Fabrication of Thymoquinone and Ascorbic Acid-Loaded Spanlastics Gel for Hyperpigmentation: In Vitro Release, Cytotoxicity, and Skin Permeation Studies.

: The demand for a safe compound for hyperpigmentation is continuously increasing. Bioactive compounds such as thymoquinone (TQ) and ascorbic acid (AA) induce inhibition of melanogenesis with a high safety profile. The aim of this study was to design and evaluate spanlastics gel loaded with bioactive agents, TQ and AA, for the management of hyperpigmentation. : Several spanlastics formulations were successfully fabricated and characterized in terms of morphology, vesicle size, zeta potential, and release. : The optimized TQ-loaded spanlastic formulation showed an average size of 223.40 ± 3.50 nm, and 133.00 ± 2.80 nm for AA-loaded spanlastic formulation. The optimized spanlastics formulation showed the highest entrapment efficiency (EE%) of 97.18 ± 2.02% and 93.08 ± 1.95%, for TQ and AA, respectively. Additionally, the edge activator concentration had a significant effect ( < 0.05) on EE%; it was found that by increasing the amount of EA, the EE% increases. Following that, the optimal spanlastics fomulation loaded with TQ and AA were incorporated into gel and explored for appearance, pH, spreadability, stability, rheology, in vitro release, ex vivo permeation study, and MTT cytotoxicity. The formulated spanlastics gel (R-1) has a pH of 5.53. Additionally, R-1 gel was significantly ( < 0.05) more spreadable than control gel, and exhibited a shear thinning behavior. Most importantly, ex vivo skin deposition studies confirmed superior skin deposition of TQ and AA from spanlastic gels. Additionally, results indicated that tyrosinase inhibition was primarily due to TQ. When comparing TQ alone with the TQ-AA combination, inhibition ranged from 18.35 to 42.73% and 24.28 to 42.53%, respectively. Both TQ spanlastics and the TQ-AA combination showed a concentration-dependent inhibition of tyrosinase. : Spanlastic gel might represent a promising carrier for the dermal delivery of TQ and AA for the management of hyperpigmentation conditions.