Aerosolization and Physical Stability of Pulmonary Dry Powder Formulations for Antibacterial Agents

Lower respiratory infections caused by antibiotic-resistant bacteria resulted in more than 400,000 deaths in 2019. Treatment of lung infections can be complicated by development of multidrug resistance, a shortage of new antibacterial drugs and inefficient drug delivery of antibiotics to the lungs through oral or intravenous route. My thesis was motivated by the need to develop novel antibacterial formulations that enable efficient drug delivery through the pulmonary route and to mitigate the risk of resistance. Specifically, the antibacterials were formulated as microscopic dry powders, which can be aerosolized and delivered to the lungs by patient’s inhalation. The goal of this work was to understand the effect of formulation on dry powder aerosol delivery and stability.

In Project 1, two important antibiotics with synergistic antibacterial property against Gram-negative bacteria – tobramycin sulfate and colistin (polymyxin E) sulfate – were combined into a dry powder formulation. This combination was of interest because it showed lower toxicity to lung epithelial cells than pure colistin. Colistin and tobramycin were combined at molar ratios 1:1 and 1:5 based on previous toxicity studies and spray dried. The combinations demonstrated significantly better aerosol performance, with fine particle fractions (FPF) of ~85%, compared to ~45% for spray dried tobramycin alone. The formulations maintained high FPF values after four weeks of storage at both 20% and 55% relative humidity (RH). Surface chemical analysis revealed colistin enrichment on the particle surface, attributed to colistin’s amphiphilic nature and lower solubility, leading to reduced particle surface energy and improved resistance to moisture-induced particle bridging. Therefore, spray-dried colistin–tobramycin formulations represent promising pulmonary therapies for treating multidrug-resistant lung infections.

Project 2 focused on developing a dry powder formulation of Pseudomonas aeruginosa bacteriophage 95 (ATCC 14211-B1) using spray drying. Among tested excipients, hydrolyzed gelatin was the most effective stabilizer, limiting titer loss to 0.6-log and preserving phage viability over 12 weeks at 4 °C. This formulation achieved good aerosol performance (emitted dose, ED 60%, FPF 77%), which improved further (ED 90%, FPF 80–86%) upon addition of 5% leucine or trileucine, without compromising stability. These findings support hydrolyzed gelatin-based dry powders as a promising strategy for pulmonary delivery of phages to combat drug-resistant infections.