Development of an inhaled liposomal-loaded azithromycin formulation for the treatment of chronic respiratory infection

Abstract

Chronic lung conditions such as cystic fibrosis and bronchiectasis are characterised by cycles of inflammation and infection. Long term antibiotics are commonly prescribed in these conditions to decrease exacerbation frequency and improve quality of life. Azithromycin is often given orally for this purpose with its benefit thought to be due to a dual antibacterial and anti-inflammatory effect. In this thesis, the aim was to develop an inhaled liposomal loaded azithromycin formulation that could be delivered via dry powder inhaler for use in chronic lung infection. By delivering the antibiotic directly to the site of action in the lungs, higher local concentrations could be achieved whilst overcoming issues with oral therapy such as systemic side effects and the exposure of bacteria at non-target sites. Furthermore, the encapsulation of azithromycin within liposomes should offer advantages in both sputum and bacterial biofilm penetration.

Results from this study showed the formulation could be manufactured reproducibly, with good stability retained following one-year storage. The liposomal loaded azithromycin formulation was as effective as free drug against both Gram positive and Gram negative clinical respiratory isolates, as well as equally effective at clearing Staphylococcus aureus infection in an in vivo mouse model of lung infection. The formulation showed no toxicity in vitro, at relevant concentrations, against human and mouse cell lines with no increase in release of inflammatory mediators. Interestingly, the liposomal formulation itself, without azithromycin, resulted in a decrease in pro-inflammatory cytokine CXCL1 from a lipopolysaccharide stimulated murine alveolar macrophage cell line in vitro. Finally, the adjustment of protectant sugar to a mixture of trehalose and dextran offered further improvements in glass transition temperature and water content. The results of this study support the potential of this formulation as an alternative to oral azithromycin in the treatment of chronic lung infection.

Date of Award	Dec 2020
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Michael Tunney (Supervisor), Vicky Kett (Supervisor) & Deirdre Gilpin (Supervisor)