Modelling receptor-mediated endocytosis in hollow microneedle-based verapamil delivery through viscoelastic skin

Drug delivered from the microneedle (MN) tip diffuses across the viscoelastic skin before entering the blood compartment and being absorbed. Reversible uptake kinetics between the blood and tissue compartments, reversible specific saturable binding with its receptors, and endocytosis are given due attention. Simulations predict that, unlike skin thinning, skin viscoelasticity and a higher Young's modulus value, as in an older person, inhibit verapamil diffusion within the skin, and metabolism stabilises the concentrations in the blood and tissue compartments. Simultaneously, the irreversible uptake kinetics improve drug concentrations in the tissue compartment, facilitating receptor-mediated endocytosis. The results also predict that internalised verapamil increases with time at slower internalisation rates; however, at higher rates, it attains a peak value before gradually diminishing. Furthermore, as the rate of lysosomal degradation escalates, the peak value of internalised concentration diminishes and shifts upward. A comprehensive sensitivity analysis has been performed because of uncertainty about several crucial parameters. Our findings align well with the existing literature.