Cutaneous delivery and biodistribution of a lipophilic natural product – bakuchiol: Comparing nanocarrier performance

Bakuchiol (BAK) is a natural bioactive agent described as a functional analogue of retinol that acts through the same cellular pathways. Its lipophilicity (log Ko/w 6.1) and oily state at ambient temperature pose significant challenges in formulation development. This study investigated the use of different nanocarriers to develop primarily aqueous formulations of BAK and their ability to facilitate its cutaneous delivery. Micelles were prepared using solvent evaporation, microemulsions (ME) were formulated using the water titration method, and nanoemulsions (NE1 and NE2 - with and without oleic acid, respectively) were produced using ultrasonication. Optimized micelles formed using D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and Poloxamer 407 demonstrated encapsulation efficiencies of 96.6 ± 3.2 % and 101.5 ± 0.3 %, with particle sizes of 28 nm (PDI 0.21) and 27 nm (PDI 0.092), respectively. NE2 had a higher encapsulation efficiency (106.8 ± 5.7 %) than either NE1 (90.2 ± 2.4 %) or ME (86.3 ± 4.6 %). The micro- and nanoemulsions exhibited larger sizes than the micelles (ME: 108 nm; NE1: 129. nm; NE2: 68 nm). Cutaneous delivery experiments demonstrated that NE1 and NE2 resulted in 3-4 fold higher BAK deposition than either the micelles or microemulsion; thus, oleic acid content was not determining BAK delivery. These findings suggest that the thermodynamic activity and molecular physicochemical properties are more important for skin delivery, than simply considering the size of the nanocarrier; which will not necessarily retain its structure upon contact with skin. Cutaneous biodistribution experiments to determine the spatial distribution of BAK confirmed that nanoemulsions effectively targeted the viable epidermis and dermis - key sites for BAK's biological effects, with concentrations 36-fold higher than the minimum effective concentration.