Multicomponent chemical enhancer formulations for transdermal drug delivery: more is not always better

Chemical permeation enhancers can permeabilize the human skin to enable transdermal delivery of drugs, but their use is often limited by the accompanying skin irritation. Novel chemical enhancer combinations based on synergistic interactions amongst their components have the potential to address this limitation. However, discovery of such combinations requires screening of large libraries of chemicals and the size of such libraries increases exponentially with the number of ingredients in the formulation. Therefore, it becomes important to develop heuristic rules for optimizing such libraries, especially at higher orders. In the present study, a formulation library containing binary, ternary and quaternary combinations was designed using a common pool of 10 chemical enhancers and was screened for skin permeation enhancement. The key question was whether increasing the number of ingredients in the formulation yields increased permeation enhancement. Formulation potencies and synergies were analyzed to elucidate the role played by the formulation order. Ternary formulations exhibited the best cost to benefit ratio as judged by the fraction of total formulations that provide high potency.