Development of dry powder antigen formulations for pulmonary vaccine delivery
thesisposted on 28.02.2017 by Sou, Tomás
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Pulmonary immunisation has gained increased recognition as a means of triggering both a mucosal and systemic immune response through aerosol delivery to the lungs. The appropriate formulation of antigens in a dry, solid state can result in improved stability, thereby removing cold chain storage complications associated with conventional liquid-based vaccines. Nevertheless, dry powder pulmonary vaccine formulations are not being widely used as yet. This thesis describes the latest developments in pulmonary vaccines, and explores the use of recent advancements in spray-drying technologies for the production of dry powder formulations for pulmonary vaccine delivery. Dry powder inhaler formulations for pulmonary delivery of antigen should be readily and consistently dispersible and aerosolisable upon inhalation by an appropriate range of patient groups and circumstances for efficient delivery. In addition, the formulation should be capable of stabilising the antigen, which is commonly a potent biomacromolecule (e.g., protein or peptide required in relatively low dose of <1 mg). In contrast to the respiratory delivery of many small molecule drugs which is commonplace via simple ordered mixtures, there is no well-characterised delivery platform that is readily adaptable to the incorporation of potent biomacromolecules. A novel multi-component particulate system suitable for pulmonary delivery of biotherapeutics is therefore highly beneficial. To investigate the potential benefits from multi-component spray-dried systems, the interaction effects of the amino acids leucine, glycine and alanine on a mannitol-based spray-dried formulation for pulmonary delivery was initially studied using a design of experiment approach. The amino acid leucine was found to facilitate particle formation and production of aerosolisable multi-component spray-dried powders that would otherwise not be suitable for aerosol application. Further results from X-ray powder diffraction studies suggested the formation of a partially ordered leucine shell resulting from self-assembly on particle surfaces was important in assisting particle separation and powder aerosolisation. The results also suggested the potential benefit of leucine in retarding crystallisation and maintaining amorphicity of the formulation. This has significant implication as an amorphous environment is required for glassy stabilisation of biomacromolecules e.g., vaccine antigens. The particle formation effect of leucine was found to be transferrable to excipients covering a range of molecular weights from polyol (mannitol), disaccharide (trehalose), polysaccharide (inulin) to synthetic polymer (PVP). These multi-component systems were found to be both amorphous with sufficiently high glass transition temperature for stability at typical ambient condition, while remaining aerosolisable with high fine particle fractions. An in vivo immunisation study using influenza vaccine co-spray-dried with trehalose and leucine was shown to produce highly aerosolisable powders that induced superior systemic and mucosal immunity after pulmonary administration. This formulation strategy was found to be promising for the production of dry powder formulations for pulmonary vaccine delivery. Multi-component spray-dried delivery systems with leucine and appropriate baseline excipients were therefore shown to produce inhalable dry powder formulations that were aerosolisable with the amorphous environment needed for stabilisation of biomacromolecules. This work presented a novel formulation strategy for the production of dry powder carrier platforms for pulmonary delivery of vaccines, and more broadly for various potent biotherapeutics.