A New Role of Fine Excipient Materials in Carrier-Based Dry Powder Inhalation Mixtures: Effect on Deagglomeration of Drug Particles During Mixing Revealed

摘要

The potential of fine excipient materials to improve the performance of carrier-based dry powder inhalation mixtures is well acknowledged. The mechanisms underlying this potential are, however, open to question till date. Elaborate understanding of these mechanisms is a requisite for rational rather than empirical development of ternary dry powder inhalation mixtures. While effects of fine excipient materials on drug adhesion to and detachment from surfaces of carrier particle have been extensively investigated, effects on other processes, such as carrier-drug mixing, capsule/blister/device filling, or aerosolization in inhaler devices, have received little attention. We investigated the influence of fine excipient materials on the outcome of the carrier-drug mixing process. We studied the dispersibility of micronized fluticasone propionate particles after mixing with alpha-lactose monohydrate blends comprising different fine particle concentrations. Increasing the fine (D < 10.0 mu m) excipient fraction from 1.84 to 8.70% v/v increased the respirable drug fraction in the excipient-drug mixture from 56.42 to 67.80% v/v (p < 0.05). The results suggest that low concentrations of fine excipient particles bind to active sites on and fill deep crevices in coarse carrier particles. As the concentration of fine excipient particles increases beyond that saturating active sites, they fill the spaces between and adhere to the surfaces of coarse carrier particles, creating projections and micropores. They thereby promote deagglomeration of drug particles during carrier-drug mixing. The findings pave the way for a comprehensive understanding of contributions of fine excipient materials to the performance of carrier-based dry powder inhalation mixtures.