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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 Tg 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 Tg 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.

Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules.Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes.The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma.The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.

Non-reducing sugars such as mannitol are widely studied as excipients for spray-dried pharmaceutical formulations. In contrast, the present study investigated the use of a range of polymers for the production of an amorphous glassy carrier platform for pulmonary delivery of potent biomacromolecules. Two different natural polysaccharides, inulin and dextran, and the synthetic polymer polyvinylpyrrolidone (PVP) were combined with leucine using spray-drying. In addition, the effect of these polymers in combination with mannitol was studied. The results showed that leucine was a very effective particle formation agent that substantially improved processing yields of the spray-dried polymer–leucine-based formulations and formed high-rugosity particles with high fine particle fractions. The work indicated the potential utilities of these multicomponent systems as a novel dry powder formulation platform for pulmonary delivery of various biomacromolecules.

Combining an amino acid and a sugar is a known strategy in the formulation of spray or freeze dried biomolecule powder formulations. The effect of the amino acid leucine in enhancing performance of spray-dried powders has been previously demonstrated, but interaction effects of several constituents which may provide multiple benefits, are less well-understood. A 3 factor 2 level (2(3)) factorial design was used to study the effects of leucine, glycine and alanine in a mannitol-based dry powder formulation on particle size, aerosolisation, emitted dose and cohesion. Other qualitative tests including scanning electronic microscopy and X-ray powder diffraction were also conducted on the design of experiment (DoE) trials. The results show that the use of glycine and/or alanine, though structurally related to leucine, did not achieve similar aerosol performance enhancing effects, rather the particle formation was hindered. However, when used in appropriate concentrations with leucine, the combination of amino acids produced an enhanced performance regardless of the presence of glycine and/or alanine, yielding significantly modified particle properties. The results from the DoE analyses also revealed the lack of linearity of effects for certain responses with a significant curvature in the model which would otherwise not be discovered using a trial-and-error approach.