Formulation of Novel Dry Powder Antibacterial Aerosols Using Central Composite Design of Experiments

Pulmonary bacterial infections are often difficult to eradicate through intravenous or oral administration of antibiotics due to the presence of bacterial biofilms and the difficulty in achieving the desired drug concentration at the site of infection. Bacterial biofilms consist of bacterial colonies surrounded by a polysaccharide matrix that protects the embedded bacteria from external threats such as antibiotics. As a result, high doses of antibiotics are typically administered, leading to adverse effects. Our lab is working on developing combination therapies consisting of an antibiotic and a nutrient dispersion compound to increase the susceptibility of the biofilm bacteria to antibiotics. The nutrient dispersion compounds act as bacterial nutrients and entice the bacteria out of biofilms, resulting in greater exposure to antibiotics. This allows for administration of lower antibiotic doses, decreasing the likelihood of adverse effects.

The objective of this study is to develop a dry powder aerosol containing colistin sulfate (antibiotic) and sodium citrate (nutrient dispersion compound), that has high yield, good aerodynamic properties, and high drug loading. Dry powder aerosols allow for direct administration of drugs to the lungs, enabling delivery of lower doses of the drug and faster onset of therapeutic activity. A central composite design of experiments, generated using Minitab® software, was used to study the effect of formulation and spray drying process parameters on the yield and aerodynamic properties of the powder. A two-level central composite design was used to generate 31 formulations across the sample space, varying solution flow rate, atomizer flow rate, leucine concentration and solution concentration. Dry powder aerosols were generated using a Büchi 190 spray dryer, keeping temperature and pressure drop constant. Leucine was used to increase the flowability of the powders. Water content of the powders was measured using a coulometric Karl Fischer titration. Pareto chart analysis of spray drying data showed that increasing atomizer flow rate and solution concentration significantly increased powder yield. Yields ranged from 10% to 70% with a majority of yields between 40% to 60%. Water content studies showed water contents between 1 to 7%.

Future studies will examine contents of colistin sulfate and sodium citrate in the powders using the high-performance liquid chromatography (HPLC) and citrate assay technique respectively. Aerodynamic properties such as mass mean aerodynamic diameter (MMAD), fine particle fraction (FPF), and emitted fraction (EF) will be measured using the next generation impactor (NGI).