Drugs as Excipients: Particle Engineering Using Pharmacological and Physicochemical Synergy

Bacterial lower respiratory tract infections (LRTI) are a major cause of global morbidity and mortality that is exacerbated by rising rates of antibiotic resistance. A further complication of such infections is that they typical occur within the context of muco-obstructive lung disease (e.g., cystic fibrosis and chronic obstructive pulmonary disease; COPD). Outside of the development of novel drugs, the problem of antibiotic resistance in LRTIs can be mitigated through two approaches: 1) administration of antibiotics that exhibit pharmacological synergy; and 2) direct delivery of antibiotics to the lung via inhalation to overcome high MICs without causing off-target toxicity. Co-inhalation of synergistic antibiotics (inhaled fixed dose combinations; iFDCs) combines these approaches.

While iFDCs have been approved for the maintenance treatment asthma and COPD, the drugs used in these products are highly potent with a wide therapeutic index. This is not the case for antibiotics, which require much higher doses for efficacy within a challenging biological environment of an infected and inflamed lung. It is unclear whether physicochemical differences in drug combinations could produce heterogeneity in lung distribution and clearance, and the impact this may have on antibiotic synergy. This represents a major gap in knowledge, which must be addressed to move antibiotic iFDCs forward into clinical use.

This presentation will discuss particle engineering strategies for the development of antibiotic iFDCs. First, the impact of differences in distribution and clearance in the lungs on the pharmacological synergy of antibiotic combinations will be examined. This knowledge will then be used to build a particle engineering strategy in which the physicochemical properties of the individual drugs are leveraged to achieve a desired release profile and distribution through airway mucus with limited use of excipients to minimize the inhalation powder burden.