Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes

Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p < 0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96 ± 0.31 μg cm−2 min−1 and 1.59 ± 0.26 μg cm−2 min−1 respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p < 0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration.