Multiple Prodrug Approach for Topical Application: Flux Across Silicone Membranes Upon Simultaneous Administration of Salicylate Esters

The barrier properties of the skin constitute a major challenge to topical drug delivery, motivating strategies to increase transmembrane flux. This study evaluates a multiple prodrug approach using salicylic acid and eight structurally related salicylate esters as a model system, hypothesising that saturated suspensions of several prodrugs could maximise thermodynamic activity and enhance total salicylic acid flux. Saturated aqueous suspensions of single, binary, and quinary prodrug systems were prepared to achieve maximal thermodynamic activity and permeation. Steady-state flux across silicone membranes was evaluated using a side-by-side diffusion cell setup under sink conditions. Solid-state characterisation by XRPD and DSC confirmed the presence of pure crystalline prodrug phases, while solubility was assessed using the shake-flask method. Prodrug solubility in multi-prodrug systems was generally unchanged or decreased, the latter indicating non-ideal solution behaviour. Individual prodrug fluxes were often reduced when co-administered with one or more prodrugs, with additive fluxes observed in 1/8 binary systems. However, total salicylic acid flux increased significantly in 2/8 binary and 2/3 quinary systems compared to the highest-performing single prodrug. Results showed that the prodrug solubilities did not govern the membrane flux. These findings suggest that, beyond thermodynamic activity, interactions affecting membrane partitioning play a key role in flux. The multiple prodrug strategy shows potential to enhance topical delivery, but its effective implementation would depend on balancing increased total flux with formulation complexity arising from non-ideal behaviour and intermolecular interactions.