Optimizing cinnamophilin delivery via SNEDDS for enhanced anti-melanogenic activity: A comprehensive evaluation of skin safety, permeability, and tyrosinase inhibition.

Skin hyperpigmentation disorders, such as melasma and age spots, result from abnormal melanin overproduction and remain a significant dermatological concern. Tyrosinase, a key enzyme in melanogenesis, represents a critical target for depigmenting therapies. Cinnamophilin (CINN), a lignan isolated from Machilus species, exhibits strong antioxidant properties and potential tyrosinase inhibitory activity. However, its poor water solubility and limited skin permeability restrict its topical application. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dermal delivery and efficacy of CINN. Molecular docking revealed the binding of CINN at the tyrosinase catalytic site through hydrogen bonding and π-π interactions, without direct coordination to catalytic copper ions. CINN also exhibited concentration-dependent tyrosinase inhibition in vitro, with an IC₅₀ value of 39.4 ± 0.1  μM. Enzyme kinetics indicated a mixed-type inhibition mechanism. The optimized CINN-loaded SNEDDS formulation exhibited a mean droplet size of 266.8  nm with a polydispersity index of 0.295 and enhanced skin permeability by approximately threefold in a PAMPA model. In α-MSH-stimulated B16F10 cells, CINN-loaded SNEDDS significantly reduced both melanin secretion and intracellular tyrosinase activity. These findings identify CINN as a natural tyrosinase inhibitor and demonstrate the potential of SNEDDS to improve its solubility, skin permeability, and anti-melanogenic efficacy for topical application.