permeation was assessed in Franz cells, and stability was assessed over six months at 4 and 25 °C (n = 3). Results: Size ranged from 113.3 nm with an SD of 13.6 nm (F4) to 181.7 nm with an SD of 2.5 nm (F2), with lecithin as the dominant factor and showing a significant cholesterol–lecithin interaction. EE% ranged from 89.41% to 91.30%, and PDI did not exceed 0.36. Zeta potential was moderately negative throughout (-15.75 to -18.58 mV) and was most negative for F4. Scanning electron microscopy confirmed spherical, uniform vesicles without drug crystallization. Release followed the Weibull model throughout. F4 produced the smallest vesicles, the highest release (94.87%), and the highest flux (Jₛₛ = 1.54 with an SD of 0.19 µg·cm-2·h-1), representing a 2.45-fold enhancement over the control, and retained 99.85% curcumin with an SD of 0.02% after 180 days at 4 °C, with only 3.1% vesicle growth. Conclusions: A compact 22 design clarified the respective roles of cholesterol and lecithin. F4 combined the smallest vesicles with the highest transdermal flux and excellent refrigerated stability, supporting phospholipid liposomes as rational topical carriers for curcumin.