Designing a multi-component spray-dried formulation platform for pulmonary delivery of biopharmaceuticals: the use of polyol, disaccharide, polysaccharide and synthetic polymer to modify solid-state properties for glassy stabilisation

For a dry powder formulation platform to be suitable for pulmonary delivery of potent biopharmaceuticals, e.g., proteins and peptides, it has to be not only efficiently and reproducibly aerosolisable, but also capable of creating a matrix suitable for stabilising the relevant biomacromolecules at temperatures appropriate for storage and distribution. This study systematically evaluated the use of excipient compounds covering a range of molecular sizes: i.e., from polyol (mannitol) and disaccharide (trehalose), to polysaccharide (inulin) and synthetic polymer (PVP K30), in conjunction with other small molecule excipients. It is recognised that larger molecular weight excipients with higher T_g values are less prone to recrystallisation, however there is limited data around the potential for the inclusion of these compounds in inhalable dry powder delivery systems, where historically the focus has been on employing mono- or disaccharides. The results demonstrated that the polymer/leucine systems retained an appropriately high T_g in spite of the relatively high moisture content after spray-drying. The results also showed that sodium citrate, in contrast to glycine and leucine, was effective in inhibiting crystallisation of spray-dried mannitol. The findings demonstrated the synergistic benefits achieved from the concurrent use of several excipients on spray-dried mannitol which have not been previously reported: leucine as a particle formation agent, sodium citrate as a glass-forming agent, and glycine as a morphological modifier.