In vitro skin permeation of mitragynine: Optimisation of antioxidants for enhanced drug stability and formulation performance.

The opioid-like characteristics of mitragynine with biased μ-opioid receptor activation are attractive for pain and addiction therapy due to less addictive issue. Our previous work has shown the potential of delivering mitragynine through the skin but drug degradation hindered a reliable understanding of its permeation behaviour. This study aims to optimise the use of antioxidants in both the receptor medium and formulations for in vitro permeation studies of mitragynine (5%w/v) using single solvent systems. The optimised receptor medium with 0.01%w/v of ascorbic acid in phosphate buffer saline was chosen due to a high mitragynine recovery that also allowed the detection of a higher mitragynine amount permeated. Dimethyl sulphoxide and Transcutol^® achieved the highest mitragynine permeation (~ 10 - 15 µg/cm²) and skin fluxes (~ 0.5 - 0.8 µg/cm²/h). While Maisine^® and propylene glycol achieved ~ 6 - 8 µg/cm² of mitragynine permeated. Labrasol^® and Lauroglycol™ showed a relatively low drug permeation (~ 1 - 4 μg/cm²). Permeation data modelling showed that skin diffusion (high apparent diffusion coefficient) was identified as the major mechanism but skin partitioning (moderate to high apparent partition coefficient) became a determining factor for the overall permeation performance. Mass balance studies revealed low mitragynine recovery (< 80%) owing to solvent-induced degradation. Further optimisation of butylated hydroxytoluene incorporation into gel formulations with selected solvents resulted in excellent drug recovery and enhanced skin permeation, even at lower drug loadings. Overall, this study highlighted the importance of enhanced drug stability with antioxidant, facilitating a more accurate assessment of mitragynine's skin permeation characteristics.